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Physiol Rev 85: 883–941, 2005;
doi:10.1152/physrev.00017.2004.
Ion Channel Development, Spontaneous Activity, and
Activity-Dependent Development in Nerve and Muscle Cells
WILLIAM J. MOODY AND MARTHA M. BOSMA
Department of Biology, University of Washington, Seattle, Washington
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I. Introduction
II. Coregulation of Ion Channel Development, Spontaneous Activity, and
Activity-Dependent Development
A. Oocyte maturation and the block to polyspermy
B. Early postfertilization changes and selective channel elimination
C. Retina and refinement of visual connections
D. Hippocampus and excitatory GABA responses
E. Cerebral cortex and coordinated Na⫹ and resting channel development
F. Cerebellar neurons, Ca2⫹ currents, and neuronal migration
G. Hindbrain and synchronized activation of motor neurons and cranial nerves
H. Spinal cord and emerging motor patterns
I. Cochlear hair cells and the loss of excitability after activity
J. Dorsal root ganglion cells, myelination, and cell adhesion molecules
K. Amphibian spinal neurons, transmitter phenotype, and low-frequency spontaneous activity
L. Ascidian muscle, inward rectifier, and activity-dependent ion channel development
M. Insect neurons and the refinement of dendritic trees during metamorphosis
N. Mammalian muscle and activity-dependent fusion of myoblasts
O. Amphibian muscle and multiple windows of activity-dependent development
P. Cajal-Retzius cells, Rohon-Beard neurons, and activity-dependent cell death
Q. Summary
III. How Spontaneous Activity Carries Out Its Developmental Functions
A. Role of [Ca2⫹]i transients
B. Developmental regulation of intracellular Ca2⫹ stores and buffering
C. Release of developmentally active neurotransmitters
D. Neurotrophins as major activity-dependent pathway
E. Relationship between synaptic plasticity in the adult and developing nervous systems
IV. Some Principles of How Ion Channels Develop to Regulate Spontaneous Activity
A. Immature voltage-gated channels with properties different from their mature counterparts
B. Immature ligand-gated channels with properties different from their mature counterparts
C. Different immature channel function due to different ion gradients early in development
D. Nonlinear developmental profiles of channels that create early periods with unique
firing properties
E. Changes in the spatial distribution of channels during development
F. Changes in the coupling of channels to intracellular events during development
G. Differences in intracellular trafficking of channel subtypes
V. Activity-Dependent Ion Channel Development as Part of the Essential Transition Between Immature
and Mature Physiological Properties
A. Voltage- and Ca2⫹-gated channels
B. Ligand-gated channels
C. Summary
VI. Clinical Implications of Activity-Dependent Nervous System Development
VII. Summary
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Moody, William J., and Martha M. Bosma. Ion Channel Development, Spontaneous Activity, and ActivityDependent Development in Nerve and Muscle Cells. Physiol Rev 85: 883–941, 2005; doi:10.1152/physrev.00017.2004.—At
specific stages of development, nerve and muscle cells generate spontaneous electrical activity that is required for normal
maturation of intrinsic excitability and synaptic connectivity. The patterns of this spontaneous activity are not simply
immature versions of the mature activity, but rather are highly specialized to initiate and control many aspects of
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0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society
883
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WILLIAM J. MOODY AND MARTHA M. BOSMA
neuronal development. The configuration of voltage- and ligand-gated ion channels that are expressed early in
development regulate the timing and waveform of this activity. They also regulate Ca2⫹ influx during spontaneous
activity, which is the first step in triggering activity-dependent developmental programs. For these reasons, the
properties of voltage- and ligand-gated ion channels expressed by developing neurons and muscle cells often differ
markedly from those of adult cells. When viewed from this perspective, the reasons for complex patterns of ion
channel emergence and regression during development become much clearer.
I. INTRODUCTION
Physiol Rev • VOL
II. COREGULATION OF ION CHANNEL
DEVELOPMENT, SPONTANEOUS ACTIVITY,
AND ACTIVITY-DEPENDENT DEVELOPMENT
In this section, we discuss 16 cell types that illustrate
different aspects of how ion channel development regulates spontaneous electrical activity, which in turn regulates some important aspect of subsequent development.
A. Oocyte Maturation and the Block to Polyspermy
We often think of complex patterns of ion channel
development as characteristic of the terminal differentiation of neurons and muscle cells. But they actually begin
even before fertilization. The ways in which ion channel
properties are modulated during development of oocytes
can be understood in the same context that governs similar later events: by knowing the developmental function
of electrical signals at these stages and asking how particular ion channels ensure that the properties of those
signals are consistent with that function.
1. Nature and developmental function
of spontaneous activity
In many organisms (including echinoderms, amphibians, nemertean worms, but not mammals), fertilization is
accompanied by a large, long-lasting depolarization
known as the fertilization potential (see Refs. 264, 265 for
review). Fertilization potentials last from several minutes
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The complex patterns of ion channel development
that occur in many excitable cells belie the notion that the
development of physiological properties in these cells can
be understood as a simple linear continuum to a single,
final set of properties. This perplexing complexity of ion
channel development can now be viewed in light of our
understanding of the critical roles of spontaneous activity
in early development. Most nerve and muscle cells generate spontaneous electrical activity during at least one
discrete stage of their development, and this activity is of
fundamental importance to their later development. Spontaneous activity regulates a large variety of developmental processes, and in doing so it occurs with patterns and
waveforms that cannot support the mature forms of activity and information processing of the cell.
For this reason, the configuration of ion channels and
receptors expressed at early stages of development are
optimized to mediate spontaneous activity and unique to
the early stages when this kind of activity occurs. This
optimization creates the appropriate electrical waveform
of spontaneous activity, synchronizes it among cells, and
mediates the Ca2⫹ influx that transduces activity into
developmental programs. In addition to optimization of
immature ion channels and their incompatibility with
many mature functions, two other general principles will
arise repeatedly in this review. The first is coordination of
the development of multiple channel types, both ligandand voltage-gated, which must cooperate to create periods of spontaneous activity. The second is the self-limiting nature of spontaneous activity. The transition between this immature period of spontaneous activity and
the mature, information processing functions of the cells
is critical. It is managed in part by making the expression
of mature ion channels and receptors, whose expression
tends of terminate spontaneous activity, dependent on the
spontaneous activity created by their immature predecessors.
The existence of distinct electrical properties early in
development that are geared toward creating spontaneous activity has important clinical implications, especially
in the field of pediatric seizure disorders.
In this review, we analyze how the patterns of ion
channel development give rise to spontaneous activity
and how that activity carries out its developmental functions. In section II we use several cell types to illustrate
the wide variety of developmental processes regulated by
spontaneous activity, and how the waveform of activity in
different cells is regulated by the expression patterns of
ion channels early in development. In section III, we discuss the mechanisms by which spontaneous activity controls developmental processes. In section IV, we propose
some general principles that govern how the ion channels
expressed at early stages differ from mature channels and
how they regulate spontaneous activity. In section V, we
discuss the critical role played by spontaneous activity in
regulating the maturation of ion channels so that cells
successfully make the transition between embryonic and
mature signaling properties. Finally, in section VI, we discuss clinical ramifications of the idea that immature neurons have electrical properties that favor spontaneous
activity.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
2. Relationship to channel development
The populations of ion channels in the egg cell membrane at the time of fertilization result from a complex
earlier process of development that has been studied in
detail in starfish. At the end of oogenesis in starfish, the
fully grown, immature oocyte awaits a hormonal signal
that will trigger its maturation and ovulation in preparation for fertilization. In starfish this hormone is 1-methyladenine (1-MA; Ref. 275). Maturation involves breakdown of the nuclear membrane, the reinitiation of meiosis, and other events that prepare the egg to be fertilized,
events that are similar to those triggered in mammalian
oocytes by progesterone.
Voltage-clamp of oocytes of the starfish Leptaserias
shows that the fully grown, immature oocyte has only two
depolarization-activated currents: an inward Ca2⫹ current
and a transient outward (A-type) K⫹ current. Action potentials can be elicited by depolarization, but because of
the large ratio of A-current to Ca2⫹ current, they do not
overshoot 0 mV. During maturation, which can be triggered in vitro and takes only 30 – 45 min, the A-current
decreases by ⬃50%, while the Ca2⫹ current remains unchanged. This increases the amplitude of the action poPhysiol Rev • VOL
tential so that it now overshoots 0 mV (424). The decrease
in A-current is caused by loss of plasma membrane during
maturation: cell capacitance decreases by precisely the
same amount and with the same time course as the A-current, and electron micrographs show an almost complete
elimination of the microvilli that characterize the surface
of the oocyte before maturation (422; see Ref. 530). Quantitative measurements of membrane surface area from the
micrographs show a close correspondence with the
change in surface area measured electrically by capacitance. The selective loss of the A-current during maturation is necessary for the mature egg to be fertilized successfully. Without the resulting increase in action potential amplitude, the fast electrical block to polyspermy is
much less efficient, fertilization is polyspermic, and abnormal development ensues (414, 415). Thus a prefertilization process of ion channel development that relates to
the first activity-dependent developmental event in the
life of the organism is required for embryonic life to begin.
The lack of decrease in Ca2⫹ current during this
massive membrane loss implies that Ca2⫹ channels are
protected from endocytosis, possibly by cytoskeletal anchoring. During oogenesis in this species, the A-current
increases gradually, accurately tracking membrane area
during a 2-yr growth interval just as it tracks the 30-min
period of membrane loss during maturation. The Ca2⫹
current, on the other hand, appears abruptly at the end of
the growth phase, dissociated from membrane addition
just as it is from membrane loss during maturation (421).
The appearance of the Ca2⫹ current coincides with the
migration of the nucleus to the animal pole at the end of
oogenesis. This raises the possibility that Ca2⫹ channels
are inserted into the membrane only at the animal pole
and are then protected from endocytosis by mechanisms
that anchor the nucleus in that position (529). Protection
from endocytosis by cytoskeletal anchoring or by accessory subunits influences ion channel development during
terminal neuronal differentiation as well (6).
Selective loss of some currents and preservation or
increases in the amplitudes of others have also been
observed during maturation of amphibian oocytes (25).
This kind of selective modulation also extends to exogenous channels expressed in oocytes (80, 536).
The patterns of ion channel development in this relatively simple system encapsulate many of the principles
that are seen in more complex central nervous system
structures. Individual currents may increase and decrease
during development, changing at distinct stages and with
specific relationships to other cellular events, such as
changes in membrane surface area or cell cycle progression and arrest. The timing and specificity of such
changes dictate changes in action potential threshold and
waveform in ways that are critical for the developmental
roles of electrical signaling at specific stages.
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to more than 1 h, depending on the species. The fertilization potential is mediated by sodium, nonspecific cation,
or chloride channels that are gated by the rise in [Ca2⫹]i
that occurs at fertilization, with contributions at early
times by voltage-gated Ca2⫹ or Na⫹ channels and possibly
by channels donated to the oocyte membrane by the
sperm. The long duration of the fertilization potential is
caused by the long duration of the [Ca2⫹]i transients at
fertilization and in many egg cells by the virtual absence
of delayed K⫹ currents to repolarize the membrane. In
addition, the resting resistance of most oocytes is very
high, creating a long time constant. It is an interesting, but
as yet unexplained, observation that oocytes (such as
those of mammals) that do not depolarize at fertilization
still have voltage-gated channels and are excitable to
direct stimulation (477). This suggests that electrical activity has functions in oocytes that we do not yet understand.
While the fertilization potential is not strictly spontaneous because it is triggered by sperm binding, it emphasizes that electrical activity plays a role in development from the earliest stages. A variety of experiments
have shown that fertilization potential mediates the fast
block to polyspermy in many organisms, acting to prevent
supernumerary sperm from fusing with the oocyte at
short times before physical mechanisms of polyspermy
block have been established (264, 292, 266, 267; see Ref.
265 for reviews). Direct current injection experiments
have shown that the depolarization alone is sufficient to
block sperm entry (264).
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WILLIAM J. MOODY AND MARTHA M. BOSMA
B. Early Postfertilization Changes and Selective
Channel Elimination
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Complex changes in ion channel expression also occur between the time of fertilization and the beginning of
nervous system formation. Most of the information about
ion channel development at these early cleavage stages
comes from work in ascidian embryos. Ascidians are
chordates whose embryos have long been a classic preparation in which to study development, partly because
many cell lineages are committed very early in development without substantial cell interactions (520; a notable
exception is the nervous lineage, which does require induction by the notochord). Some species have the additional advantage of an intensely pigmented muscle lineage, so muscle lineage cells can be recognized even at
early cleavage stages and in dissociated preparations.
Before fertilization, eggs of the ascidian Boltenia
villosa express Na⫹, Ca2⫹, and inwardly rectifying K⫹
currents. After fertilization these three currents are eliminated, each at a specific stage. The Na⫹ current is lost
within 2 h, at the time of first cleavage, but the Ca2⫹
current is retained (51, 240, 120). The Ca2⫹ current is
eliminated later, at gastrulation, and the inward rectifier
even later, at neurulation. The inward rectifier is particularly interesting. In the 12 h before it is eliminated, the
inward rectifier is maintained in all cells of the embryo at
a constant density. Because the total surface area of all
cells in the embryo at gastrulation is ⬃10 times that of the
egg, there must have been a 10-fold upregulation of the
inward rectifier during this period, either by addition of
new channels or unmasking of preexisting ones. Then,
after this intense period of upregulation, the inward rectifier is eliminated in all cells in only a few hours (51, 208).
This kind of active maintenance of channel density followed by abrupt disappearance suggests roles both for
the presence of the channel early and its absence later. In
this case, it is likely that maintenance of the inward
rectifier, which is the only resting conductance of these
cells, combined with the loss of the Na⫹ current, prevents
generation of action potentials during the cleavage phase
of early development. As discussed below, the disappearance of the inward rectifier is the trigger for spontaneous
activity in these cells. Superimposed on all of these
changes is the cyclical appearance and disappearance of
a hyperpolarization-activated Cl⫺ channel with each cell
division (52, 598).
A very interesting analogous result to the above selective elimination of Na⫹ current (INa) after fertilization,
but retention of Ca2⫹ current (ICa), is seen in another
ascidian, Ciona intestinalis. The egg cell of this species
does not have a low-threshold INa, but rather a second,
low-threshold ICa similar to the T-type Ca2⫹ current. It is
this low-threshold ICa that is lost after fertilization in
Ciona, while the high-threshold ICa is retained (11). This
suggests that the functional significance in both species is
the elimination of the low-threshold inward current that
could lead to aberrant spiking during cleavage, independent of the identity of the channel that carries it. Such
aberrant spiking might be triggered by the activation of
mechanosensitive ion channels, which are a prominent
feature of ascidian oocytes (423).
Some of the most extensive work on ion channel
development in early embryos has been done by Takahashi and colleagues, working on cleavage-arrested embryos of the ascidian Halocynthia roretzi. The egg cell of
this species expresses Na⫹, Ca2⫹, delayed K⫹, and inwardly rectifying K⫹ currents (460). If embryos at various
early stages of development are cleavage-arrested with
cytochalasin, the cells differentiate into a variety of mature cell types without dividing. This differentiation is
accompanied by specific changes in the patterns of ion
channel expression (245, 456). So, for example, if cleavage is arrested at or before the four-cell stage, cells develop into an epidermal type, characterized by expression
of Ca2⫹, inwardly rectifying K⫹, and Ca2⫹-activated K⫹
currents. Later cleavage arrest yields cells that differentiate into neural or muscle types, which express different
patterns of ion currents. The cleavage-arrested one-cell
embryo is large enough that the time course of ionic
current expression can be followed in real time as it
differentiates from egg to epidermal cell (244). The egg
Ca2⫹ current disappears before gastrulation, and then a
mature epidermal form reappears later. The mature Ca2⫹
current shows Ca2⫹-dependent inactivation, whereas the
egg form shows voltage-dependent inactivation (243).
Oddly enough, in the closely related species H. aurantium, the egg-type Ca2⫹ current reappears and then it
subsequently changes into the mature form (243). The
Na⫹ current disappears entirely from the cleavage-arrested egg as it develops, since the epidermal cell type
into which it develops does not express a functional Na⫹
current. The disappearance of the Na⫹ current is very
gradual and follows a complex time course, with a transient peak of density as the larval tail elongates (243). In
a further elegant series of experiments, this group developed an in vitro two-cell neural induction system, in
which individual cleavage-arrested neural- and notochord-lineage cells are placed into physical contact and
subsequently separated to study the exact developmental
timing of induction, as well as the timing of competence
in each cell (454, 455, 457). With the use of this system, it
was shown that neural induction triggered the expression
of a neural-type Na⫹ channel whose biophysical properties were distinct from the Na⫹ channel expressed in the
egg (461, 462).
Early postfertilization channel development has also
been studied in mammalian oocytes. These cells express
functional Ca2⫹ currents and generate action potentials
(459, 477, 630), acquiring this property during the growth
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
C. Retina and Refinement of Visual Connections
1. Retina: nature of spontaneous activity
It has been known for quite some time that the
mammalian retina generates spontaneous activity early in
development, before it is capable of responding to light,
and that this activity involves retinal ganglion cells
(RGCs) and cholinergic synaptic transmission (381). With
the understanding that the spontaneous activity was intimately involved in the patterning of retinogeniculate connections (535), more attention began to be paid to its
mechanisms. Using extracellular unit recording, Galli and
Maffei (192) and Maffei and Galli-Resta (362; both in rat
retina) demonstrated that neighboring RGCs showed temporally correlated action potentials during this activity,
Physiol Rev • VOL
and proposed that such correlations might act in a Hebbian manner to strengthen their connections to downstream targets. We now know that this activity takes the
form of spontaneous waves of action potentials and
[Ca2⫹]i transients (169, 616). Such spontaneous activity
before the onset of patterned vision occurs in a wide
variety of vertebrates, including mouse (17), rat (192),
rabbit (637), ferret (389), cat (389), chick (620), turtle
(533), and salamander (76) (see Refs. 167, 615, for reviews).
The basic properties of retinal waves have been established using a combination of multielectrode array
recording, whole cell recordings from single cells, and
[Ca2⫹]i imaging. Activity in the form of bursts of action
potentials lasting 2– 4 s, occurring at intervals of 1–2 min,
sweeps across large regions of the retina at speeds of
80 –140 ␮m/s (389). RGCs participate in this activity, generating brief bursts of action potentials riding on a large
depolarizing wave (618). These waves spread across “domains” in the retina, initiated apparently at random in
different regions (169, 170). Some kind of refractory period prevents the rapid reoccurrence of waves in single
regions. The idea of some form of postevent refractoriness as a determinant of the interval between waves is
likely to hold in other spontaneously active developing
structures, like the spinal cord (576). In retina it is supported by the finding of postburst depression of RGC-RGC
synapses, whose time course of recovery is similar to the
interval between waves (234), and by computational models (85, 86). In chick retina the propagation of these waves
seems somewhat more widespread, with activity often
moving outward to the edges of the retina (90, 535, 620).
Although early experiments indicated that this activity
was sensitive to block by tetrodotoxin (TTX), thus implying that the [Ca2⫹]i transients required Na⫹-dependent
action potential activity (389), it is now understood that
this is not strictly true. TTX reduces the amplitude of the
[Ca2⫹]i transients during activity (563), indicating that
although RGC action potentials are not essential for wave
propagation, they are necessary for the full amplitude
of Ca2⫹ entry during waves and probably also to permit
detection of the waves with extracellular recording
methods.
Although spontaneous activity persists for a long
time during development before the establishment of patterned vision, the mechanisms generating that activity
and propagating it across the retina change dramatically.
At early stages, experiments in ferret and rabbit retina
indicate that ACh is the primary transmitter involved in
wave propagation, consistent with the fact that the retinal
circuitry at those stages is mainly dependent on the cholinergic starburst amacrine cells (168, 619, 637). At later
times in this early period, GABA becomes involved as an
excitatory transmitter in the waves (563, 619), reflecting
the presence of GABAergic amacrine cells. At these
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phase of oogenesis (162). After fertilization, this Ca2⫹
current shows a transient increase in density near the
second meiotic division (627) and then decreases in amplitude and disappears by the eight-cell stage (413).
Some of these changes in ion channel expression in
cleavage-stage embryos may be related to the fact that
electrical activity and Ca2⫹ influx appear to play a role in
neural induction. Induction by the lectin ConA is accompanied by long-lasting increase in [Ca2⫹]i and is inhibited
by L-type Ca2⫹ channel blockers. L-type Ca2⫹ channel
agonists can trigger neural induction of ectoderm (426).
L-type Ca2⫹ channels are expressed in the embryo in
dorsal ectoderm at the appropriate stages (154), and induction by mesoderm in vivo activates these channels and
causes [Ca2⫹]i transients in ectoderm (321, 322). In vivo
imaging of Xenopus embryos reveals spontaneous [Ca2⫹]i
transients in the presumptive forebrain region of the dorsal ectoderm, although not in the presumptive spinal cord.
L-type Ca2⫹ channel blockers produce defects in anterior
nervous system structures (322).
Later, specific patterns of ion channel expression
appear in presumptive neural tissue. Outward K⫹ currents
and T-type Ca2⫹ currents are expressed in rat floor plate
epithelium (188). As discussed below, proliferative cells
of the cortical ventricular zone also express delayed outward K⫹ currents (480).
The above studies show that complex patterns of ion
channel development are triggered by fertilization. These
proceed throughout the early cleavage stages of embryogenesis, and usually involve specifically timed elimination
of voltage-gated currents, as well as cyclical activation of
channels by the cell cycle. Thus the electrophysiological
properties seen at the start of terminal differentiation in
many excitable cells reflect a complex history of ion
channel development that begins even before fertilization.
Aside from polyspermy block, the roles of electrical signaling during oogenesis, maturation, and early cleavage
stages are as yet poorly understood.
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Physiol Rev • VOL
These results, like those in cortex, emphasize the
difference between the kinds of activity that neuronal
circuits are capable of generating and the activity that
actually occurs. Inducing activity by artificial means may
yield valuable information about the underlying functional circuitry and potential mechanisms of activity that
a given structure may draw upon in creating spontaneous
activity. Studying the actual spontaneous activity itself
reveals how the structure makes use of that circuitry and
those mechanisms.
An interesting recent finding points to the possibility
that retinal waves may also propagate into the retinal
ventricular zone (VZ), providing some kind of feedback to
the zone from which retinal cells arise (574). Waves in the
VZ showed close spatial and temporal relation to the
retinal waves, and pharmacological studies indicated that
the VZ waves involve muscarinic ACh receptors, and
likely require the retinal waves, but not vice versa. Mature
retinal glia can also generate [Ca2⫹]i waves, which can
modulate retinal ganglion cell light responses (439, 440).
2. Retina: refinement of retinal ganglion cell
connections by activity
The parameters of retinal waves, such as propagation
speed and emerging differences in the participation of
various types of RGCs, are critical for how activity encodes RGC identity to target structures. The establishment of correct patterns of connections between RGCs
and their primary targets in the brain is one of the best
known examples of how intrinsic molecular tags and
electrical activity cooperate during brain development. To
understand the roles of electrical activity in RGC projections, it is important to understand the anatomical and
functional differences among the various species of animals in which the work has been done. Three points are
particularly important: 1) the location to which RGC axons project. In cold-blooded vertebrates (amphibians,
fish), RGCs project to the optic tectum, which is the main
visual processing center in these species. In rodents and
birds, RGCs project both to the tectum (superior colliculus) and to the lateral geniculate nucleus in the thalamus
(LGN). The relative projections to those two structures
differ among species (200, 337). In the higher mammals
(cats, ferrets, primates), the visual cortex has evolved as
the main processing center, and RGCs project primarily to
the LGN as the synaptic relay center that sends visual
information to the cortex. The superior colliculus in the
higher mammals and birds serves important functions in
the control of eye movement, but not as a processing
center for visual perception.
2) The second important point is the developmental
timing and initial accuracy of RGC projections to their
primary targets in relation to eye opening and the appearance of patterned visual input (see Refs. 543, 615 for
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stages (and perhaps later), the spread of activity appears
to involve endogenous adenosine acting via A2 receptors
to increase intracellular levels of cAMP (563).
At later stages, as glutamatergic synapses between
bipolar cells and RGCs develop, glutamate becomes essential for wave generation and ACh becomes less important (619, 637). GABA also becomes inhibitory (178), reflecting its transition from excitatory to inhibitory action
due to changing intracellular chloride concentration (see
sect. IVC). The appearance of glutamatergic bipolar cell
participation in the activity also correlates with the appearance of differences in the participation of ON and
OFF RGCs in waves (323), reflecting a developing role for
the waves in segregation of ON and OFF terminals within
the lateral geniculate nucleus (see below). This developmental change in the transmitters and circuitry underlying spontaneous activity is also seen in spinal cord and
reflects a remarkable stability in spontaneous activity
even as the cells and circuits mediating it undergo developmental changes. The timing of this change in retina is
plastic. When the early cholinergic waves are eliminated
in mouse knockouts of the ␤2-subunit of the nicotinic ACh
receptor, glutamate-dependent waves appear several days
earlier than normal (17). This may reflect a form of compensation that ensures stability of spontaneous activity
during certain critical stages of development, even in the
face of disruptions to the mechanisms that create it.
Gap junctional communication also seems to be involved in retinal waves. In chick, blockers of gap junctions suppress spontaneous waves (620). In salamander
retina, they disrupt the short-time correlations between
firing of neighboring cells (76), and in mouse they increase the interval between waves and decrease the number of cells participating in a wave (544).
As is true in developing cortex (see sect. IIE), the
retina can be induced to generate similar waves under
conditions that increase neuronal excitability (L-type
Ca2⫹ channel agonists). Also as in cortex, these waves are
not generated by the same mechanisms as normal spontaneous activity. In retina, the induced waves persist in
the presence of antagonists of DL-␣-amino-3-hydroxy-5methylisoxazole-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), glycine, and GABA receptors, which
block normal waves at various stages of development.
Like normal waves, however, induced waves are suppressed by gap junction blockers and by agents that disrupt the action of adenosine (544). The overlap in properties of these two forms of activity implies that retinal
circuitry has several mechanisms of propagating waves of
activity, involving classical chemical synaptic transmission pathways, electrical communication via gap junctions, and spread of activity via adenosine action on the
cAMP second messenger system. The degree to which
each participates may depend on developmental stage as
well as the physiological states of the participating cells.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
Physiol Rev • VOL
ity that is correlated between neighboring RGC axons as
a means of map refinement, fish were raised in stroboscopic light to synchronize activity across wide regions of
RGCs. Stroboscopic light, but not diurnal light or darkness, phenocopied the TTX effects on map refinement
(118, 525). Thus artificially synchronizing all RGC inputs
does disrupt map formation, but on the other hand, the
retinotopic map forms normally in darkness. These results imply a more complex scheme in which spontaneous
activity even during stages when visual input is functional, is necessary for map refinement. Recent experiments in regenerating fish optic nerve add another layer
of complexity: the retinas do not generate spontaneous
waves of activity during regeneration, and in fact, overall
firing rates of RGCs were depressed as their tectal projections refined during regeneration. Furthermore, blocking retinal activity during this period did not affect activity
in tectal neurons, making a Hebbian scheme of refinement
more difficult to envisage (296).
In amphibians there is direct evidence that coactivity
of adjacent RGCs during spontaneous retinal waves
serves to mediate long-term changes in synaptic efficacy
where the two RGCs converge onto a single tectal neuron
(634). These experiments were done in frog at early
stages when RGC axon terminals are still widespread in
the tectum, and synapses have a combination of NMDA
and AMPA receptors. Repetitive stimulation of a single
input to a tectal neuron causes homosynaptic potentiation, which requires action potentials in the postsynaptic
neuron, but which does not affect other inputs. Pairing of
two inputs potentiates both as long as the postsynaptic
cell spiked. This included potentiation of a previously
subthreshold input as long as it fired within 20 ms before
the suprathreshold input. Simultaneous stimulation of
two subthreshold inputs could potentiate both as long as
they summed to trigger postsynaptic activity.
In mice, the retinotopic map in the superior colliculus (tectum) is refined to a much greater degree during
early development, before development of visual input
(see above). Nonetheless, activity is still required from
RGCs for map refinement, as shown by using mice lacking
the ␤2-subunit of the ACh receptor, which is essential for
spontaneous waves of activity at these early stages (388).
This activity-dependent refinement requires functional
NMDA receptors (543).
When innervation of one tectum by both eyes is
induced, eye-specific layers are formed (see above), implying that differential activity between the two eyes can
drive segregation of their projecting axons, since presumably the molecular targeting cues are the same for axons
from the two eyes. Blocking RGC activity with TTX prevents eye-specific segregation (67) and can even reverse
segregation that has already occurred (495). These results
imply that activity is not simply permissive for formation
of retinotectal maps predetermined by other factors, but
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review). In cold-blooded vertebrates, the retinotopic map
of initial RGC projections is fairly accurate, although
there is substantial remodeling and refinement of that
map, partly to compensate for retinal and tectal growth
(494). This period of refinement occurs after the establishment of patterned vision, and thus the activity dependence of refinement in these animals could reflect activity
driven by visual input, although the relative roles of visually driven and spontaneous activity are not entirely clear
(see Ref. 296). In rodents, RGC projections to the superior
colliculus are less accurate initially, and subsequent refinement takes place before the retina has become functional. Birds are similar in this regard. Thus the activity
dependence of refinement reflects spontaneous retinal
activity. In higher mammals, RGC projections to the LGN
are also initially fairly inaccurate, and refinement occurs
before the establishment of functional vision.
3) The degree of binocular input to the RGC projection site is important. Although adult cold-blooded vertebrates have binocular pathways in the tectum, there is not
the eye-specific layering that is seen in the LGN of higher
mammals. However, eye-specific tectal fields can be created by surgical manipulations that create direct binocular innervation of the tectum (tectal ablation, third eye
implants) (see, e.g., Refs. 495, 499, 512, 513 for reviews).
Thus both retinotopic projections and eye-specific termination fields can, and have been, studied in these animals.
In rodents, although there is binocular projection to the
LGN, it is small compared with that in higher mammals,
and so true eye-specific layers are not present, although
eye-specific fields do exist and are studied (200; see, e.g.,
Ref. 255). In birds, retinotectal projections are almost
exclusively contralateral, a pattern that arises by elimination, in an activity-dependent manner, of ipsilateral projections that are present earlier (159, 615, 624). In higher
mammals with substantial binocular vision, true binocular projections to the LGN exist in the form of eye-specific
layers, created in part by activity-dependent pruning of
initial connections (see below; Ref. 615).
Axons of RGCs projecting to the tectum in lower
mammals, chicks, and cold-blooded vertebrates undergo
a period of refinement into restricted terminal zones in a
retinotopic pattern. In fish in which this pattern is being
reestablished during regeneration of cut optic nerves,
blockade of retinal activity by TTX injection prevents this
topographic map refinement, although axon outgrowth
and initial projections to the tectum are normal (397). The
same activity dependence has also been shown during
initial development of this map in zebrafish, by abolishing
RGC activity using the macho mutant, which reduces
RGC Na⫹ currents and blocks their activity, or TTX (199).
Similar experiments have been done in developing chick,
in experiments using TTX or the Na⫹ channel opener
grayanotoxin to disrupt retinofugal activity (295). To test
the hypothesis that patterned visual input provides activ-
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at different times. Confirming this is the finding that disrupting correlations in activity between neighboring
RGCs while leaving the overall frequency of activity intact
did not disrupt eye-specific layering (253). Reinforcing the
idea of the role of correlated activity strengthening retinogeniculate synapses in the Hebbian-like mechanism is the
finding that retinal activity is passed onto geniculate neurons, and that stimulated RGC firing at frequencies near
those occurring during spontaneous waves can induce
long-term potentiation (LTP)-like synaptic strengthening
(425). However, findings that blockade of RGC activity by
TTX does not completely eliminate eye-specific layer formation at early stages, and that even in the chronic presence of TTX, delayed layer refinement does occur (although not to normal levels of sharpness)(119), indicate
that neural activity may not be the sole player in regulating retinogeniculate mapping. It is also possible that redundant mechanisms exist that can at least partially compensate for loss of activity (see Ref. 513). Recent evidence
suggests the involvement of immune system molecules in
activity-dependent LGN layering (255).
Activity also is involved in the finer-grain segregation
of mammalian retinogeniculate connections. ON- and
OFF-center RGCs innervate distinct sublaminae in the
LGN (567), and this segregation requires activity in the
retina before visual input is functional (124, 221). Unlike
eye-specific layer formation (548), formation of ON and
OFF sublaminae does require activity of NMDA receptors
(221), and subsequent activation of the neuronal nitric
oxide (NO) synthase-NO-cGMP pathway (123, 125, 320).
Although these findings reinforce the idea of LTP-like
synaptic strengthening by correlated pre- and postsynaptic activity, ON/OFF segregation does not involve the
activation of “silent” synapses by induction of AMPA receptors in LGN neurons (247). Segregation of ON and
OFF RGC connections in the geniculate appears to rely on
their different patterns of activity, which in turn appears
to be due to a divergence of their intrinsic ion channel
properties early in retinal development (436).
Activity-dependent refinement and pruning of axons
in the visual system is not restricted to RGC connections.
Spontaneous activity regulates branching and organization of LGN axon projections in the visual cortex. Block
of activity by TTX prevents correct branching and causes
some axons to project to the subplate of areas outside of
their normal visual cortex target area (89, 238).
In many of these experiments, as well as those described below, one must be aware that blocking spontaneous activity with TTX, for example, does not necessarily eliminate all periodic activity in the system. Ca2⫹dependent action potentials, spontaneous transmitter
release, and possibly other forms of activity may still
occur and be responsible for some developmental phenomena. In systems such as the retinotectal and retinogeniculate pathways, the assumption is that activity in the
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that activity can instruct the formation of a map that does
not occur under normal circumstances. Block of tectal
NMDA receptors can also desegregate the RGC terminals
in the presence of continued afferent activity, and exogenous NMDA can sharpen the borders of eye-specific
regions (113). Activation of NMDA receptors appears to
act by a combination of elimination of inappropriate axonal branches and stabilization of appropriate ones (488,
512). Interestingly, nitric oxide does not seem to be involved downstream of these NMDA effects (499).
In higher mammals, such as cats, ferrets, and primates, there is extensive binocular innervation of the
LGN by RGCs, and eye-specific layers form in each LGN
before visual input is possible (see Refs. 513, 615 for
reviews). These layers form by pruning of an initial innervation pattern in which axon terminals originating from
different eyes are intermixed (560). Blockade of spontaneous activity originating in the retina at the stages during
which this layering occurs (see above) prevents eye-specific layers from forming and leaves the earlier, wider
branching patterns of axons in the LGN in place (535,
561). Although the original experiments were done with
intracranial infusions of TTX, later intraocular TTX injections confirmed that the activity in question does indeed
arise from the retina (476). The long-term effects of TTX
treatment on layering are not completely clear. Layers
appear to form almost normally at long times during
chronic TTX treatment (119), but activity block after layering is complete can cause desegregation (97). The
mechanisms by which activity acts involves competition
between RGC terminals from different eyes: increasing
activity in one eye expands its territory in the LGN, but
increasing activity in both eyes leaves layering mostly
intact (476, 562). Even so, NMDA receptor activity does
not appear to be involved in this competition-based formation of layers (548), although it does seem to be involved in formation of LGN sublaminae containing different RGC cells types (see below). After the period of
eye-specific layer formation, retinal spontaneous activity
continues, although its mechanism changes from cholinergic to glutamatergic (see above). Selective elimination
of the early, cholinergic activity in mice deficient in the
␤2-subunit of the ACh receptor disrupts layering, demonstrating that the early retinal activity is required (432,
508). Interestingly, in these experiments, eye-specific
patches of RGC terminals were still formed in the LGN
(432).
The patterns of spontaneous activity recorded from
the retina at these stages seem well-suited to encode both
spatial location of RGCs within one eye and ipsilateral
versus contralateral identity. The movement of waves of
activity across one retina results in contiguous RGCs
showing correlated activity (362), and the short duration
of the waves compared with their frequency of occurrence would result in activity from the two eyes occurring
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
form of Na⫹-dependent action potentials must propagate
along axons to carry out its developmental functions. In
other preparations, however, local effects of activity may
be more resistant to TTX.
3. Retina: outgrowth of retinal ganglion cell axons
4. Retina: dendritic patterning of RGCs
The spontaneous activity that sweeps across the developing retina appears to have a function in the elaboration of dendritic trees in the retina, as well as on the
patterns of RGC axon elaboration in the LGN. Retinal
spontaneous activity helps to segregate the dendrites of
ON and OFF RGCs within the retina, much as activity
segregates their axon terminals into different LGN sublaminae, although the degree to which activity instructs
this is a matter of debate. Bodnarenko and Chalupa (54)
and Bisti et al. (43) report a strong requirement for
metabotropic glumatergic transmission in this process,
whereas Bansal et al. (17) find more subtle effects. Blocking activity in RGCs with TTX also eliminates their ability
to extend dendrites into RGC-free areas created by injury
(142).
5. Retina: relationship to channel development
Ion channel development in various retinal cell types
is likely timed to regulate spontaneous activity, although
many details remain unclear. In cat and mouse retinal
ganglion cells, a negative shift in the voltage dependence
of activation and a positive shift in the inactivation curve
of INa combine with increased INa density to help bring
about the early appearance of repetitive firing ability (510,
546). Later expression of Ca2⫹-activated K⫹ currents and
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speeding of recovery from inactivation of INa may contribute to changing the firing patterns of retinal ganglion
cells from bursting during spontaneous retinal waves to
more sustained firing needed for encoding visual information (509, 604, 605).
Divergence of ion channel properties in different retinal cell types is also likely to regulate how spontaneous
activity occurs, although not always in obvious ways.
Late-emerging differences in the intrinsic properties of
ON and OFF RGCs allow them to participate differentially
in spontaneous retinal waves of activity, a difference
which probably instructs their differential projections in
the LGN (436). More perplexing are changes in excitability of starburst amacrine cells. In the rabbit, these cells
express large Na⫹ currents and action potentials just
before eye opening, and then lose INa and excitability over
the next several weeks (636). Because spiking ability
coincides with the period of spontaneous retinal activity,
it was presumed that the transient expression of INa allows starburst amacrine cells to participate in this activity. Direct recordings showed, however, that despite their
ability to spike, these cells do not generate action potentials during retinal waves (635; see Ref. 563). This may
imply a different function for Na⫹ currents, perhaps in the
development of intrinsic properties of these cells.
Optimization of channel properties is also likely to
occur downstream in the visual system to tune the responses of LGN neurons to spontaneous activity in RGCs.
During these stages, LGN neurons express NMDA receptors containing the NR2B subunit, which gives glutamateinduced synaptic currents a much longer time course than
in the adult. This would clearly favor temporal summation, and in fact, such summation is observed in neonatal
rat LGN in response to retinal spontaneous activity (349;
see sect. IVB).
D. Hippocampus and Excitatory GABA Responses
1. Nature of spontaneous activity
During the first postnatal week, rat hippocampal neurons generate spontaneous and highly synchronous
bursts of activity known as early network oscillations
(ENOs) or giant depolarizing potentials (GDPs) (35, 194).
These take the form of large synaptically driven depolarizations and bursts of action potentials, with associated
bursts of [Ca2⫹]i transients, occurring at an overall frequency of 0.4 –2/min (194). GDPs occur in the entire population of CA1 and CA3 pyramidal cells, in interneurons,
and in hilar, septal, and dentate gyrus neurons (194, 284,
324, 326, 391, 566). GDPs are primarily GABAergic events,
but also have substantial NMDA components and, at least
at later stages, AMPA components as well (35, 55, 194,
326). Similar events have been recorded in vivo in both
anesthetized and freely moving neonatal rats (325). The
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It has been known for some time that direct electrical
stimulation can reversibly arrest axon outgrowth and
cause growth cone filopodial retraction in both invertebrate and vertebrate neurons (115, 176). As in other cases
of activity-dependent events, stimulation in a burst, or
phasic, pattern is more effective than tonic stimulation
(176). But early in development, activity may stimulate
initial axon outgrowth. Recent experiments indicate that
activity interacts with various trophic factors in intricate
ways to regulate axon outgrowth and pathfinding. In retinal ganglion cells, peptide trophic factors stimulate axon
outgrowth, but only at slow rates in the absence of activity. Electrical stimulation at physiological frequencies
greatly speeds outgrowth stimulated by these factors
(201). Interestingly, the pattern of stimulation that proved
most effective was brief bursts of action potentials delivered at 1-min intervals, closely approximating the pattern
of spontaneous synchronous activity seen normally in
developing retina and many other areas of the mammalian
central nervous system (see sect. IIIA2; Ref. 201).
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ipating neurons. Thus the origin of spontaneous GDPs in
the neonatal hippocampus remains somewhat of a mystery, with evidence pointing to more than one potential
pacemaker region and to a network property that can
operate without a single discrete pacemaker.
2. Developmental roles of spontaneous activity
Much of this work focuses on the apparent paradox
of “silent synapses” early in development (see Ref. 226).
In the hippocampus, the large majority of synapses at P0
are pure NMDA, or silent, synapses, so named because in
the absence of other receptor types, glutamate cannot
activate them due to the voltage-dependent Mg2⫹ block of
the NMDA receptor. It is known that repeated pairing of
presynaptic activity with postsynaptic depolarization can
“AMPA-fy,” or induce, functional synapses by inducing
functional AMPA receptors. The problem is that, early in
development, there may not be a sufficiently high density
of AMPA receptors on the postsynaptic cell for repeated
presynaptic activity to depolarize the postsynaptic cell
enough to trigger induction. It has been proposed (226)
that spontaneous, GABAergic GDPs might provide the
coincident pre- and postsynaptic depolarization to activate Hebbian mechanisms of synapse strengthening. Indeed, it has been recently shown that pairing of mossy
fiber stimulation with spontaneous GDPs can induce a
form of LTP, including induction of previously silent synapses (279).
At least one of the activity-dependent developmental
programs in hippocampal neurons may serve to make
activity self-limiting. Spontaneous activity in hippocampus depends on excitatory GABAA actions (see sect. IVC).
Application of GABAA blockers blocks activity and delays
the appearance of KCC2 chloride pump mRNA, whose
expression lowers intracellular Cl⫺ concentration and
converts GABAA action to inhibition. Enhancing activity
by KCl depolarization accelerates the switchover and the
KCC2 mRNA expression (193).
3. Relationship to channel development
Spontaneous activity in hippocampus relies on the
excitatory action of GABA, which is unique to developing
neurons (reviewed in sect. IVC). It has been known for
some time that GABAA actions are excitatory early in
development, due to the high intracellular Cl⫺ concentration at these stages (reviewed in Refs. 34, 469, 470). Some
of the early reports of this phenomenon were of experiments done in hippocampus (430, 431). That spontaneous
activity in hippocampus depends on excitatory GABA
transmission is apparent from both the effects of GABAA
blockers on activity (see above) and from the fact that the
developmental disappearance of spontaneous GDPs parallels closely the switchover to inhibitory GABAA action
(283).
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disappearance of spontaneous GDPs at the end of the
second postnatal week correlates closely with the change
in intracellular Cl⫺ concentration that converts GABA
action from excitatory to inhibitory (283). [Note that there
is some disagreement as to the timing of GDP disappearance and GABA switchover. Khazipov et al. (283) postulate that earlier estimates are biased by the use of intracellular recording methods, which might disrupt intracellular Cl⫺ concentration and/or introduce leak resistance
effects into the measurements.]
It is not completely clear whether the synchronous
GDPs that occur throughout the hippocampus are driven
by a specific pacemaker region. Strata et al. (566) presented evidence that hilar neurons serve this function, at
least for GDPs in the CA3 region. In hippocampal slices,
surgical isolation of the hilus from CA3 abolished CA3
GDPs but left those in hilar neurons intact. Paired recordings showed that hilar GDPs preceded CA3 GDPs with a
consistent 5- to 10-ms latency. Dye injections showed gap
junctional coupling among hilar neurons and block of gap
junction channels with octanol suppressed GDPs. Finally,
voltage clamp of hilar neurons showed the presence of a
putative pacemaker current (Ih), and Cs⫹ block of Ih
slowed or blocked GDPs. Other experiments point to
different pacemaker regions. Leinekugel et al. (324) used
an intact two hippocampi plus septum preparation to ask
whether septal neurons might act as pacemakers for
spontaneous GDPs. They found that spontaneous GDPs
propagate temporally to the hippocampi from the septum
and that when partially isolated, the septum maintains a
higher GDP frequency than the hippocampi. When the
hippocampi were completely isolated from the septum,
however, the hippocampi retained the ability to generate
GDPs while the septum did not. They propose a pacemaker role from the septum, but an additional requirement of activity generated in the hippocampi to perhaps
raise the level of excitability in the septum so that it can
serve its pacemaking function. These two results are not
necessarily incompatible. Strata et al. (566) worked in
transverse slices, with CA3-hilus connections intact but
with no septal-hippocampal connections. It remains possible that the hilar neurons generate a pacemaker signal
that propagates to both the CA3 region and to the septum,
which in turn propagates a pacemaker-like signal back
into the hippocampus. Work by Menendez de la Prida and
Sanchez-Andres (392, 393) and Menendez de la Prida et al.
(391) makes an equally convincing case that GDPs are an
emergent network property that can be generated by
almost any subset of the hippocampal circuit. This hypothesis is based on data showing that isolated “islands”
of CA1, CA3, and dentate gyrus can each generate spontaneous GDPs. Further data from paired recordings show
that GDPs are triggered when the overall network activity
rises to a level that can generate a threshold frequency of
excitatory postsynaptic potentials (EPSPs) within partic-
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
The developmental profile of the hyperpolarizationactivated cation current Ih may also influence hippocampal spontaneous activity. Ih is well known as a pacemaker
current in a variety of cells (473, 504), and in particular,
hilar neurons in the hippocampus appear to rely on Ih to
drive spontaneous GDPs in other hippocampal regions
(566). Ih density peaks in the early postnatal hippocampus
(596) and thus may play a role in spontaneous activity.
Another potential pacemaker current, the T-type Ca2⫹
current, is also present at higher density in neonatal hippocampal neurons than later (94).
1. Cortex: nature of spontaneous activity
There are a large number of reports of spontaneous
activity in rat and mouse cortical neurons, particularly in
the first postnatal week. Most of these involve activity
that is synchronous in small contiguous clusters of neurons, or involves more subtle correlations of activity
among slightly more scattered cells. In many of these
instances, activity is not actually spontaneous, but is elicited by altered ionic conditions, ion channel blockers, or
transmitter agonists. These experiments show that the
perinatal neocortex has the ability to generate activity
with a variety of complex forms of spatial and temporal
synchronicity.
A) NEURONAL DOMAINS. In rat cortex during the first postnatal week, clusters of 5–50 cells in a columnar orientation generate synchronous [Ca2⫹]i transients (632). Different clusters can be seen to generate this activity apparently randomly, with an interval of ⬃4 min between
events in different clusters. Although columnar in orientation, the clusters do not correspond to obvious functional units such as barrels. This activity does not appear
to be caused by synchronous electrical activity, but rather
by an inositol 1,4,5-trisphosphate (IP3)-mediated [Ca2⫹]i
release that spreads from a trigger cell through the cluster, which seems to be defined by gap junctional coupling
(277, 631). A similar form of activity is seen in mouse
cortex at these stages, and knockout experiments suggest
the involvement of the 2 subunit of the NMDA receptor
in regulating the spread of the [Ca2⫹]i transient (453),
although how is unclear. It is possible that these coupled
units and the [Ca2⫹]i signaling within them might represent a precursor to a modular architecture in the mature
cortex.
B) CORRELATED ACTIVITY PATTERNS AMONG LAYER I NEURONS. A
very interesting observation in the context of early cortical development is the presence of correlated patterns of
[Ca2⫹]i transients among neurons of layer I, including
both Cajal-Retzius and non-Cajal-Retzius cells (4, 531).
This activity is not synchronous across large numbers of
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cells, but correlations among groups of cells can be detected by comparing correlation coefficients in pairs of
cells to those expected from random activity at the same
mean frequency (531). This pattern of activity in layer I
was only rarely observed spontaneously, but could be
evoked by high levels of extracellular K⫹ (50 mM). The
[Ca2⫹]i transients were quite long in duration (⬎100 s),
and were not blocked by TTX, although TTX did block the
correlations among the transients (531). Correlations
among cells involved chemical synaptic transmission, including glutamate, GABA, and ACh receptors. Correlations were not blocked by blockers of gap junction channels, indicating that direct electrical communication is
not involved, thus distinguishing this activity from the
neuronal domains discussed above. It is not clear whether
these [Ca2⫹]i transients are caused by Ca2⫹ entry during
electrical activity, or represent release from internal
stores. Their long duration suggests the latter, but their
sensitivity to block by Ni2⫹ suggests that Ca2⫹ entry may
at least be the initial trigger for internal Ca2⫹ release. This
hypothesis is also more compatible with the action of TTX
in blocking correlations among cells within the network.
It seems possible that Ca2⫹-dependent activity in cell
bodies may trigger the long [Ca2⫹]i transients, but axonal
Na⫹-dependent action potentials may be required to propagate the activity to other cells in the correlated network.
The function of this type of activity in layer I is not clear,
although communication between layer I cells and the
apical dendrites of developing pyramidal neurons is likely
to be involved (531). Activity that is synchronous between
layer I neurons (both Cajal-Retzius and non-Cajal-Retzius)
can be evoked under low-Mg2⫹ conditions, which activates silent NMDA receptors (549). The question remains,
though, as to whether this activity is intense enough
under normal (not high [K⫹]) conditions to carry out the
proposed functions. The possibility of a deep cortical
trigger for layer I activity is raised by the work of Dammerman et al. (131), who reported that electrical stimulation of GABAergic axons passing through layer I could
excite cortical pyramidal neurons in neonatal rat cortex.
These fibers arise in the zona incerta (ZI) of the thalamus
and could represent a subcortical pathway capable of
driving activity across large regions of the developing
cortex. This hypothesis is strengthened by the direct recording of spontaneous activity in ZI neurons (131).
C) INDUCED LARGE-SCALE WAVES OF ACTIVITY. Cortical slices
can generate waves of activity (measured either as electrical activity or [Ca2⫹]i transients) when treated with
cholinergic agonists (287) or TEA (475). Although induced under artificial conditions, these waves reveal the
capabilities of the neonatal cortex to initiate and propagate large-scale waves, synchronous among many neurons, over large physical distances. These waves require
the activity of voltage-gated Na⫹ channels and seem to be
propagated via glutamatergic synapses more than
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E. Cerebral Cortex and Coordinated Naⴙ
and Resting Channel Development
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WILLIAM J. MOODY AND MARTHA M. BOSMA
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subthreshold for generating this kind of widespread spontaneous activity. The former possibility is strengthened by
the finding that spontaneous synchronized activity recorded in hippocampal slices also occurs in vivo (325).
E) SPONTANEOUS ACTIVITY IN CULTURED CORTICAL NEURONS. A
strikingly similar form of widespread spontaneous activity appears in cortical neurons from E15-E16 rat brain that
have been in culture for 1–3 wk (467, 602), somewhat later
chronologically than widespread activity in acute slices of
neonatal cortex. The spontaneous [Ca2⫹]i transients occur at similar frequencies and had similar durations to
those found in intact neonatal cortex. It is unclear
whether this activity arises from the same mechanisms as
that in cortical slices. In culture, this activity seems to be
driven by a pacemaker population of neurons in the subplate and is as a result blocked by GABAA antagonists.
GABAA blockers do not block similar activity in rat neocortical slices, indicating that a GABAergic subplate pacemaker is not necessary in that preparation.
2. Cortex: developmental effects of spontaneous
activity: migration
In the embryonic mammalian neocortex, excitatory
pyramidal neurons are produced in the VZ and migrate
radially through the intermediate zone (IZ) to form the
layers of the cortical plate (CP) (10). A second major path
of migration involves inhibitory interneurons that arise in
the ganglionic eminences (GEs) and migrate tangentially
into the neocortex (374, 375). The wealth of information
about the timing of cell cycle events and migratory pathways (see, e.g., Refs. 578, 579) has greatly facilitated
studies of ion channel development in this preparation.
Experiments by Komuro and Rakic (297, 299, 300)
have shown that migration of cerebellar granule cells
depends on Ca2⫹ influx through N-type Ca2⫹ channels
and NMDA receptors (see sect. IIF). It is likely that neuronal migration in cortex is similarly activity dependent.
NMDA receptor activity stimulates chemotactic movements of mouse neocortical VZ cells (but not cortical
plate cells from the same stages) (32). Application of
NMDA receptor antagonists to intact slices blocks migration of VZ cells into the cortical plate, showing that endogenous glutamate levels are acting as a migratory stimulus. The existence of high levels of glutamate in the
cortical plate at these stages is consistent with its role as
a migratory attractant. [Interestingly, the situation is different in rat, where GABA seems to serve the role as a
chemoattractant (29 –31).]
Experiments on identified tangentially migrating neurons (arising in the GEs) show that they possess functional NMDA, AMPA, and GABAA receptors, all of which
can cause [Ca2⫹]i transients when stimulated (396, 552).
They also express functional voltage-gated Na⫹ channels
that are activated during GABAA receptor stimulation and
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GABAergic ones. In the case of TEA, gap junctions seem
also to be involved in wave propagation (475). The triggering of these waves by cholinergic agonists suggests
that these agonists may substitute for cholingergic inputs
from subcortical structures that are disrupted in brain
slices (287). Such inputs may serve to raise the overall
level of excitability in the neonatal cortex to a point
where glutamatergic synaptic interactions can synchronize large neuronal populations. Cholinergic agonists can
trigger such waves only during the first postnatal week,
indicating that the intrinsic neuronal properties and synaptic circuitry of the neonatal cortex are specifically optimized for such functions.
D) SPONTANEOUS WIDESPREAD SYNCHRONOUS ACTIVITY. Two reports indicate that both rat and mouse neonatal cortical
neurons can generate spontaneous [Ca2⫹]i transients that
show widespread synchrony among a very large percentage of neurons in the cortex (121, 195). These [Ca2⫹]i
transients result from electrical activity, as judged both by
TTX sensitivity and by extracellular field potential recordings. Although GABA is excitatory to cortical neurons at
these stages (E18-P5), activity is not blocked by GABAA
antagonists, at least in rat. Activity is blocked by antagonists to NMDA and non-NMDA glutamate receptors. Unlike in the retina, the pharmacological profile of activity in
cortex does not change as development progresses (195).
The [Ca2⫹]i transients occur at low frequencies of ⬃1/min
to ⬃1/12 min and propagate across the cortex at ⬃1.5–2.5
mm/s. The activity emerges in the cortex just before birth,
peaks at P0, and ceases by about P5 (121, 195). In each
case, transients were studied in somewhat elevated (4.5–5
mM) [K⫹]. The posterior-anterior propagation of this activity, starting in the entorhinal cortex (195), might suggest that hippocampal activity acts as a pacemaker for
cortical activity. Cortical activity, however, does not consistently propagate in this direction and occurs at lower
frequencies than that in hippocampus (195). Analysis of
slices in which the participation of neurons in synchronous activity was ⬍50% showed that participating neurons were spatially clustered, implying a network in
which mechanisms of synchronicity are widely distributed and are weaker between distant neurons than contiguous ones (121).
A recent report documents synchronous [Ca2⫹]i transients induced by blockers of glutamate transport in
P0-P5 rat cortex (139). This raises the question of how to
interpret these experiments where activity is induced by
slightly elevated external [K⫹] or glutamate transport
blockers. It is likely that both stimuli compensate for loss
of activity during preparation and maintenance of slices,
due to loss of extracellular glutamate by diffusion or loss
of subcortical excitatory inputs. But it is also possible that
cortex in vivo is not spontaneously active, or at least less
so than in vitro. In that case, activity induced by these
stimuli indicate that in vivo cortex is only marginally
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
3. Cortex: developmental effects of spontaneous
activity: later differentiation of neurons
and circuits
After cortical neurons enter the cortical plate, spontaneous activity takes the form of the widespread, synchronous burst of action potentials and [Ca2⫹]i transients
occurring at P0, as described above. Although few clear
functions for this activity have yet been reported, there
are several likely possibilities.
The effect of synchronous activity in promoting survival is seen in cultured cortical neurons, in which TTX
reduces, and KCl depolarization enhances, survival. Furthermore, survival is selective for neurons that are active
synchronously with other neurons (601). Activity-dependent survival of cortical neurons requires Ca2⫹ influx via
voltage-gated Ca2⫹ channels and/or NMDA receptors
(196, 465, 577). Brain-derived neurotrophic factor
(BDNF), parathyroid hormone-related peptide, and pituitary adenylate cyclase activating polypeptide (PACAP)
have each been implicated as mediators of activity-dependent survival (196, 309, 464, 577), which also seems to
involve p38-mitogen-activated protein kinase, which
phosphorylates and activates the transcription factor
MEF2 (365).
Other activity-dependent processes that occur near
birth in large numbers of cortical neurons include dendritic arborization (which involves Ca2⫹ entry through
L-type Ca2⫹ channels, activation of calmodulin kinase IV
and CREB phosphorylation; Ref. 493), and myelination
(140).
Finally, as discussed above for the hippocampus,
activity that is synchronous in pre- and postsynaptic partners may serve in a Hebbian fashion to strengthen synapses that are initially too weak to establish paired activity on their own (see Ref. 226). Indeed, in mouse barrel
cortex, the critical period for plasticity and refinement of
Physiol Rev • VOL
thalamic inputs overlaps closely with the period during
which LTP can be experimentally elicited (122; but see
Ref. 503 for the contrary result in visual cortex).
4. Cortex: activity and neural migration: relationship
to channel development
Proliferative cells of the neocortical VZ express delayed K⫹ currents (5, 402, 480), BK Ca2⫹-activated K⫹
currents (399, 402), and excitatory GABA receptors (468).
BK channels in VZ cells often show a high-frequency
flicker mode of gating that is rarely seen in mature cells
(399). It is not clear to what extent proliferative VZ cells
express voltage-gated Ca2⫹ currents. Flow cytometry experiments coupled with KCl depolarization and [Ca2⫹]i
imaging did not detect VZ Ca2⫹ currents (371). On the
other hand, patch-clamp recordings using monovalent
permeation through Ca2⫹ channels in divalent free solutions to greatly increase current amplitudes did detect
multiple Ca2⫹ current types in VZ cells (480). This may be
a species difference, since the latter experiments were
done in mouse and the former in rat, or simply a detection
difference. In either case, the fraction of VZ cells expressing Ca2⫹ currents in the patch-clamp experiments was
low enough that the possibility that only VZ cells that have
exited the cell cycle express Ca2⫹ currents could not be
ruled out (480).
Some caution is needed in interpreting results obtained in VZ recordings, for several reasons. First, after
E12 (in mouse), a significant fraction of VZ cells has
exited the cell cycle and begun to migrate (579). Conclusions about delayed K⫹ currents in proliferative cells are
drawn from experiments showing that these currents are
expressed at E9, before any VZ cells exit the cell cycle
(Albrieux and Moody, unpublished data), and from the
fact that 100% of VZ cells express delayed K⫹ currents at
E12-E14, when the majority of VZ cells are still proliferative (480). Similar logic applies to the finding of Ca2⫹activated K⫹ currents in VZ cells (81, 399). A second
problem arises from extensive electrical coupling among
VZ cells (353). If this is accompanied by electrical coupling, then currents that occur in only a few cells might be
shunted by the low input resistance of coupled clusters
and thus not detected. Or, currents might be assigned to
the wrong cell type due to spread from a different, but
coupled, type. This problem is not significant in mouse
VZ, where electrical coupling is much weaker than in rat,
although dye coupling is similar (480). Taking advantage
of this property, we were able to show that a subset of VZ
cells express functional Na⫹ currents starting at E14
(480) and that the fraction of total VZ cells represented by
this subset approximated those that have exited the cell
cycle at that stage. This implies that Na⫹ current expression is a very early event following cell cycle exit in
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participate in creating GABA-induced [Ca2⫹]i transients
(552). Neurons of this tangential migratory stream make
close contact with neurites of corticofugal axons arising
from the CP. This suggests that glutamatergic CP neurons,
arising from the cortical VZ by radial migration, can release glutamate onto the processes of tangentially migrating GABAergic neurons (396). That this process might
affect migration is indicated by the finding that activation
of AMPA receptors causes neurite retraction in these
tangentially migrating neurons (483). It is also possible
that bidirectional communication exists between these
cell types, because AMPA receptor activation also leads
to GABA release from the tangentially migrating neurons,
which could influence radially migrating neurons from the
cortical VZ as well as have autocrine effects on the tangential stream (484).
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cortical neurogenesis. A similar conclusion was reached
in rat by physically uncoupling cells (404).
As neuronal precursors migrate out of the VZ into the
IZ, Na⫹ currents and ionotropic amino acid receptors are
strongly upregulated, while outward IK density is unchanged and dye coupling is greatly reduced (372, 373,
480, 481). Each of these changes would increase responses to transmitters and other depolarizing influences.
It is not known whether Ca2⫹ currents are upregulated as
cortical neurons begin to migrate.
5. Cortex: perinatal spontaneous synchronized
activity: relationship to channel development
Physiol Rev • VOL
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After migrating neurons enter the cortical plate, we
begin to see a new pattern of ion channel development,
which appears to be related to the occurrence of spontaneous, synchronous activity, centered around P0 (121,
195). Between E16 and P2 in pyramidal neurons, INa
density shows its largest increase while IK density does
not change. A few days after this increase in INa density,
the resting resistance of the neurons falls by almost fivefold (481). The occurrence of spontaneous, synchronous
[Ca2⫹]i transients closely tracks these changes. [Ca2⫹]i
transients first appear at E16, as INa starts to increase, and
their occurrence declines markedly after P1, when input
resistance falls (121, Fig. 9). These data suggest that a
threshold INa density is at least permissive for activity to
occur and that the decrease in resting resistance postnatally reduces the ability of the neurons to respond to
synaptic inputs and to their own sodium currents to the
point where spontaneous synchronous activity ceases.
The role of INa may not be simply to increase neuronal
excitability so that [Ca2⫹]i transients can occur. Analysis
of data at early embryonic stages indicates that spontaneous transients occur in many cells, but asynchronously,
and then later become synchronized during the increase
in INa (121). This suggests that the increase in INa density
may serve more to increase transmitter release and synchronize cells than to render them sufficiently excitable to
generate [Ca2⫹]i transients in the first place. Ca2⫹ currents with both transient and sustained components also
appear in cortical neurons just as spontaneous activity
starts (Moody, unpublished data).
After the period of spontaneous, synchronous activity is over in the first few postnatal days, the electrical
properties of cortical neurons continue to develop over
the next several weeks. The hyperpolarization-activated
cation current Ih appears at about P0 and develops rapidly
near the end of the first postnatal week (481) (it is present
earlier in Cajal-Retzius cells; Ref. 360). The persistent Na⫹
current increases threefold in density over the first three
postnatal weeks (9). Overall Ca2⫹ current density also
increases, although the subtype composition of the currents remains relatively constant (352). Between P5 and
P7, there is an abrupt increase in the density of BK-type
Ca2⫹-activated K⫹ channels (278). It is during this period
that the mature diversity of cortical neuron firing types
emerges, including the “fast spiking” and “regular spiking”
phenotypes. This differentiation is driven in part by cellspecific expression of a slowly inactivating, 4-aminopyridine (4-AP)-sensitive K⫹ current, identified from singlecell RT-PCR analysis as Kv3.1 (382).
It is not only the voltage-gated channels whose patterns of expression appear optimized for spontaneous
activity and Ca2⫹ entry at early stages in the cortex.
Ligand-gated channels, too, have unique properties in embryonic and perinatal cortical neurons. AMPA receptors
in a variety of neurons, including those of brain stem,
cerebellum, hippocampus, retina, and cortex, lack the
GluR2 subunit early in development (91, 161, 312, 318,
343, 346). Unlike GluR2-containing receptors, these
AMPA receptors are permeable to Ca2⫹. Because AMPA
receptors do not show a voltage-dependent Mg2⫹ block,
this form can admit Ca2⫹ to cells even at negative potentials (see Ref. 146). NMDA receptors in embryonic and
early postnatal cortical neurons also have a unique subunit composition and properties that are different from
those in the mature cells. NMDA receptors in immature
neurons contain NR2B (or NR2D) subunits, which give
the channel a much slower deactivation time (127, 239,
626). As neurons mature, deactivation kinetics speed as a
result of substitution of the NR2A subunit (182, 246). The
exact developmental function of NMDA receptors containing the NR2B subunit and the long time course of the
currents they mediate is not entirely clear. The immature
subunit composition would clearly favor temporal summation, and in fact, such summation is observed in neonatal rat LGN in response to spontaneous activity from
retinal ganglion cells (349). It would also, as in the case of
the ACh receptor, be better matched to the high input
resistance and long time constant of immature cells (see
sect. IVB). In addition, the longer duration EPSCs in immature cells would be expected to admit more Ca2⫹ to
cells during activity, possibly allowing more effective triggering of gene expression and synapse stabilization (122,
289, 487). But it is not entirely clear that developmental
plasticity in synapse function is tightly related temporally
to the period of immature NMDA receptor expression
(see Ref. 503), or that in cases where a good temporal
relation exists under normal conditions, that the longduration immature NMDA responses are required for the
plasticity (347).
Finally, as in hippocampal neurons, the high intracellular [Cl⫺] in immature cortical neurons makes GABAA
action excitatory (307, 353, 355, 359, 468, 469, 470), although as discussed above it is not clear the degree to
which excitatory GABAergic transmission participates in
cortical spontaneous activity.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
In summary, the spontaneous synchronized activity
in P0 neocortex occurs at a time when the properties of a
large number of voltage- and ligand-gated channels all
favor such activity: Na⫹ currents that are newly increased
in density, newly developed Ca2⫹ currents, high input
resistance, long-lasting NMDA responses, Ca2⫹-permeable AMPA receptors, and excitatory GABAA transmission.
F. Cerebellar Neurons, Ca2ⴙ Currents,
and Neuronal Migration
Physiol Rev • VOL
G. Hindbrain and Synchronized Activation
of Motor Neurons and Cranial Nerves
1. Nature of spontaneous activity
The hindbrain is unique in that neurons are born
within transient compartments (rhombomeres) that determine the neuronal fate of progeny within them. In
addition, cells are unable to mix between the rhombomeric compartments until the transient borders disappear. Neurons differentiate first in the even-numbered
rhombomeres, later in the odd-numbered rhombomeres.
In chicks, the hindbrain is segmented between HH stages
12 and 24, in mice between E8.5 and E11.5, and in zebrafish, between hpf 18 and 36 h postfertilization (hpf).
Motor neurons in the hindbrain include somitic motor
neurons, which innervate somitically derived muscle,
much as in the spinal cord; in addition, there is a population of branchiomeric motor neurons that innervate
muscles derived from the branchial arches (reviewed in
Ref. 189). The branchiomeric trigeminal motor neurons
derive from r2, facial motor neurons from r4. Early segmental identity in the hindbrain is determined by the Hox
genes, a family of closely related transcription factors that
are differentially expressed in the rostral-caudal axis of
many animals, including vertebrates. These genes dictate
later expression of segment-specific genes, which play
roles in segment-specific neuronal fate and determination.
B) CHICK HINDBRAIN. Extracellular motor root recordings
[in elevated external K⫹ (8 mM)] in chick hindbrain branchiomeric nerves did not show any activity until stage 24,
when periodic episodes of activity were observed with an
interval rate of ⬃1 min (averaged over stages 24 –26) (98,
99, 183). These changed over developmental time (up to
stage 36), with more bursts of activity in each episode,
with the interval between episodes lengthening to 2.4 min.
These episodes were synchronous between the different
pairs of recorded motor roots (V versus VII, IX, X or XII),
and synchronous between the two sides of the hindbrain
(183, 186). Different sections of the hindbrain, when
transected along the midline or divided in the rostrocaudal dimension, were each able to generate independent
rhythms, and were no longer synchronized with the other
cranial roots. It was not clear which region of the hindbrain had the strongest ability to lead the other portions.
However, when the VIIth nerve region was isolated, it had
the ability to maintain the same rhythm seen previously in
the intact tissue, and rostral isolated fragments had a
faster rhythm than isolated caudal fragments. The synchronous behavior between the nerve roots was present
through several important developmental events in the
hindbrain: neuronal migration and differentiation, and the
formation of brain stem nuclei (186). Because each fragment of the hindbrain was able to maintain rhythmic
activity, the authors postulate that the activation of a
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A variety of studies, mostly done in granule cells of
the developing cerebellum, have shown that Ca2⫹ influx
through both voltage- and ligand-gated channels is an
essential regulator of neuronal migration (300). Cerebellar granule cells express N-type Ca2⫹ channel protein just
after they exit the cell cycle and upregulate the number of
those channels as they migrate (297). Selective blockers
of N-type Ca2⫹ channels decrease the rate of granule cell
migration up to 75%. Blockers of L- or T-type Ca2⫹ channels have no effect (297). Ca2⫹ imaging studies show that
migrating granule cells exhibit spontaneous [Ca2⫹]i transients lasting ⬃1 min at an average frequency of ⬃13/h. At
the peak of each [Ca2⫹]i transient, the forward speed of
the cell is high, and during each trough between [Ca2⫹]i
transients, the cell is stationary or moves slightly backwards (299). Suppressing transients with conotoxins or
creating transients with high KCl slowed or speeded migration, respectively (299). Ca2⫹ influx into granule cells
during activation of the NMDA receptor has similar effects on migratory rate (298). Spontaneous opening of
NMDA channels has been recorded in granule cells in
cerebellar slices, and the frequency of these openings
increases dramatically as the cells enter the migratory
phase (507). N-type Ca2⫹ channel activity has also been
implicated in neuronal migration in Caenorhabditis elegans, where loss-of-function alleles of the N-type Ca2⫹
channel gene unc-2 disrupt migration of specific neurons
without altering axonal outgrowth (580).
The mechanisms by which activity and [Ca2⫹]i transients regulate migration are not yet clear. Direct effects
of [Ca2⫹]i on cytoskeletal elements and cell motility are
likely candidates, but other, more complex events are also
probably involved. For example, expression of cell adhesion molecules and extracellular glycoproteins that are
known to affect neuronal migration are activity dependent at the appropriate developmental stages and in response to physiologically relevant levels of activity (260,
515). Neuronal migration in other areas of the central
nervous system (CNS), such as the olfactory placode,
hypothalamus pathway, is similarly inhibited by blocking
electrical activity (191).
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Physiol Rev • VOL
With the use of [Ca2⫹]i imaging in mouse hindbrain
with motor neurons identified by retrograde dextran labeling, the development of activity in identified branchiomeric motor neurons was monitored at earlier stages
(218). To quantify synchronicity, [Ca2⫹]i records were
idealized so that each [Ca2⫹]i transient in an individual
cell that crossed a criterion threshold was given an amplitude of 1.0, and all [Ca2⫹]i points below threshold were
given an amplitude of 0.0. By averaging such idealized
records from all cells in a given experiment, a summary
record was created in which the amplitude of each [Ca2⫹]i
transient had a value between 0.0 and 1.0, indicating the
fraction of neurons that participated synchronously in
that event. These experiments showed that E9.5 neurons
had very slow and infrequent [Ca2⫹]i transients, while
E10.5 events were much shorter in duration. At E11.0,
events were much more frequent, and abruptly at E11.5,
all motor neuron transients became highly synchronized
expressing [Ca2⫹]i transients every 1–2 min. This is the
stage at which rhombomere borders disappear. The
events at E9.5 and 10.5 were dependent on extracellular
Ca2⫹ but were not blocked by TTX, while the activity at
E11.5 was completely blocked by low doses of TTX.
These results indicate that between E10.5 and E11.5, TTXsensitive Na⫹ channels become functionally expressed in
the developing neurons, while during the interval of
E11.0 –11.5, mechanisms of synchronization become
abruptly expressed.
Analysis of mice in which specific Hox genes have
been inactivated have shown the roles of certain classes
of segment-specific neurons in controlling respiratory
rhythm in neonatal animals. Krox-20 is a transcription
factor normally expressed in rhombomeres 3 and 5 (before and during segmentation) and regulates Hox-related
genes. Deletion of Krox-20 leads to deletion of r3 and r5,
and a severe phenotype in which newborn animals have
reduced respiratory rate and increased periods of apnea,
often dying within hours of birth (263). In addition, the
jaw-opening motor patterns in the newborn Krox-20
(⫺/⫺) animals were reduced. Naloxone, an inhibitor of
the opioid system regulating respiration, had the effect of
increasing the respiration rate and increasing viability in
these animals (184). Anatomical and physiological studies
indicated that nonnoradrenergic reticular neurons, which
were postulated to be specific respiratory rhythm-promoting nuclei in the brain stem, were deleted or reduced, and
the respiratory rhythm was significantly slower than in
control littermates. In Krox-20 mutants, although the facial motor nucleus appears fairly normal (due most likely
to the population of r4-derived neurons), the trigeminal
motor nucleus is dramatically reduced. This is probably
caused by a trophic or inductive factor normally present
in r3 that is needed for normal trigeminal neuron development in r2. Since in chick the expression of a GABAergic inhibition leading to the more “mature” respiratory
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central pattern generator driving all of the nerves synchronously was not the underlying mechanism for synchronous nerve root activity. Instead, they propose that
each region is able to generate rhythmic activity, perhaps
in a manner similar to that seen in early spinal cord (see
below) and that the activity is coordinated between segments by a different subset of neurons. In the hindbrain,
there is possible input from reiterated sets of reticular
neurons that are present in the units of tissue derived
from each rhombomere. It is postulated that the early
rhythm in hindbrain motor neurons is modified in the
older animal to play a role in the oral components of the
respiratory rhythm. This work and the relationship to late
fetal and adult respiratory rhythms are reviewed in Champagnat and Fortin (95).
Experiments using a combination of ventral root and
single cell recording from developing hindbrain (185; reviewed in Ref. 62) revealed that the initiation of the more
mature episodes containing high-frequency bursting depended on the development of a GABAergic input that
causes hyperpolarization and rebound bursting; this is
presumably after the Cl⫺ gradient is maintained at the
mature value. The burst interval is regulated by Ih. During
development in the segmented hindbrain, the expression
of the ability of the motor neurons to generate the response to GABA and the high-frequency response is determined by the odd-numbered rhombomeres. In rhombomeres that are isolated and then allowed to develop in
vitro, only the odd-numbered rhombomeres were able to
express the high-frequency rhythm. In a more intact hindbrain, high-frequency rhythm expression depends on interactions between adjacent even- and odd-numbered
rhombomeres; in isolated segmental configurations where
a rostral odd-numbered rhombomere was paired with the
neighboring caudal even-numbered rhombomere the
high-frequency rhythm occurred, while the opposite pairing expressed only the “immature” low-frequency rhythm.
C) MOUSE HINDBRAIN. In a similar mouse hindbrain preparation, nerve root recording at embryonic (E) days 10.5,
12.5, and 14.5 showed spontaneous activity; at embryonic
day 10.5 (E10.5), different nerve roots were not synchronized, and rostral root frequency was faster than that
recorded in more caudal roots, demonstrating a possible
rostral-to-caudal developmental sequence. At E12.5 lowfrequency activity synchronized between different nerve
roots was recorded, with a slightly longer interepisode
interval than the more caudal lower frequency events at
E10.5 (interval of 75 s; Refs. 1, 98, 99). The activity at
E12.5 is similar to that seen in chick stage 24, and in both
animals this is recorded soon after the disappearance of
the rhomobomere boundaries. At E14.5, the high-frequency activity is recorded, which is synchronized between nerve roots; this is also similar to the timing of the
appearance of high-frequency activity in chick.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
2. Developmental roles of spontaneous activity
Spontaneous activity in developing motor neurons
coincides with the onset of neuromuscular junction formation and spontaneous movement in the head and limbs.
At the onset of synchronized activity in the mouse hindbrain, trigeminal motor growth cones are initiating synaptic connections with their peripheral motor targets, and
spontaneous neural activity may be important in neuromuscular junction formation. In addition, trigeminal and
facial motor neurons undergo dramatic somal migration
within the hindbrain, and activity-dependent processes,
with concomitant fluctuations in [Ca2⫹]i, may play a role
in the correct navigation of the cells within the growing
hindbrain. The importance of these neuronal populations
undergoing appropriate developmental sequences is
shown by deletions in hindbrain-specific genes (see
above). Functions needed at birth, such as respiratory and
Physiol Rev • VOL
feeding patterns, may require the endogenous rhythms
that are expressed early in hindbrain development.
3. Relationship to channel development
Relatively little is known about the ion channels that
play roles in the expression of spontaneous activity in
hindbrain neurons. Synchronization of [Ca2⫹]i transients
in mouse hindbrain occurs abruptly at E11.5 and requires
the expression of TTX-sensitive Na⫹ channels, which are
not important in the nonsynchronized activity seen at
earlier stages (218). In addition, GABAergic inputs and
modulation by Ih are required in chick hindbrain to
alter the rhythm from an immature low-frequency type
of activity to a mature pattern (185). However, other
ion channels and receptors have not been carefully
characterized yet.
H. Spinal Cord and Emerging Motor Patterns
1. Nature of spontaneous activity
The developing spinal cord expresses both spontaneous neuronal activity as well as activity that is driven or
modulated by a variety of excitatory agents, including
NMDA, serotonin, high K⫹, or electrical or sensory stimulation. Spontaneous activity in spinal and hindbrain motor neurons is accompanied, at the appropriate developmental stage, by movement of the muscles innervated by
the active neurons. The expression of spontaneous motility in most vertebrates develops in a rostral to caudal
fashion, initially as relatively small random movement
and proceeding to highly patterned motility with alternating flexor and extensor motor output as well as activity
that alternates on the two sides of the body. This may be
dictated by the general rostral-caudal developmental pattern of development, including the ability to generate
spontaneous electrical activity. In chick, motility begins
at day 3.5 of incubation in one area of the body, while
later involving the whole body (222, 223). In mouse, spontaneous motility begins at embryonic day (E)12.5, is usually initiated near the head (70% of the movements), and
is propagated in a rostrocaudal direction. Those movements that initiate at other positions often propagate in
the same direction (571). The similarities in generation of
spontaneous movement in chick and mouse (similar Carnegie stages, initiation ⬃1 day after muscle innervation by
the motor neurons, rostrocaudal pattern of motility) suggest that there is conservation of this developmental feature, and thus, that it is important to development in
general. Because spontaneous activity continues through
the period of innervation, developmental changes in the
pattern of that activity (described below) are likely to
influence muscle, as well as neuronal, differentiation.
A) ZEBRAFISH SPINAL CORD. An elegant series of experiments using video microscopy has elucidated the se-
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rate requires the presence of a specific odd-even rhombomere patterning (185), it is possible that the mature
respiratory rate requires r3 and r5 and is deleted in
Krox-20 (⫺/⫺) mice.
A similar analysis of early gene expression and the
regulation of rhythmic activity is seen in mice in which
the Hoxa1 gene, normally expressed from the posterior of
the mouse up to the r3-r4, is deleted. The resultant homozygous mice die near birth from anoxic episodes and
have malformations in the inner ear, bones of the skull,
and deletion or misplaced cranial nerves, stemming from
the reduction of r4 and deletion of r5 (88, 106, 358, 376).
Neonatal mutant mice express an unusual pattern of respiratory rhythm, due most likely to an increased input
from an ectopic group of reticular neurons that mediate
the respiratory rhythm (62, 150). These ectopic neurons
are most likely derived from r3-r4 neurons that acquire an
inappropriate, more rostral, fate.
Additional gene deletion experiments examining respiratory patterns have examined the deletion of the
NMDA-R1, Phox2a (expressed in cranial sensory and motor nuclei), BDNF (required neurotrophic factor for the
survival of chemosensory neurons in the respiratory system), and kreisler (r5-specific transcription factor) genes;
in the cases of NMDA-RA, Phox2a, and BDNF, respiratory
drive is strongly decreased (63, 158, 184, 597), while in
kreisler-deleted neonates the respiratory and jaw opening
rate is unusually high (98, 99). Given that NMDA receptors
are likely involved in the generation of early embryonic
rhythms and that certain subclasses of sensory neurons
may also drive rhythmic activity, it would be interesting to
examine the expression of the early embryonic rhythmic
pattern in these mutated animals to determine the
changes that may mediate the alterations in respiratory
rhythm.
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Physiol Rev • VOL
B) CHICK SPINAL CORD. Spontaneous bursts of activity can
be recorded from ventral roots in chick spinal cord at
stage 24 [embryonic day (E)4], although due to their small
size, this is done only with some difficulty. From stages 25
to 28.5 (E6), the interval between episodes of activity
lengthens, changing from 1- to 2-min intervals at stage 25
to intervals of ⬃7 min at stage 28.5, with more bursts
recorded during each episode. The mechanism underlying
the bursts included synaptic interactions and gap junctional coupling (408). Although NMDA or kainate receptor
stimulation modulates the activity, application of receptor
blockers either alone or in combination did not abolish
the spontaneous activity, indicating that though glutamate
receptors are present at stages 25 and 28, they are likely
not the primary mechanism that generates the spontaneous activity. GABAergic circuits were involved in the
spontaneous activity between stages 21 and 25, since both
stimulators and blockers of GABA receptors altered the
activity, with the effect of blockers being stronger at the
later stages; glycinergic inputs regulate spontaneous activity after stage 28 (228). However, the strongest candidate for mediating the spontaneous activity was nicotinic
AChR input, specifically those receptors that do not contain the ␣7-subunit, since ␣-bungarotoxin (BTX) did not
block the activity. This is in contrast to the later (E10 –12)
chick spinal cord activity where ␣-BTX does block spontaneous activity (316).
Spontaneous activity is also recorded in older (E7E11) chick embryos, and by E10 episodes comprised of
several cycles of bursting activity occur every 10 –20 min
(575). These episodes are generated by networks of neurons, residing primarily in the ventrolateral regions of the
spinal cord that include interneurons, since the activity
can be recorded in ventral roots or the ventrolateral funiculus, an interneuron tract (449). The network properties that drive spontaneous activity include synaptic interactions between neurons that are primarily excitatory,
and different transmitters may be able to substitute as
drivers of activity if one subset of transmitters is removed. For example, if glutamate and nicotinic receptors
are blocked, after a period of time, GABAergic/glycinergic
inputs are able to replace the element of excitability and
initiate spontaneous activity (107, 448, 575). Each episode
is preceded by a heightened state of excitability as shown
by recordings using intracellular techniques, and after
each episode, levels of spontaneous activity are much
reduced (449). Experiments using combined imaging and
recording techniques showed that motor neurons, perhaps due to their intrinsic higher excitability, were able to
stimulate network episodes by activating R-interneurons
which then spread excitation through the network of
neurons via functionally excitatory GABAergic inputs
(610). Intervals between episodes are mediated by a form
of cellular depression that includes alterations in the driv-
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quence of motor behaviors in the developing zebrafish
(516). The first spontaneous activity consists of alternating trunk contraction was seen at 17 hpf; this activity
increased in frequency and then decreased to ⬍0.1 Hz
after 10 h (27 hpf). During this time, at 21 hpf, touch
responses, consisting of coiling of the body, were elicited.
These responses increased in speed of contraction until
48 hpf. In addition, after 26 hpf, the embryos were able to
respond to touch by swimming. Each of these behaviors
appeared abruptly, as if the circuit were wired correctly
with no experience-dependent modification, and then became functional. The behaviors were arrested by application of nicotinic synaptic blockers. Lesioning the brain
above the level of the hindbrain did not modify any of the
behaviors, and additionally removing the hindbrain did
not affect the spontaneous contractions (but did block the
other two behaviors). Removal or lesion of the rostral
hindbrain did not affect touch responses or swimming,
while lesioning at the level of the caudal hindbrain interfered with both behaviors (516).
The earliest spontaneous activity in zebrafish is correlated with spontaneous inward currents recorded from
motor neurons (517); these spontaneous inward currents
occur on the same developmental time scale as the early
alternating trunk contractions and are distinct from synaptic events, which are glycine mediated. The spontaneous inward currents remain during block of synaptic release (low Ca2⫹/high Mg2⫹), but were abolished by TTX.
The frequency of the events was affected by holding
potential, suggesting that the activity is an intrinsic property or arises as an emergent property of a local circuit,
rather than being driven by a remote, upstream pacemaker. Heptanol and cytoplasmic acidification blocked
the events, suggesting the involvement of gap junctional
coupling. Given the small number of motor neurons at
these stages, a local circuit composed of electrically coupled premotor neurons and motor neurons seems a strong
candidate for the mechanism mediating spontaneous
activity.
In addition to spontaneous depolarizations in the
motor neurons, several classes of interneurons in the
early spinal cord also express periodic depolarizing
events, especially those neurons that are ventrally located
(518). These events are independent of synaptic inputs (in
fact, were still present in the presence of botulinum
toxin), but were completely abolished by gap junction
blockers. The active ventral interneurons were shown to
be electrically coupled to other active interneurons and
motor neurons on their ipsilateral side by the use of
paired patch recording. The authors propose that spontaneous activity is triggered by Ca2⫹ channel-mediated
events in combination with Na⫹ currents, which are then
spread synchronously throughout the network as well as
being strengthened by electrical coupling.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
Physiol Rev • VOL
inhibitory transmitters, glycine acting between segments
and GABA acting within each segment. The group of
glycinergic interneurons expressed a dihydro-␤-erythroidine hydrobromide (DH␤E)-sensitive ACh receptor that
allowed inputs from motor neurons to elicit propagated
episodes (227).
At all stages examined, application of serotonin was
able to elicit activity; this activity was synchronized on
the two sides of the cord in early animals (E13), but
alternated between the two sides of the cord in later
animals (72). E15 appears to be a transitional stage, where
serotonin-stimulated activity was not completely synchronized between the two sides; strict synchronicity was
reestablished in the presence of strychnine, suggesting
that the mature activity that alternates between the two
sides of the spinal cord is mediated by glycinergic contralateral interneurons, and develops soon after E15. Thus
the time point of E14.5–15 is again suggested to be a
crucial time point in the maturation of rhythmic patterns.
That serotonin can initiate activity demonstrates that
those receptors are present and able to modulate rhythmic activity well before the innervation of the spinal
cord by the descending serotonergic inputs from the
raphe (16).
In the neonatal spinal cord, activity more representative of the adult pattern is seen; this latter pattern
consists of evoked locomotor-like activity with extensors
and flexors acting in an alternate pattern and with alternating responses from the two sides of the cord. Although
periods of spontaneous activity are observed at postnatal
day (P)0 – 4, recordings in the lumbar spinal roots show
that they are considerably more variable than the patterns
recorded in the earlier embryonic animals, with additional
variability in the appearance of alternating patterns, either left-right or flexor-extensor alternation [613 (4 K⫹)].
Spontaneous activity is clearly alternating in lumbar roots
at P0 –2, while sacral roots are less mature in their patterns. Raising the probability of NMDA receptor channel
opening by perfusing Mg2⫹-free solution increases the
rhythmogenicity [56 (4 K⫹)], and the probability of alternating rhythm in the caudal spinal cord (72).
Stimulation of sensory inputs also elicits left-right
alternations in lumbar and sacral spinal cord, as shown
with a combination of [Ca2⫹]i imaging and ventral root
recording (59). In response to stimulation, alternating
activity is recorded that propagates from rostral to caudal
in the spinal cord. Spontaneous activity recorded under
these conditions also moved from rostral to caudal. Propagation of the signal under conditions of sensory stimulation occurred at the rate of 15 ␮m/ms, although there
was an apparent increase in velocity of propagation in the
lower lumbar region (58). Several experiments also demonstrate that the sequence of rostral to caudal developmental events may also dictate the ability of different
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ing force for Cl⫺, reducing the effective input for GABA
(108).
C) MOUSE SPINAL CORD. Developmental aspects of mouse
spinal cord locomotor physiology have been reviewed
recently (58, 612). Spontaneous activity is recorded in
lumbar motor nerves in the E11.4 –14.5 spinal cord and
consisted of both major episodes that propagate throughout the lumbar cord, and local episodes, recorded on a
single motor nerve (227). Intervals between major episodes increased over the developmental time (from 2 min
at E11.5 to ⬃8 min at E14.5), as did the episode duration.
The spontaneous episodes were synchronized between
the two sides of the spinal cord, an indication that reciprocal inhibitory synapses between the two sides had not
yet been expressed. At a higher concentration of extracellular K⫹ (4.5 mM) in spinal cord preparations with
attached medulla, similar spontaneous activity was recorded at E12.5 and E13.5 (633). However, at E14.5, an
additional class of episodes was observed, with relatively
long episode durations compared with the events at all
other stages, and longer postepisode silent period (interval of ⬃11 min, compared with the interval for the shorter
duration events of ⬃1 min). These events were not recorded at any other stage. At E15.5–16.5, the short-duration episodes occurred at long intervals of 10 –15 min, and
the spinal cord engaged in activity ⬍1% of the time; at
E17.5, short-duration events again became quite frequent
but relatively irregular, with intervals of 1 min, and the
spinal cord experienced a much higher rate of activity.
Spontaneous activity was expressed equally in the rostralcaudal spinal cord at the E12.5–13.5, shifted to rostral
predominance at E15.5–16.5, and then to caudal predominance at E17.5. Activity at E14.5 showed no clear rostral
or caudal directionality, and this stage appeared to mark
a transitional time, where two distinct rhythms are expressed as development of a more mature phenotype
appears (633); the immature regular short-duration events
recorded at E12.5–13.5 gave way after E14.5 to more
mature irregular short-duration events.
Applying agonists or antagonists of glutamate receptors did not modulate the spontaneous activity, suggesting that glutamate receptors are not yet expressed in the
circuit generating spontaneous activity (227). [At later
developmental stages, glutamate inputs are required for
rhythmic activity (71).] In addition, GABA antagonists
lengthened the interval between episodes but did not
block activity, indicating that inputs from this transmitter
system can modulate spontaneous activity but are not
required for the expression of that activity.
Glycinergic transmission was required for the propagation of activity throughout spinal cord segments, but
not for the generation of local episodes. This implies a
model in which local episodes are dependent on a network composed of motor neurons and GABAergic interneurons, while propagated activity is driven by the two
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WILLIAM J. MOODY AND MARTHA M. BOSMA
Physiol Rev • VOL
sides, with additional alteration between the medial and
lateral portions of each side (141). These spontaneous
fluctuations were dependent on extracellular Ca2⫹ and
could also originate in quadrants dissected from the
whole cord, implying that the networks responsible for
mediating spontaneous activity are distributed throughout different regions of the cord.
Pharmacological experimentation examined the role
of different transmitter systems in causing the spontaneous activity. Kynurenate or CNQX had little effect on the
activity at E14.5 or E15.5. At E16.5, activity in cervical
regions was blocked by these antagonists, although it
sometimes reappeared in the presence of blocker; in the
lumbar cord, kynurenate or CNQX did not block activity
(437, 498). At later stages, glutamate receptor blockade
abolishes activity; thus there is a rostral to caudal progression in the development of glutamate-mediated spontaneous activity in the spinal cord. Activity up to stage
E17.5 was blocked by strychnine (437, 498) and bicuculline (498), indicating that the classic inhibitory transmitters lead to spontaneous activity at early stages. In addition, because of the change in the Cl⫺ reversal potential
during the same range of developmental stages, GABAergic blockers initially caused an early abolition of activity,
while the same blockers used at later stages caused an
augmentation of activity (311, 498). Ren and Greer (498)
also showed that nicotinic receptor blockade led to cessation of spontaneous activity at E13.5-E17.5.
Spontaneous activity in the early embryonic rat spinal cord is synchronized between different segments of
the spinal cord and between the left and right sides of the
animal. More mature patterns of activity (post E17.5),
most of which are induced by application of excitatory
neurotransmitters (most often glutamate or serotonin),
are recognized by the alternation of activity between the
two sides of the animal and between antagonistic motor
neuron groups. The application of strychnine, a blocker of
glycinergic receptors, caused alternating activity to become synchronized, implying that glycinergic inputs, inhibitory at this stage (E20.5), were required to produce
the alternating patterns between the two sides of the cord
(311). Because both glutamatergic and glycinergic stimulation induced activity, these authors proposed that these
two transmitter systems were involved in stimulating activity; that activity is initially synchronized, while later in
development it becomes alternating because of the more
negative reversal potential for Cl⫺. The switch between
synchronized and alternating patterns was also shown by
[Ca2⫹]i imaging of the commissural interneurons in the
spinal cord, which have increases in [Ca2⫹]i in synchrony
with ventral root activity, and mediate the relationship
between the two sides of the cord. At earlier stages
(E15.5), these commissural neurons synchronize the two
sides via excitatory synaptic GABAergic inputs, shown by
removal of extracellular Ca2⫹ or application of antago-
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regions of the spinal cord to generate rhythmic activity at
specific developmental stages (56, 443).
Rhythmic activity is consistently evoked by bath application of drugs, although activity generated by such
pharmacological manipulations was much slower than
that seen spontaneously (613; reviewed in Ref. 58). Combinations of serotonin, NMDA, and dopamine were able to
elicit patterned alternating activity, which was slower in
frequency than that generated spontaneously. Different
combinations of pharmacological agents modified the periods of overlap during alternating activity. Midline sectioning of the cord generated slower cycles of activity on
the hemi-cords. Application of MK801 or AP5 slowed but
did not block activity, while CNQX completely blocked
the activity (613). This evidence indicates that NMDA
receptors likely modulate activity but are not required for
its generation, whereas non-NMDA (AMPA/kainate) receptors are required for the activity (56, 72).
D) RAT SPINAL CORD. Several recent reviews have described the maturation of locomotor networks in the developing rat (110, 111), the spatial distribution of the
pattern generation mechanism, especially in the hindlimb
region (285), and the ability of sensory inputs to modify
motor output (474). We will concentrate on the spontaneous activity present in the early embryo.
In the rat, spontaneous motor neuron output is
present at E13 (209), before responsive muscle contraction. In isolated E13.5–15.5 spinal cords, spontaneous
activity is recorded (437; ⬃6 K⫹) that is present on cervical and lumbar roots, in which the cervical segments
lead the lumbar segments. At E16.5, the lumbar roots
begin to lead the cervical roots and have additional spikes
of activity that are not propagated to the cervical segments. The role of the leading segments was elucidated by
transection experiments; dividing the cord at E14.5
showed that although both rhythms were slowed, the
cervical rhythm was more rapid than the lumbar. Separation at E15.5 demonstrated equal abilities of the two cord
portions to generate spontaneous activity, and the cervical rate was slowed to a greater extent than the lumbar
rate. Division at E16.5 showed that the lumbar cord was
able to independently generate activity, and at a much
higher rate than the cervical cord. Thus the ability of
different regions of the spinal cord to drive spontaneous
activity changes over development. These results have
been extended by experiments exploiting recording from
a more complete rostral-caudal range (498). These
showed that at E14.5, thoracic segments lead both cervical and lumbar regions, and that until approximately E17,
the spinally generated patterns were also recorded in the
brain stem, on cranial nerve XII. Imaging with voltagesensitive dyes combined with field recording showed that
E15 embryos had synchronized spontaneous voltage fluctuations on the two sides of the cord, while spontaneous
fluctuations in postnatal animals alternated on the two
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
2. Developmental roles of spontaneous activity
In addition to the known role of pruning of inappropriate or supernumerary inputs to the NMJ, spontaneous
motor neuron activity may function at earlier stages to
enable correct matching of pre- and postsynaptic partners. The pathfinding of motor axons into their motor
units in E4 chick lumbar spinal cord requires the correct
expression of spontaneous activity, which at this early
stage is mediated by glycinergic receptors. The mechanism of this pathfinding includes the activity-dependent
processing of cell adhesion molecules and guidance molecules used to sort axons at the initial exit point of the
neural tube (228). Appropriate matching axons with target motor units ensure that the spontaneous muscular
movements occur; these may influence bone and connective tissue growth in the animal.
Physiol Rev • VOL
3. Relationship to channel development
The repertoire of excitatory inputs that mediate
spontaneous activity in spinal cord neurons give rise to a
secondary feature, which is that they are functionally
redundant: blockage of two inputs (glutamatergic and
nicotinic) slows spontaneous activity only temporarily,
with reactivation of the same rate of activity by increased
glycinergic or GABAergic input (chick, Ref. 448). Functional circuitry also changes with development, with
AChR subunit switching occurring between E4 and E10
(chick; Ref. 316) and excitatory inputs switching from
GABA to glycine (chick; Ref. 228). Chick motor neurons
express large overshooting action potentials at E4, contributed by Na⫹ channels; expression of the Na⫹ currents
increases over several days, with later differential increases in K⫹ channel expression shortening the action
potential (387). Early expression of Ca2⫹ channels in
chick motor neurons are dominated by high-voltage-activated channels, while more mature motor neurons largely
express N- and L-type Ca2⫹ channels (387).
I. Cochlear Hair Cells and the Loss of Excitability
After Activity
1. Nature of spontaneous activity
During development, inner hair cells (IHCs) of the
cochlea show spontaneous action potentials from E18 to
P6 with a peak frequency of ⬃5 Hz (368, 369). A single
spontaneous action potential is capable of triggering exocytosis of transmitter from the IHC (40, 369). This implies
that spontaneous activity is communicated to brain stem
auditory nuclei, and indeed, such activity has been recorded in the brain stem at these stages (216, 272, 304,
341). This spontaneous activity itself is modulated by
cholinergic innervation from the superior olive that is
itself a transient developmental phenomenon (198, 542).
Thus efferent spontaneous activity arising in the brain
stem is likely to interact with afferent spontaneous activity in IHCs.
2. Developmental roles of activity
Spontaneous activity in IHCs is involved in transneuronal survival and death, a phenomenon extensively studied in the auditory system (see Ref. 511 for review).
Neurons of the VIIIth nerve, which are activated during
spontaneous activity of hair cells, make synapses in the
brain stem in the cochlear nucleus. Functional deafferentation, either by cochlear ablation or block of VIIIth nerve
activity, causes pronounced and rapid neuronal death in
the cochlear nucleus (see Ref. 428), with first events in the
postsynaptic cells visible within 12 h. These effects are
specific to developing animals and can be rescued by
providing synaptic activity onto cochlear neurons but not
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nists in a split-bath recording arrangement. At E18.5–20.5,
the effect of GABA is superceded by glycine, mediating
alternation of activity in a very similar way to the GABA
effect. At E16.5, slices of spinal cord were used to demonstrate that the mechanisms mediating the synchronous
activity of the two sides of the cord were contained within
one-half (anterior-posterior slices) of a single segment
(200 ␮m slice), but not within one-quarter of a segment
(100 ␮m slice).
Electrical coupling between neurons is one mechanism that allows synchronization of activity. In motor
neurons, synchronized or correlated activity may be crucial in the ability of presynaptic neurons to initiate the
between-cell communication required for the establishment of end plates. Correlated activity causes the
postsynaptic cell to express correct junctional proteins
and signals, and a polyinnervated synapse is formed. In
the developing rat spinal cord, electrical coupling in the
form of halothane-sensitive electrical coupling is mediated by specific classes of connexins, which are downregulated during the initial steps of synapse elimination in
rats (96). During the initial period of synapse elimination
(postnatal week 1), spontaneous activity is relatively low
but highly correlated temporally (478). Experiments in
awake moving mouse pups during the period of synapse
elimination in the lumbar spinal cord have shown that the
junctional coupling decreases as synapse elimination occurs in mice (478) and that pharmacological blockade of
gap junctions in mice abolished the correlated activity in
the motor neurons, perhaps disrupting normal synaptic
connectivity (479). Thus a mechanism that seems to be
crucial during early development to direct synapse formation may lessen in importance as end plates become
singly innervated. However, there is evidence that electrical coupling is used in adult motor neuron behavior, in
either normal or abnormal situations (286).
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WILLIAM J. MOODY AND MARTHA M. BOSMA
by stimulating them directly. The survival promoting action of VIIIth nerve activity relies on stimulation of
metabotropic glutamate receptors, which act to keep
[Ca2⫹]i in cochlear neurons at low levels (639). Neuronal
cell death appears to involve activation of caspase-3
(429). These studies demonstrate an intimate relationship
between developmental patterns of spontaneous activity,
the resulting activity in the VIIIth nerve, and neuronal cell
survival in the auditory brain stem.
3. Relationship to channel development
Physiol Rev • VOL
J. Dorsal Root Ganglion Cells, Myelination,
and Cell Adhesion Molecules
1. Nature of activity
Embryonic dorsal root ganglion neurons begin to
generate spontaneous action potentials at about E16,
when axon terminals begin to reach the periphery. Initially, activity occurs at relatively low frequencies (⬍0.5
Hz) but speeds to frequencies of up to 10 Hz near birth
(see Ref. 174 for review).
2. Developmental roles
In cultured DRG neurons, direct stimulation of the
neurons at 0.1 Hz reduces myelination, but 1-Hz stimulus
has no effect. These frequencies are similar to those that
trigger expression of cell adhesion molecules and to normal frequencies of spontaneous activity in DRG neurons
at these stages (565). Further experiments on DRG neurons showed that direct electrical stimulation of the neurons induces [Ca2⫹]i transients in both the neurons and
cocultured Schwann cells, secondary to the release of
ATP from the neurons (564). The Schwann cell [Ca2⫹]i
transients result in CREB phosphorylation and arrest of
the Schwann cell in a nondividing “predifferentiated”
state. Shrager and Novakovic (541) reported that myelin
development in embryonic spinal cord slices was unaffected by TTX treatment, but as the authors point out,
growth factors present in the culture medium might substitute for activity in inducing myelination.
The expression of different cell adhesion molecules
in DRG neurons is activity dependent and shows differential frequency sensitivity (260). N-cadherin and L1 are
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Mature IHCs are the primary auditory sensory receptors in the cochlea. They have an impressive ability to
transduce high-frequency mechanical inputs into membrane potential oscillations and transmitter release. To do
this, they rely on an interplay between inward Ca2⫹ currents and outward Ca2⫹-activated K⫹ currents to create
rapid oscillations in membrane potential, rather than full
action potentials (see Ref. 173 for review). Individual
IHCs have specific frequency tuning curves, which are
created in part by variability in kinetics of the Ca2⫹activated K⫹ current. This results from alternative splicing of the channel transcript and modification of the
channel properties by accessory subunits (489 – 491). Although IHCs do not generate action potentials in the
adult, they do early in development (190, 368, 369). In
mouse, the period during which IHCs are capable of
generating full action potentials extends from about E18
to P12. Thus the onset of spontaneous activity appears to
coincide with the appearance of spike-generating ability,
but the cessation of spontaneous activity occurs before
spike-generating ability is lost (368, 369). The events that
terminate the ability to generate action potentials in IHCs
have some features in common with those that modify
firing properties in Xenopus spinal neurons and ascidian
muscle (see sect. II, K and L). During the period of action
potential generation, the dominant outward K⫹ current is
voltage-gated and slowly activating (190, 308, 368, 550).
Later, a rapidly activating Ca2⫹-activated K⫹ current appears (at about P10-P12 in mouse and 2 days prehatching
in chick), which effectively terminates spike-generating
ability. The expression of IK(Ca) correlates approximately
with the onset of hearing. Its expression requires the
preceding period of spontaneous activity created in part
by its absence. In mice lacking Cav1.3 Ca2⫹ channels and
hence these early action potentials and spontaneous activity, IK(Ca) fails to develop (73). In addition, at least in
mouse, resting potential (Vrest) becomes more negative
with development and the inactivation versus V curve for
the voltage-gated outward K⫹ current shifts more positive, thus increasing the magnitude of K⫹ current available during depolarization (368). Superimposed on these
changes is the transient expression of an inwardly rectifying K⫹ current, which appears at E15.5 (mouse) and
disappears after the onset of hearing at P12 (367). Loss of
inward currents also contributes to the loss of excitability. Both Na⫹ and Ca2⫹ currents appear in these cells just
before birth and reach peak densities at P5, correlating
closely with the period of spontaneous activity. Both INa
and ICa are then dramatically downregulated between P5
and P12 (the onset of hearing), ICa by ⬃70%, and INa
completely (369). This coordinated developmental appearance of rapidly activating outward K⫹ currents and
downregulation of both inward currents serves to terminate spike-generating ability and allows their maturation
as functional transducers of high-frequency inputs.
In cells like IHCs, which are excitable only transiently during development, the presumption is strong
that electrical activity is serving a developmental function. It will be very interesting to explore other nonneurally derived cells that are inexcitable in the mature state,
to see whether early expression of ion channels creates
similar early periods of excitability and signaling. This
point is discussed further in section IVD2.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
both downregulated by 0.1 Hz activity, although only L1 is
downregulated at 1.0 Hz, and NCAM expression is not
regulated by activity. It is possible that activity-dependent
changes in cell adhesion are involved in defasciculation of
DRG axons in the periphery and in Na⫹ channel clustering at nodes of Ranvier (361). Activity has also been
implicated in differentiation of the dopaminergic phenotype in DRG neurons (79).
3. Relationship to channel development
K. Amphibian Spinal Neurons, Transmitter
Phenotype, and Low-Frequency
Spontaneous Activity
1. Nature of activity
Developing Xenopus embryonic spinal neurons generate a variety of waveforms of spontaneous [Ca2⫹]i transients (212, 214). [Ca2⫹]i “spikes” are clearly triggered by
spontaneous action potentials that propagate throughout
the cells. These occur at very low, but reproducible, frequencies of 1–3/h during the first 10 h in culture after
neurons are removed from the neural plate. They also
occur in the embryonic spinal cord in vivo (558). Neurons
in single cell cultures show normal differentiation of activity-dependent properties, indicating that spontaneous
activity is cell-autonomous (237). When imaged in vivo,
[Ca2⫹]i transients are seen to be synchronous among
small clusters of neurons in the spinal cord, with cluster
size and position consistent with the hypothesis that neurons that differentiate together as a small group generate
spontaneous [Ca2⫹]i transients in synchrony (558). This
finding is important in that it shows that complex forms of
Physiol Rev • VOL
synchrony of spontaneous activity in vivo can emerge out
of subpopulations of interconnected, but independent,
oscillators. This emphasizes that intrinsic properties that
are instructive for spontaneous activity interact with the
emerging synaptic circuitry of the nervous system to create appropriate patterns of activity.
In contrast to Ca2⫹ “spikes,” [Ca2⫹]i “waves” occur
locally in the soma and growth cone and appear to result
from Ca2⫹ entry through a channel open at the resting
potential (214). Waves have a longer duration than spikes
(33 vs. 9 s). Waves in the growth cone occur at higher
frequencies than soma spikes (8 –10 vs. 1–3/h). Growth
cone filopodia also show local [Ca2⫹]i transients driven by
substrate interaction (203). These findings indicate that
within the complex spatial structure of developing neurons, several types of spontaneous activity can occur at
the same time.
2. Developmental roles
A series of elegant experiments in which naturally
occurring spikes and waves were blocked and then artificially stimulated [Ca2⫹]i transients imposed at various
frequencies showed that these events are both necessary
and sufficient for several aspects of neuronal differentiation. When spikes and waves are eliminated in 0 Ca2⫹
medium, the normal speeding of delayed K⫹ current activation does not occur, fewer neurons develop the GABA
phenotype (quantified by both GABA immunoreactivity
and GAD transcripts), and neurites are abnormally long
(145, 248, 249, 557, 607).
To demonstrate sufficiency of [Ca2⫹]i transients,
transients were artificially imposed on neurons in Ca2⫹free medium by brief applications of high K⫹ ⫹ Ca2⫹
medium (214). When transients were imposed at normal
spike frequencies, K⫹ current speeding and GABA phenotype were both rescued. Remarkably, imposed transients
at 1/h did not rescue K⫹ kinetics at all, whereas transients
at 2/h rescued kinetics completely (see Fig. 4b in Ref.
214). This indicates a very sensitive and finely tuned
mechanism for decoding even very low frequencies of
Ca2⫹ transients. Similar results were obtained for rescue
of the GABA phenotype, with 1 transient/h not rescuing
and 3/h restoring GABA phenotype completely (see Fig.
4c in Ref. 214). Neurite length, however, was not rescued
by spike-frequency transients, but when wave frequencies
of 8 –9/h were imposed, neurite length reverted to control.
Neurite outgrowth appears to be regulated by growth
cone [Ca2⫹]i waves via calcineurin-mediated dephosphorylation of GAP-43 (319). This shows that the two types of
transients encode different aspects of neuronal differentiation, partly by virtue of their different frequencies.
More recently, Borodinsky et al. (65) showed that activitydependent regulation of transmitter phenotype in this
system was “homeostatic,” with high levels of activity
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In DRG neurons, the Na⫹ channel Nav1.3 is expressed early, peaking at E17 and then disappearing by
about P15. The timing of Nav1.3 expression corresponds
with a period of spontaneous activity. Because Nav1.3 has
particularly rapid recovery from inactivation, it may help
to induce spontaneous, repetitive firing in developing
DRG neurons (128, 171). The expression (measured as
both mRNA and protein levels) of two other Na⫹ channel
types, Nav1.8 and Nav1.9, is downregulated by activity in
DRG neurons (291), although it is not yet known whether
spontaneous activity actually downregulates these channels during normal development. Nav1.8 and Nav1.9 show
fairly negative voltage dependence and slow inactivation
kinetics, so changes in their expression would have
marked effects on excitability in the neurons. Similarly,
different Ca2⫹ current subtypes show distinct developmental regulation in DRG neurons (241), and Ca2⫹ current expression shows similar dependence on the specific
patterns of stimulation as do other activity-regulated molecules (331).
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3. Relationship to channel development
Xenopus spinal neurons, including the transient population of sensory Rohon-Beard neurons, become excitable shortly after their last round of DNA synthesis, at the
neural tube stage. (It may well be that their precursors
show a complex pattern of channel development, as discussed in section II, A and B). During the early stages of
excitability, Xenopus spinal neurons generate long-duration action potentials that are primarily Ca2⫹ dependent.
During the next 24 – 48 h, the action potential shortens by
⬃100-fold and becomes more Na⫹ dependent and less
2⫹
Ca dependent (556). These changes are all cell-autonomous, proceeding normally in single-cell cultures (237).
Under voltage clamp, the major change during this
period is a large increase in density and activation rate of
the delayed K⫹ current and an increase in Na⫹ current
density. The high-threshold Ca2⫹ current does not change
in amplitude (19, 451). Thus the shortening of the action
potential reflects the changes in delayed K⫹ current amplitude and kinetics. The loss of apparent Ca2⫹ dependence of the action potential seen in current clamp reflects not a loss of the Ca2⫹ current but the truncation of
Physiol Rev • VOL
action potential duration by the changes in the delayed
K⫹ current to a duration at which the Ca2⫹ current contributes little to the spike waveform (18, 19). Modeling
studies indicate that the increase in amplitude of the
delayed K⫹ current plays a bigger role in spike shortening
than the speeding of K⫹ current kinetics (350). Although
all spinal neurons show spike shortening in this preparation, different molecular subtypes of K⫹ channels are
involved in different cells, including xKv1.1, xKv2.1, and
xKv3.1 (47, 500, 600). This diversity of outward K⫹ currents may help create the different patterns of spontaneous [Ca2⫹]i transients seen in different classes of spinal
neurons (65).
The long duration of the early action potentials is
critical for the developmental effects of spontaneous activity. Modeling studies show that the long-duration action potentials do indeed admit more Ca2⫹ (350). Misexpression of a mature delayed K⫹ channel shortens the
immature action potential and eliminates at least some
aspects of the activity-dependent developmental events
(271), but only in culture, not in vivo (270). It would be
interesting to know whether expressing the mature K⫹
current simply shortens the action potential, or might also
act to reduce spontaneous activity itself by reducing the
time during which net inward current flows during depolarization (see, e.g., Ref. 208).
These studies suggest several important principles.
One is that action potentials may exist in an “embryonic”
form that is more efficient in carrying out its developmental role, that is to occur spontaneously and admit Ca2⫹ to
the cell in amounts and patterns to trigger activity-dependent developmental programs. Another is that spontaneous activity can be instructive, not just permissive, in its
developmental role, as shown by the ability of artificially
imposed activity to rescue development in cells where
activity is blocked. A very interesting unresolved question
is what regulates the very low but stable frequencies of
spontaneous action potentials in these cells.
L. Ascidian Muscle, Inward Rectifier, and
Activity-Dependent Ion Channel Development
1. Nature of spontaneous activity
Muscle cells of developing ascidian embryos generate spontaneous bursts of action potentials for a period of
6 – 8 h just following exit from the cell cycle at the start of
neurulation. This activity takes the form of bursts of
action potentials at 2– 4 Hz lasting an average of 20 s
separated by silent periods of slightly more than 1 min
(129). Activity occurs well before the appearance of innervation and the development of contractility. Because
these action potentials are Ca2⫹ dependent (ascidian
muscle cells do not express Na⫹ currents at any stage of
development), this activity presumably results in sponta-
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increasing expression of inhibitory transmitters at the
expense of excitatory transmitters, and blockade of activity doing the opposite.
Similar roles of activity and/or [Ca2⫹]i transients in
reducing neurite outgrowth have been reported in retina
(91), cerebellar Purkinje neurons (242, 523; but see Refs.
496, 493), and neuronal cell lines (101). In dentate granule
cells, dendritic spine maturation depends on neuronal
activity (151).
Other neurons also show activity-dependent transmitter phenotype. For example, mouse spinal neurons
show spontaneous activity in culture, and blocking that
activity with TTX downregulates enkephalin expression
(2). This effect can be rescued by Ca2⫹ channel agonists.
Activity also affects the response of Xenopus neuron
growth cones to guidance molecules. In culture, axons are
repulsed by netrin-1 early in development but attracted
only 8 –10 h later (409). At the early stages, simulation
inverts the normal repulsion by netrin to attraction. At
late stages, electrical stimulation increases the sensitivity
of axons to attraction by netrin, and blocking Ca2⫹ channels inverts the attractive response to repulsion (252).
These responses involve a complex interaction between
the type of netrin receptor, [Ca2⫹]i, and intracellular levels of cAMP and cGMP (444). Overexpression of the
UNC5 Netrin receptor converts the response of the axon
to netrin from attraction to repulsion and inverts the
effect of netrin on the growth cone L-type Ca2⫹ current
from augmentation to reduction (444). Similarly, increasing the ratio of intracellular cAMP/cGMP shifts the axonal
response from attraction to repulsion.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
neous [Ca2⫹]i transients, although these have not been
measured directly. Spontaneous activity in these cells
occurs in isolated cells developing in culture, and thus is
cell autonomous (129). Whether activity is synchronous
among muscle cells in vivo is not known.
2. Developmental roles of spontaneous activity
3. Relationship to channel development
We discussed above the early postfertilization
changes in ion channel properties in embryos of the ascidian Boltenia villosa. In this embryo, the period between fertilization and gastrulation is characterized by
the sequential elimination of the Na⫹ current, then the
Ca2⫹ current, and then at the start of neurulation, the
inwardly rectifying K⫹ current (51, 208). These experiments were part of a larger study of ion channel development in the muscle cells of this embryo.
Taking advantage of the endogenous pigment that
marks muscle-lineage cells in this embryo, we used perforated patch methods to voltage clamp muscle-lineage
cells at all stages of development. In the gastrula, these
cells are inexcitable and express only an inwardly rectifying K⫹ current, which is their sole resting conductance.
This inexcitability, reflecting as it does a complex history
starting at fertilization during which these cells have lost
their previously acquired depolarization-activated currents, emphasizes that electrophysiological studies that
commence at the start of their terminal differentiation can
miss a complex preceding history of ion channel development.
A few hours after gastrulation, three simultaneous
events occur that dramatically change the electrical properties of these cells (129, 208). 1) The inward rectifier
disappears, leaving the cells with almost no detectable
resting conductance. 2) A high-threshold, inactivating calcium current appears and rapidly reaches much higher
density than found in the oocyte. 3) A slowly activating,
voltage-gated delayed K⫹ current appears for the first
time in development. If transcription or translation is
blocked, the Ca2⫹ and outward K⫹ currents fail to appear,
whereas the inward rectifier disappears normally. This
combination of events causes the cells to become excitable and, because of the loss of their resting conductance,
spontaneously active.
Physiol Rev • VOL
This period of spontaneous activity ends because of
two near-simultaneous events that occur 6 – 8 h after the
inward rectifier disappears. The inward rectifier reappears (an event that requires transcription), and a rapidly
activating, Ca2⫹-activated K⫹ current appears for the first
time in the development of the cells. These two events
terminate spontaneous activity and shorten the duration
of the action potential by ⬃10-fold. In addition, a new
Ca2⫹ current appears at this time and increases rapidly in
density to contribute ⬎80% of the total Ca2⫹ current. It
can be distinguished from the immature Ca2⫹ current
present at earlier stages by voltage dependence (20 mV
more positive), lack of inactivation, and differential conotoxin sensitivity (129).
If spontaneous activity is blocked, the cells fail to
develop the rapidly activating Ca2⫹-activated K⫹ current,
and as a result, the action potential fails to acquire the
short duration required for the mature contractile function of the muscles in larval swimming (129). These results contrast somewhat with Xenopus spinal neurons, in
which action potential shortening occurs normally when
activity is blocked (45). This is probably because in Xenopus neurons, K⫹ current speeding and increased density are two separable phenomena. In ascidian muscle,
however, the increase in density is due to the expression
of a new, more rapidly activating K⫹ current, so the two
are linked.
We next asked to what extent the channels present in
immature and mature muscle are optimized for their particular functions. Immature muscle generates bursts of
spontaneous activity but has no need to respond to neural
input, since the nervous system has no neuromuscular
connections at these stages and the muscle cells are not
yet contractile. Activity is serving a purely developmental
function. Mature muscle has very different requirements.
It must respond to neural input and be able to contract
at 10 Hz or more to mediate larval swimming, which
is essential for dispersion and maintenance of genetic
diversity.
To ask how channels at each stage are optimized for
these functions, we used action potential waveform
clamp (386). In this method, action potentials or bursts of
spontaneous activity are recorded from cells under normal conditions, and then are digitized and replayed into
cells as voltage-clamp commands. We replayed these
waveforms into cells of the same and different stages than
those that generated them. The utility of the method
derives from the fact that the waveforms are replayed into
cells under conditions that isolate the voltage-gated Ca2⫹
currents (e.g., intracellular Cs⫹). The current flowing during an action potential or activity waveform command
under these conditions (after leak and capacitative current subtraction) represents the Ca2⫹ current flowing during activity, and thus the flux of Ca2⫹ into the cell.
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One of the major functions of spontaneous activity in
ascidian muscle is to trigger the later expression of the
Ca2⫹-activated K⫹ current, which shortens action potential duration and helps to terminate the period of spontaneous activity. This is discussed in the next section. Activity-blocked cells also fail to organize their actin filaments properly and are only minimally contractile
compared with normal muscle.
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WILLIAM J. MOODY AND MARTHA M. BOSMA
Physiol Rev • VOL
expression of mature ion channels that terminate the
activity. This principle is expanded on in section V.
M. Insect Neurons and the Refinement of
Dendritic Trees During Metamorphosis
Some motor neurons in insects are preserved during
metamorphosis, and their structure and connections are
remodeled to serve new functions (587). In Manduca
motor neuron, MN5 innervates slow crawling muscle in
the larva and fast flight muscle in the adult. In making this
transition, MN5 acquires a higher firing threshold and
much decreased excitability to make the transition from a
tonically firing slow motor neuron to one that fires only
once or twice per wingbeat during flight. This is accomplished by an 80% decrease in resting resistance combined
with a large increase in the magnitude of voltage-gated K⫹
currents (155). Like most insect neurons, the soma of
MN5 does not generate full-size action potentials at either
the larval or adult stages. However, for a brief period in
pupal life, the soma can generate action potentials, and
does so spontaneously. The development of Ca2⫹ currents is coordinated with these changes. A small, sustained Ca2⫹ current is expressed in larval MN5, but disappears by early pupal stages. Then, at the time of soma
excitability and spontaneous firing, a large Ca2⫹ current
with both transient and sustained components appears,
which is maintained into adulthood. Soma excitability is
eliminated after the pupal stages by a large increase in
outward K⫹ currents. Some excitability could be restored
by blocking these K⫹ currents. Although the developmental role of spontaneous activity is unclear in this cell, the
period during which it occurs correlates with the end of a
period of extensive dendritic remodeling and branch
growth. Ca2⫹ imaging experiments indicate that during
the period of dendrite extension, local dendritic [Ca2⫹]i
transients occur, suggesting a localization of Ca2⫹ channels in dendritic compartments. At the end of the period
of dendritic growth, soma activity appears and Ca2⫹ transients now are generated throughout the cell (156).
This work emphasizes that large, transient changes in
firing properties may occur in particular compartments of
individual cells during development. It would be interesting to know whether transient periods of excitability are
a general property of developing arthropod neuronal somata, which are generally inexcitable in the adult. It is
known that normally passive, nonspiking crayfish neuronal somata become capable of generating action potentials after axotomy (315).
N. Mammalian Muscle and Activity-Dependent
Fusion of Myoblasts
During development of vertebrate skeletal muscle,
mononucleated myoblasts fuse into multinucleated myo-
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Using this strategy, we reached the following conclusions (130).
1) Long-duration immature action potentials do not
admit more Ca2⫹ to the cell than short-duration mature
action potentials, because during development the amplitude of Ca2⫹ current increases in exact proportion to the
decrease in action potential duration. Ca2⫹ influx during
long-duration immature action potentials, however, is
spread over a much longer period of time. Part of this is
due to the obvious fact that the action potential is simply
longer. Part is due to the fact that the immature, inactivating Ca2⫹ channels reopen in transiting from the inactivated to the closed states (547), thus creating a
postspike burst of Ca2⫹ entry at voltages where driving
force on Ca2⫹ is high.
2) During bursts of spontaneous action potentials in
immature cells, Ca2⫹ enters the cells almost continuously,
including during the period between individual action
potentials. This is due to the more negative voltage dependence of the immature Ca2⫹ current compared with
the mature one. The potentials at which the former is
activated but the latter would not be falls precisely in the
range of potentials of the interspike voltage trajectory
during spontaneous activity. Shifts in channel voltage dependence are common in development (see sect. IVA).
3) The burst length of spontaneous activity is set by
accumulating inactivation of the immature Ca2⫹ current.
If brief voltage-clamp commands mimicking spontaneous
action potentials are delivered at burst frequencies, the
Ca2⫹ current declines by 50% by the end of a burst equal
in action potential number to the average burst of spontaneous activity. Blocking inactivation by using Ba2⫹ as
the permeant ion eliminated this effect. Bursts of action
potentials in mature cells did not cause accumulating
inactivation of the mature Ca2⫹ current. The lack of inactivation of the mature Ca2⫹ current, in contrast, allows
rapid repetitive firing, essential for rapid contraction relaxation cycles in larval swimming.
4) The increased amplitude and activation rate of the
composite outward K⫹ current in mature muscle restricts
Ca2⫹ entry to the brief duration of the spike itself, guaranteeing rapid relaxation of muscle after activation.
The work on ascidian muscle emphasizes the concept that many properties of the ion channels present at
each stage of development are finely tuned to mediate
specific patterns of spontaneous activity that occur at that
point in development. We also see in these cells the
complex transition between immature and mature electrical properties, critical to the cell because the properties
of ion channels present in the immature state are not
compatible with mature function. An important, and probably generally applicable, concept arising from this work
is the feedback between embryonic ion channels, spontaneous activity, and mature ion channels. Embryonic channels regulate spontaneous activity, which in turn triggers
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
O. Amphibian Muscle and Multiple Windows
of Activity-Dependent Development
In embryonic Xenopus muscle, the delayed K⫹ current develops in two phases, with a multi-hour lag between two periods of increasing density (339). The inward
Na⫹ current continues to increase in density during this
lag, suggesting a period of increased excitability due to
the temporary increase in inward-to-outward current ratio. Blocking the Na⫹ current during this time suppresses
the second phase of K⫹ current development, implying
the existence of spontaneous activity at those stages,
although it was never directly measured (339). Activity
block also suppresses development of the inwardly rectifying K⫹ channel.
Results like these would normally be interpreted to
indicate that the second phase of delayed K⫹ current
development depends on activity, whereas the first phase
does not, since it was not affected by blocking activity.
There is a problem with this interpretation, however.
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Because the first phase of K⫹ current development occurs
before any inward currents are present, there is no activity to block. Thus it is possible that both phases could
depend on activity, but only the second phase does so
normally because that is when activity is possible. To test
this idea, we expressed a mammalian brain Na⫹ channel
in developing muscle to create spontaneous activity at
abnormally early stages and indeed found that the first
phase of development of the endogenous delayed K⫹
current was advanced to earlier stages (as was development of the inward rectifier) (338). This emphasizes the
point that developmental events may be responsive to
activity even if activity does not normally occur at those
stages. Blocking endogenous activity will not reveal this.
Although this “latent” activity dependence may not operate under normal circumstances, it may under pathological conditions, such as the early occurrence of seizure
activity in the developing brain, or the exposure to excitatory pharmacological agents.
P. Cajal-Retzius Cells, Rohon-Beard Neurons,
and Activity-Dependent Cell Death
A large body of literature has demonstrated that electrical activity and depolarization enhance the survival of
embryonic neurons, leading to the hypothesis of selective
survival of neurons that successfully make synaptic connections and thus participate in activity (466). Activity
does not always promote survival of developing neurons,
however. In two populations of temporary neurons that
undergo programmed cell death as populations, zebrafish
Rohon-Beard neurons, and mammalian Cajal-Retzius neurons, there is evidence for excitotoxic effects of spontaneous activity. In Cajal-Retzius cells, in vivo application of
NMDA blockers protects against normal apoptosis (405).
In culture, cell death is prevented by TTX or AMPA receptor blockers, but not by NMDA receptor blockers
(137). The discrepancy between these two results may be
a species difference (rat vs. mouse) or the choice of
NMDA blockers (Mienville and Pesold used a noncompetitive antagonist and Del Rio et al. a competitive blocker).
In zebrafish Rohon-Beard neurons, blocking activity by
eliminating Na⫹ currents either pharmacologically or genetically reduces cell death (573).
In both types of neurons, early activity-dependent
apoptosis may be related to their unique configuration of
ion channels expressed at early stages compared with
neighboring neurons. Cajal-Retzius neurons upregulate
NMDA receptors markedly between E18 and P11, and
during these stages they have significantly more positive
resting potentials than non-Cajal-Retzius neurons (405). It
is not clear what channels mediate the more positive
resting potential. Their resting potentials are in the range
that can remove the voltage-dependent Mg2⫹ block of the
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tubes. The fusion process is driven by a specific change in
membrane potential determined by the coordinated activity of three types of ion channels (37, 41, 179, 342). As part
of the program to achieve competence to fuse, myoblasts
hyperpolarize to a membrane potential of around ⫺65
mV. This hyperpolarization is achieved in two stages, due
to the effects of newly expressed EAG and Kir 2.1 channels. Just before fusion, T-type (␣1H) Ca2⫹ channels are
expressed by the myotubes. The K⫹ channel-mediated
hyperpolarization brings the membrane potential into the
range for the “window current,” the steady Ca2⫹ current
generated through the T-type Ca2⫹ channel at potentials
at which its activation and inactivation versus voltage
curves overlap. At these potentials, T-type channels open
but do not inactivate completely. The window Ca2⫹ current thus generated provides a steady influx of Ca2⫹ into
the cell. This increases [Ca2⫹]i, which is the primary
trigger for fusion. It is not entirely clear whether the
membrane potential is held in this range for window
currents during fusion, but since TTX does not block
fusion, Na⫹-dependent action potentials are not required.
Thus Ca2⫹ entry occurs in the absence of action potentials, using the outward K⫹ current to balance Ca2⫹ influx,
allowing the steady entry of Ca2⫹ at high driving force.
Similar mechanisms allow hair cells to generate rapid
membrane potential oscillations in response to high-frequency sound, and allow crustacean slow muscle fibers to
generate large, graded Ca2⫹ entry for graded contractility
(12, 173, 419, 420).
T-type currents are especially prominent at early
stages of development in a variety of cells. Their potential
roles in shaping spontaneous activity and Ca2⫹ influx are
discussed in section IVD1.
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WILLIAM J. MOODY AND MARTHA M. BOSMA
Q. Summary
Several common themes emerge from the above
studies of spontaneous activity.
Activity tends to occur as bursts of action potentials
with long interburst intervals. For most cells studied,
interburst intervals are between ⬃1 and 20 min. The
exceptions appear to be in two sensory systems, DRG
cells and cochlear hair cells, where action potentials occur in steady patterns with frequencies of 0.5–10 Hz.
There may, however, be longer-interval patterns to these
high frequencies, which approximate the interburst intervals in other cell types. It is very interesting that imposed
stimulus intervals for either [Ca2⫹]i transients or action
potential bursts of ⬃1/min are particularly effective at
triggering various downstream events such as specific
gene expression (see sect. IIIA2).
Establishing such long intervals is likely to involve
some kind of long-term depression or inactivation that
affects synaptic transmission, voltage-gated ion channels,
ion concentration gradients, or all three. Studies in spinal
cord neurons, retinal ganglion cells, and ascidian muscle
support this idea.
Spontaneous activity is often synchronous among
populations of cells. Synchronicity among small clusters
of cells, sometimes created by spread of waves of activity
across a tissue, is likely to encode spatial information to
downstream targets or to coordinate other developmental
events among contiguous cells.
Spontaneous activity is quite robust under conditions
in which circuitry is changing. This is seen in many different ways. In ascidian muscle and Xenopus neurons,
activity persists even in individual, isolated cells. In cortex and retina, activity can be reestablished in dissociated
cultures (234, 467, 602), although it is possible that the
Physiol Rev • VOL
activity may be different in some respects from that in
situ. In retina and spinal cord, activity persists during
periods of development when significant changes in the
synaptic circuitry and transmitters occur. Finally, in spinal cord at least, activity is reestablished during chronic
application of receptor blockers that initially suppress
activity. [This latter property is reminiscent of mature
motor pattern generators, such as the crustacean stomatogastric ganglion, in which activity reemerges after initially being suppressed by eliminating neuromodulatory
input (202).]
Spontaneous activity regulates a wide variety of developmental processes at all stages. For example, it is
now clear that as central axons grow, navigate, and prune,
an intricate series of regulatory events occurs involving
trophic factors, neuroattractant and repulsive molecules,
electrical activity, and intracellular second messenger levels. Pruning of inappropriate connections and strengthening of appropriate synaptic connections is only one of the
later activity-dependent events in this process.
As discussed in section III, many but not all of the
effects of activity are mediated by Ca2⫹ entry through
voltage- and ligand-gated channels. And many, but not all,
involve specific gene expression triggered by Ca2⫹-dependent second messenger systems.
Finally, as discussed at length in sections IV and V,
spontaneous activity relies on combinations of voltageand ligand-gated ion channels and electrical and chemical
synaptic circuitry that are unique to those stages of development. These serve dual roles. The first is to generate
the appropriate patterns of electrical activity needed to
trigger activity-dependent developmental programs. The
second is to ensure the correct magnitude, frequency, and
spatial distribution of Ca2⫹ entry during that activity.
Ca2⫹ entry is regulated both by the Ca2⫹-permeable channels themselves and by their responses to the voltage
profile of activity as shaped by other, non-Ca2⫹-permeable
channels.
III. HOW SPONTANEOUS ACTIVITY CARRIES
OUT ITS DEVELOPMENTAL FUNCTIONS
The wide variety of developmental events that spontaneous activity initiates are nearly all secondary to the
Ca2⫹ influx during the activity. In many cases the resulting transient increases in [Ca2⫹]i are linked to the expression of specific genes. In other cases, Ca2⫹ activates
cytoskeletal elements or exocytosis to carry out its developmental roles. The variety of activity-dependent developmental events and the feedback loops that connect
them are discussed in sections III, IV, and V and are summarized in Figure 1.
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NMDA receptor, thus promoting tonic Ca2⫹ influx. Ca2⫹
influx may be further promoted by the early expression of
repetitive firing ability in these cells. Voltage-clamp studies combined with single-cell RT-PCR show that CajalRetzius neurons express Na⫹ currents of the Nav1.3 isoform very early in development, by E12 (5). Voltage-clamp
measurements on neonatal Cajal-Retzius cells show that
they express the pacemaker current Ih and repetitive
firing ability earlier than other cortical neurons (287, 360).
Finally, excitatory GABA responses persist in CajalRetzius cells much later than in other cells, presumably
because they show delayed expression of the KCC2 chloride pump (400).
Rohon-Beard neurons show the same delayed switchover to inhibitory GABA action (505), and additionally
have been shown to have a different incidence and pattern of spontaneous [Ca2⫹]i transients at early stages (65).
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
911
A. Role of [Ca2ⴙ]i Transients
Nearly all activity-dependent developmental events
that involve gene expression are triggered initially by
Ca2⫹ influx and the resulting transient increases in
[Ca2⫹]i. The responses of cells to [Ca2⫹]i transients are
determined by their amplitude, frequency, pathway of
entry, and spatial location.
1. Amplitude
Obviously, enough Ca2⫹ must enter the cell to trigger
the appropriate downstream events. For example, many
instances of activity-dependent development rely on
Ca2⫹-induced Ca2⫹ release from internal stores (CICR)
(249), which requires a threshold amount of Ca2⫹ entry to
occur. Usachev and Thayer (590, 591) have clearly shown
such a threshold behavior of CICR in DRG neurons,
where a difference between seven and nine action potentials in a single burst crossed the threshold Ca2⫹ entry
required for CICR and resulted in a fivefold increase in the
Physiol Rev • VOL
amplitude of the [Ca2⫹]i transient. Thus the structure of
spontaneous bursts may be tightly controlled so that this
threshold is reliably crossed. Triggering sufficient CICR
may be important to initiate regenerative [Ca2⫹]i waves
(60), perinuclear Ca2⫹ “puffs” (340), or [Ca2⫹]i waves that
propagate over the cytoplasm to engulf the nucleus (588),
to create nuclear Ca2⫹ transients that can activate specific
transcriptional events (see Refs. 100, 232). The dual tasks
of the CICR system in this context are to avoid spurious
Ca2⫹ release, or “noise,” and to maintain a safety factor
that ensures that Ca2⫹ entry, even during low-frequency
spontaneous activity, is securely able to trigger CICR. The
IP3-releasable store uses cooperative IP3 plus Ca2⫹ binding and IP3 receptor inactivation to guard against inappropriate release of Ca2⫹ into the cytoplasm (366). The
CICR system in developing Xenopus neurons has a very
high safety factor, such that reductions of Ca2⫹ influx
during activity of up to 100-fold only reduce the [Ca2⫹]i
transient in the nucleus by less than 2-fold and the [Ca2⫹]i
transient in the cytoplasm by less than 5-fold (see Fig. 4 in
Ref. 249).
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FIG. 1. Diagram of the wide variety of developmental events triggered by spontaneous activity. The blue boxes at the top indicate events that
are not linked to the influx of Ca2⫹ during activity, but rather directly to changes in membrane potential or increases in [Na⫹]i. Red dashed lines
and arrows indicate negative-feedback loops. Green dashed lines and arrows indicate positive-feedback loops.
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WILLIAM J. MOODY AND MARTHA M. BOSMA
2. Frequency
Encoding the frequency of activity into the amplitude
of a downstream response requires some sort of molecular integration mechanism, many of which exist in developing nerve and muscle. The simplest integrator is the
membrane time constant, which is long in many immature
cells due to their high input resistance (see sect. IVD3),
combined with the slow kinetics of many immature ligand-gated channels (see sect. IV, A and B). The next level
of integration comes in the form of summation of [Ca2⫹]i
transients during repetitive action potentials, because the
rise and fall of [Ca2⫹]i is slow compared with the voltage
transient of the action potential. Longer time integration
occurs in this system because the [Ca2⫹]i transient caused
by CICR has a much longer duration than the transient
caused by Ca2⫹ entry during the burst (see Fig. 2 in Ref.
591). Secondary to either type of [Ca2⫹]i transient are
cascades of second messenger systems whose responses
long outlast the transients themselves, and thus provide
temporal amplification of the initial response. These can
create a 10-fold or more amplification of the time course
of the initial [Ca2⫹]i transient, even at the level of the first
stage of protein kinase activity (407, 623).
In addition to this kind of simple integration based on
the progressively slower kinetics of processes downstream of Ca2⫹ entry, other specific properties of various
second messenger systems create even more long-lasting
“memories” of activity in very few molecular steps. Three
examples illustrate these kinds of processes. First, cooperative autophosphorylation of CaMK occurs at high levels of calmodulin (CaM) occupancy, rendering CaMK constitutively active even after CaM dissociation (160, 229).
This can create long-lasting increases of CaMK activity
during low-frequency [Ca2⫹]i transients. Second, proPhysiol Rev • VOL
tease, kinase, or phosphatase activity can similarly create
constitutively active second messengers. This is seen, for
example, in the Ca2⫹-dependent cleavage by calpain of
protein kinase C (PKC) (572). Third are physical translocation processes, such as the movement of CaM into the
nucleus under the influence of [Ca2⫹]i (126, 334), which
can have a “priming” effect so that normally slow responses to [Ca2⫹]i transients become more rapid when
the [Ca2⫹]i transients are repeated (395). Another example of translocation is the NF-ATc transcription factor,
which in hippocampal neurons moves to the nucleus on
Ca2⫹ entry under the influence of the phosphatase calcineurin, which unmasks nuclear localization sequences
on the protein. This results in a residence of NF-ATc in
the nucleus for more than 2 h after a 3-min depolarization
of the cell (206).
By integrating and encoding even very low frequency
spontaneous activity using these, and other as yet undiscovered mechanisms, developing neurons and muscle
cells have established a set of developmental responses
that are finely tuned to both the frequency and temporal
patterns of spontaneous activity (see Ref. 82 for review).
These responses often show not only the ability to create
long-lasting changes in gene expression triggered when
the frequency of activity rises above a certain value, but
the further ability to frequency tune different responses to
different frequencies, or different patterns, of activity.
This kind of frequency tuning has been known for some
time in the control of fast- and slow-twitch skeletal muscle, where cross-innervation can modify contractile properties to be appropriate for the identity of the innervating
motor neuron. Stimuli delivered in patterns appropriate to
the innervating motor neuron can mimic the effects of
cross innervation on muscle gene expression (157). Expression of different cell adhesion molecules depends on
the frequency of activity in DRG neurons, as discussed in
section IIJ. In T lymphocytes, activation of the transcription factors NFAT, Oct/OAP, and NF␬B by [Ca2⫹]i transients is sharply tuned to transient frequencies near 1/min
(149, 332). Optimal frequencies of near 1/min have been
reported in several other systems. In DRG neurons, for
example, MAPK activation, CREB phosphorylation, and
c-fos expression are all triggered more efficiently by
bursts of action potentials delivered at 1-min intervals
than they are by the same number of action potentials at
steady frequency (175, 537). BDNF release from hippocampal neurons (see below) is best triggered by brief
high-frequency bursts at 20-s intervals (14). This optimization of responses at near 1/min burst frequencies is
particularly interesting because spontaneous, synchronous bursts of action potentials and/or [Ca2⫹]i transients
occur at those frequencies in developing retina, hindbrain, hippocampus, and cortex (see sect. II).
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Other processes downstream of Ca2⫹ entry are
graded with the amplitude of the [Ca2⫹]i transient. So, for
example, the amount of calmodulin translocation to the
nucleus, which is critical in activity-dependent gene expression (395), is controlled by [Ca2⫹]i in a graded manner in the physiological range of 0 – 600 nM [Ca2⫹]i (334).
Amplitude of the initial [Ca2⫹]i transients may also determine the identity of the downstream second messenger
pathways that are activated. Wu et al. (622) showed that
large increases in [Ca2⫹]i in hippocampal neurons (triggered by a brief KCl depolarization) result in CREB phosphorylation lasting more than 1 h. This long-lasting response was triggered by sequential activation of a fast
calmodulin kinase (CaMK) pathway followed by a slower,
but longer lasting, mitogen-activated protein kinase
(MAPK) activation. Smaller amplitude [Ca2⫹]i transients,
however, triggered only the CaMK pathway and resulted
in more transient CREB phosphorylation.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
3. Physical pathway of Ca2⫹ entry
Physiol Rev • VOL
gene expression (100, 231, 232). CREB phosphorylation
itself may be mediated by both nuclear Ca2⫹ and by
second messenger pathways activated by submembrane
Ca2⫹ (230, 395). In some activity-dependent genes, such
as BDNF, multiple upstream regulatory elements may
respond to different aspects of activity (103, 104, 583). In
addition, the specific linkage between L-type Ca2⫹ channels may be malleable with activity. Following initial CaM
translocation to the nucleus under the influence of Ca2⫹
entry through L-type channels in hippocampal neurons,
additional stimuli that closely follow the first one induce
CREB phosphorylation that is quicker than the first and
less dependent on L-type Ca2⫹ channels (395).
Complicating the issue of specific communication
between channel types and intracellular messenger pathways leading to gene transcription are two additional
factors: differences among cell types and different stimulus paradigms. For example, CaM translocation to the
nucleus following L-type Ca2⫹ channel activation is more
pronounced in hippocampal neurons than in dentate gyrus neurons, probably related to the tonic levels of CaM in
the nucleus in the absence of stimulation (395). The stimulus used to depolarize the cell is also very critical in
judging the conclusions drawn about channel specificity.
In petrosal ganglion neurons, patterned electrical stimuli
and tonic depolarization by KCl both induced activitydependent gene expression similarly, and as expected the
effect of patterned electrical stimuli was blocked by TTX,
whereas that of KCl depolarization was not. Less expected, however, was the finding that the effects of KCl
depolarization required L-type Ca2⫹ channels but those of
patterned electrical stimuli required N-type Ca2⫹ channels. This emphasizes that KCl depolarization is not a
physiological stimulus and its tonic nature may inactivate
channels such as the N-type Ca2⫹ channel and thus prevent assessment of its participation in activity-dependent
events (78). Further studies showed that the two types of
stimuli activated gene expression using different patterns
of second messenger pathways (78, 79). Although this
kind of problem clearly does not explain all results indicating channel specificity (see, e.g., Refs. 134, 394), it does
emphasize that an unphysiological stimulus paradigm
may preferentially activate channel types that are not the
ones used under physiological conditions. In other cell
types, P/Q-type Ca2⫹ channels preferentially activate gene
expression over N-type channels, relying on carboxy-terminal sequences (569), and possibly on their selective
coupling to different intracellular Ca2⫹ stores (521). The
confounding effects of stimulus specificity has also been
raised in hippocampal neurons by experiments of Hardingham et al. (233). These experiments showed that
NMDA channel activation was equally effective as L-type
Ca2⫹ channel activation in stimulating CREB activity and
BDNF expression, contrary to some previous results (e.g.,
Refs. 196, 231). This discrepancy is due to the use of
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Many experiments have shown that the route
through which Ca2⫹ enter the cell determines the patterns
of gene expression triggered by activity. The L-type Ca2⫹
channel and the NMDA receptor are particularly effective
pathways for activity-mediated transcriptional events involving CREB phosphorylation (for reviews, see Refs.
136, 611). Thus synaptic stimuli are much more effective
in hippocampal neurons in triggering nuclear CREB phosphorylation than action potentials evoked antidromically,
because synaptic events preferentially activate both Ltype Ca2⫹ channels and NMDA receptors (134, 394). Ltype Ca2⫹ channel blockers preferentially block CaM
translocation to the nucleus in hippocampal neurons following depolarization (135, 395) and the tonic phase of
CREB phosphorylation following depolarization of cortical neurons (148). The preferential linkage of the L-type
channel to CREB phosphorylation and CRE-dependent
transcription occurs even when several other Ca2⫹ channel types contribute to the [Ca2⫹]i transient caused by
activity (148). L-type Ca2⫹ channels are also linked to
activation of the transcriptional domains of upstream regulatory factors that cooperate with CREB in activation of
BDNF transcription (103) and to the translocation of
NF-AT transcription factors to the nucleus (206). Similar
preferential block of activity-mediated transcriptional
events is seen for the NMDA receptor (135, 233). This
specificity is not related to differences in the global cytoplasmic [Ca2⫹]i transients created by Ca2⫹ entry through
different channels. In hippocampal neurons CREB phosphorylation is sustained following Ca2⫹ influx through
L-type Ca2⫹ channels, but transient after influx through
NMDA receptors, a difference which remains when the
different stimuli are adjusted so that both events produce
the same [Ca2⫹]i transient (231). Furthermore, blocking
the global cytoplasmic [Ca2⫹]i transient with a slow Ca2⫹
buffer that leaves the submembrane microdomain [Ca2⫹]i
transient in place does not prevent activity-dependent
transcriptional events following stimuli that activate Ltype Ca2⫹ channels and NMDA receptors (134, 230). The
preferential linkage between L-type Ca2⫹ channels and
CREB phosphorylation relies on a combination of the
interaction of the “IQ motif” in the ␣1C subunit with
calmodulin (148) and a PDZ interaction sequence at the
carboxy terminus of the same subunit (608). A similar
situation exists for the NR1 subunit of the NMDA receptor
(see Ref. 116 for review).
The linkage between these specific channels and
transcriptional events is by no means simple or absolute.
Evidence in AtT20 cells and hippocampal neurons indicates that rapid nuclear [Ca2⫹]i transients not linked to
Ca2⫹ entry through specific channel types may be required to activate CREB binding protein which participates along with CREB phosphorylation in activating
913
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WILLIAM J. MOODY AND MARTHA M. BOSMA
bath-applied glutamate, as opposed to synaptic stimulation, to activate NMDA receptors. Bath glutamate also
activates nonsynaptic NMDA receptors, which trigger a
CREB shutoff pathway. Activation of NMDA receptors
can also serve to refill intracellular Ca2⫹ stores in preparation for subsequent release by other triggers (588).
4. Spatial distribution of Ca2⫹ entry
B. Developmental Regulation of Intracellular Ca2ⴙ
Stores and Buffering
Superimposed on all of the above patterns of [Ca2⫹]i
transients are developmental changes in intracellular
Ca2⫹ release mechanisms. Ca2⫹ release mechanisms
show rapid and regionalized developmental changes
(166), and developmental changes in both Ca2⫹ release
mechanisms and Ca2⫹ buffering molecules are influenced
by activity (69, 398).
C. Release of Developmentally Active
Neurotransmitters
Not all effects of activity are mediated by the actions
of [Ca2⫹]i transients on gene expression. In addition to
rapid effects of [Ca2⫹]i on cell motility (see, e.g., Ref. 319),
increases in [Ca2⫹]i can trigger secretion of developmenPhysiol Rev • VOL
D. Neurotrophins as Major
Activity-Dependent Pathway
Neurotrophins are one of the most important class of
molecules whose secretion and action are controlled by
spontaneous activity. They are involved in complex feedback loops in the developing nervous system and are
major players in mediating activity-dependent developmental phenomena (see Ref. 585 for review). As discussed
above, the transcription of BDNF is triggered by patterned electrical activity and [Ca2⫹]i transients, as is the
transcription of other neurotrophins (356). In addition,
BDNF secretion is stimulated by activity, and preferentially by certain patterns of activity (patterned bursts as
opposed to tonic depolarization or steady firing) that
mimic the patterns of spontaneous activity recorded in
many areas of the CNS (50-Hz bursts lasting 2 s repeated
every 20 s) (14, 15; see also Refs. 8, 50). Furthermore,
electrical activity can induce expression of the trk neurotrophin receptors (8, 42), thus providing a mechanism by
which neurotrophins selectively affect electrically active
neurons (383).
The multiplicity of interactions between spontaneous
activity and neurotrophins creates the possibility of complex autocrine and paracrine feedback loops in the developing nervous system, and indeed such feedback loops
appear to be widespread. In hippocampal pyramidal neurons, activity-dependent Ca2⫹ entry through L- and Q-type
Ca2⫹ channels increases the number of calbindin-positive
neurons that develop, an effect that is mediated by secretion of NT-3 and its activation of trkC receptors (68). A
similar autocrine feedback loop involving BDNF probably
regulates neurite extension during development of embryonic cortical neurons (196) and DRG neurons (625).
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Activity-dependent developmental events not only
depend on how much, how often, and how Ca2⫹ enters
the cell, but on where it enters as well. In addition to the
“microdomains” of Ca2⫹ entry, where complexes of channel proteins and intracellular signaling molecules exist
(see above; Ref. 46), the gross spatial distribution of Ca2⫹
entry is tightly regulated during development and allows
distinct developmental functions to be carried out by
different types of activity simultaneously within the same
cell. Good examples of spatially localized [Ca2⫹]i transients are seen in Xenopus spinal neurons and insect
motor neurons, as discussed in section II, K and M.
Although these local [Ca2⫹]i transients often act via
local signal transduction pathways to affect processes
such as growth cone motility, local action does not necessarily preclude the involvement of new gene expression. Local [Ca2⫹]i transients can affect nuclear events at
a distance (see above). In long-term synaptic plasticity,
local transmitter action even at distant synaptic terminals
can trigger gene expression, and the products of that
expression can act specifically at the terminals that initiated the events because of a process of “tagging” that
occurs when the terminals are initially activated (377). If
homologous processes exist in developing neurons, then
local [Ca2⫹]i transients could trigger local developmental
events that depend on global gene expression.
tally active molecules. In many cases these molecules are
transmitters, which in early development have profound
neurotrophic actions on cell proliferation, migration, and
other processes (31, 32, 355; see Refs. 34, 469, 470 for
reviews). In addition to demonstrating the developmental
effects of exogenously applied neurotransmitters such as
GABA and glutamate, it has been shown in many cases
that receptors for those transmitters are tonically activated in developing neurons by endogenously released
agonists (48, 49, 180, 181, 300, 354, 355, 592; see Refs. 469,
470 for brief reviews). Evidence for endogenous activation is seen, for example, in migrating granule neurons of
the cerebellum, where the frequency of opening of NMDA
channels increases as cells enter the migratory phase
(507). In some cases, these transmitters may be released
in a nonsynaptic, activity-independent manner (see, e.g.,
Ref. 138), but in others their presence may be regulated by
vesicular release and possibly by electrical activity in
growing axons (see, e.g., Ref. 396).
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
E. Relationship Between Synaptic Plasticity
in the Adult and Developing Nervous Systems
The close relationship between developmental and
adult neuronal plasticity has been appreciated for some
time (276), but recent studies have brought this relationship into clearer focus (see Refs. 435, 555). Much of this
work focuses on the apparent paradox of “silent synapses” early in development, as discussed above in section II, D and E. This work raises the possibility that one
role of widespread synchronous activity in the CNS is to
Physiol Rev • VOL
provide pairing of pre- and postsynaptic activity to
strengthen appropriate synaptic connections during development. As discussed in section IIC, evidence exists in
the retinotectal system of amphibians that pairing of inputs to tectal neurons, possibly as a result of spontaneous
activity, can trigger long-term increases in synaptic efficacy. Constantine-Paton and Cline (117) provide a critical
review of the differences between adult and developmental forms of plasticity.
IV. SOME PRINCIPLES OF HOW ION
CHANNELS DEVELOP TO REGULATE
SPONTANEOUS ACTIVITY
The studies of ion channel development in the cells
discussed above suggest some important general principles that govern how ion channel development is related
to spontaneous activity. We summarize these principles in
general form here, and then in the rest of this section
review examples of how they are applied in a variety of
cells.
Developing neurons (and muscle cells, and probably
other cell types as well) pass through at least one transient state during which their firing properties are different from the mature state. During this time, spontaneous
activity is favored. This temporary state is created by the
transient occurrence of a different configuration of ion
channel expression than that found at maturity, and in
some cells by a transient pattern of synaptic interactions
that are different from those found at maturity.
Differences in the function of immature ion channels
may be created by differences in the intrinsic properties
of channels, in the concentration gradients of permeant
ions, in the timing of expression of some channel types
relative to others, in the spatial distribution of channels,
or in the coupling of channels to intracellular events.
The pattern of channel expression at stages during
which spontaneous activity occurs is optimized to produce the correct patterns of activity in the context of the
synaptic circuitry that exists at those stages (if any does
exist), and to ensure the appropriate magnitude, kinetics,
physical pathway, and spatial distribution of Ca2⫹ entry
during that activity to trigger downstream developmental
programs.
The properties created at early stages to carry out
these functions are unlikely to be compatible with the
mature functions of the cell, so the transition between the
immature and mature patterns of ion channel expression
is critical.
This transition is mediated in part by making the
expression of certain mature ion channels dependent on
the spontaneous activity created by the immature ion
channels.
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One of the more intriguing feedback systems involves BDNF effects on the development of GABAergic
transmission, which appears to involve both positive- and
negative-feedback loops that change rapidly with development. During stages when GABA is excitatory, due to
high intracellular chloride concentration (see sect. IVC),
GABA can stimulate BDNF expression in a variety of
neurons, an effect that disappears as GABA converts to an
inhibitory transmitter (38, 447). During these stages,
BDNF can acutely increase GABA miniature end plate
current frequency, thus creating a positive-feedback loop
(447). But BDNF also stimulates expression of the KCC2
Cl transporter, which exports chloride ions and converts
GABA to an inhibitory transmitter, thus terminating its
ability to stimulate BDNF expression (3).
Because ion channels and [Ca2⫹]i transients show
complex spatial distribution within developing neurons, it
is not surprising that interactions between electrical activity and neurotrophin effects can be heterogeneous
within single cells. In cortical pyramidal neurons, for
example, spontaneous action potentials support BDNF
effects on apical, but not basal, dendritic growth (383).
Completing one of the many feedback loops between
neurotrophins and electrical activity and its resultant
Ca2⫹ entry are effects of neurotrophins on various ion
channels. In cortical neurons, NT-3 application (but not
other neurotrophins) causes a prolonged stimulation of
the Ca2⫹-activated K⫹ current (250). BDNF, on the other
hand, rapidly excites cortical, hippocampal, and cerebellar neurons at very low concentrations (273), an effect
mediated by the Nav1.9 sodium channel (53). In BDNF
knockout mice, the development of repetitive firing ability
in retinal ganglion neurons is substantially delayed due to
late upregulation of the Na⫹ current (510), which would
likely have a profound impact on activity-dependent wiring in the retina-LGN circuit. An intriguing compensatory
action of neurotrophins acting in a paracrine manner is
seen in Xenopus neuromuscular synapses (441). In this
system, blockade of neuromuscular transmission results
in spike broadening in the presynaptic neurons, an effect
mediated by a decrease in the delayed K⫹ current secondary to a loss of a trophic action of NT-3.
915
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WILLIAM J. MOODY AND MARTHA M. BOSMA
A. Immature Voltage-Gated Channels With
Properties Different From Their
Mature Counterparts
Physiol Rev • VOL
B. Immature Ligand-Gated Channels With
Properties Different From Their
Mature Counterparts
There are also substantial differences in the kinetics
of ligand-gated channels between immature and mature
cells. Fetal muscle expresses ACh receptors with a subunit composition ␣2␤␥␦, with the ␥-subunit giving them a
longer open time (177, 410). Later the receptors switch to
the adult ␣2␤␧␦ form, which has a shorter open time. This
appears to be an example of impedance matching to the
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The kinetics of ion channels expressed in many immature cells are slower than in mature cells. This was
illustrated above in the ascidian and Xenopus examples.
In both cases, outward K⫹ currents are small and slowly
activating early in development and speed later. Speeding
of outward currents during development is very common
(19, 208, 368, 451). Small, slowly activating outward currents have several effects in immature cells, not all of
them obvious. First, they may allow more Ca2⫹ to be
admitted during activity compared with a short-duration
spike. For example, if the long-duration spike in developing Xenopus neurons is truncated by experimentally expressing a rapidly activating K⫹ current, activity-dependent developmental events are disrupted (271). It is not
always true, however, that long-duration immature action
potentials admit more Ca2⫹ than their briefer counterparts, because increases in inward Ca2⫹ currents during
development may compensate for spike shortening (130).
In these cases, it may be the slower kinetics, rather than
the magnitude, of Ca2⫹ entry that is critical (130). Second,
slow outward currents increase the time during which net
inward current flows during a depolarizing stimulus (see
Fig. 7 in Ref. 208). This makes the cell more responsive to
slow depolarizations, which may be common as pacemakers for spontaneous activity early in development. Third,
inactivation of Ca2⫹ currents during longer spikes may
allow Ca2⫹ channel reopening during the falling phase of
the action potential (547), admitting disproportionately
large amounts of Ca2⫹ because of the large driving force.
Finally, by broadening the action potential, slow outward
currents can cause cumulative inactivation of inward currents during bursting, which may be an important mechanism controlling the patterns of spontaneous activity in
developing cells. This is seen in ascidian muscle, where
the slow outward current is expressed at the same time as
an inactivating Ca2⫹ current, and Ca2⫹ current inactivation appears to set burst duration during spontaneous
activity (130). Kinetic changes in other currents can have
profound effects on the development of firing patterns
as well. In rat retinal ganglion neurons, speeding of
recovery from inactivation of INa appears to play a
major role in the postnatal appearance of sustained,
repetitive firing ability (605).
In other cases, the voltage dependence of channels
rather than their kinetics is different in the immature cell.
Shifts in voltage dependence of channels are very common during development, including differential shifts in
inactivation and activation curves. Again, one example is
seen in ascidian muscle, where the immature Ca2⫹ current activates at more negative potentials than the mature
Ca2⫹ current, allowing it to admit Ca2⫹ between spikes in
a burst (130). A high percentage of neonatal cerebellar
Purkinje neurons are spontaneously active, even when
completely isolated from synaptic inputs. The Na⫹ current in these cells has a more negative voltage dependence of activation, but the same inactivation versus voltage (hinf) relation, as that in the inactive cells (438). This
results in a “window current” where the two relations
overlap in immature cells. The window current, which
drives spontaneous activity, is absent in inactive cells.
Hippocampal astrocytes show a pronounced negative
shift in the hinf curve for the Na⫹ current during development, probably due to a developmental switch in Na⫹
channel types (551). Chick cardiac ventricular muscle
cells also show a negative shift in the hinf curve of the Na⫹
current with development, which reduces the overlap, or
window current, where the activation and inactivation
curves overlap (514). The large window current early in
development triggers spontaneous activity, which is absent in the mature cells. A similar shift occurs during
development of hair cells. In addition to the outward K⫹
current speeding during development, part of the program
that eliminates excitability in these cells after the period
of spontaneous activity is over is a positive shift in the hinf
curve for the outward current coordinated with a negative
shift in the resting potential (369). These two changes
make more outward current available during depolarization, thus helping to eliminate spiking. In cat retinal ganglion cells, a negative shift in the voltage dependence of
activation and a positive shift in the inactivation curve of
INa combine with increased INa density to help bring
about the early appearance of repetitive firing ability
(546). A similar negative shift in the INa activation curve
combined with increased INa density is seen in mouse
retinal ganglion cells (510). Furthermore, developmental
changes in the intrinsic properties of ON and OFF RGCs
allow them to participate differentially in spontaneous
retinal waves of activity, a difference which probably
instructs their differential projections in the LGN (436). It
is likely that many cases of variations in properties of
immature voltage-gated channels from their mature counterparts are caused by the differential expression of accessory, or beta subunits (225, 489 – 491, 534).
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
Physiol Rev • VOL
ditions, that the long-duration immature NMDA responses
are required for the plasticity (347).
AMPA receptors also show pronounced developmental changes in function. AMPA receptors lacking the
GluR2 subunit are permeable to Ca2⫹, unlike GluR2-containing AMPA receptors. Because AMPA receptors do not
show a voltage-dependent Mg2⫹ block, this form can admit Ca2⫹ to cells even at negative potentials (see Ref. 146
for review of AMPA receptors). A variety of neurons,
including those of brain stem, cerebellum, hippocampus,
retina, and cortex, express AMPA receptors lacking the
GluR2 subunit early in development (91, 161, 312, 318,
343, 346) and are thus permeable to Ca2⫹. In the migratory
IZ of the developing cortex, tangentially migrating neurons originating in the basal telencephalon express Ca2⫹permeable AMPA receptors and are in close proximity to
axons originating in the cortical plate, which could release glutamate to activate these receptors and possibly
influence migration (396; see also Ref. 552).
C. Different Immature Channel Function Due to
Different Ion Gradients Early in Development
Profound changes in the function of ligand-gated
channels need not rely on differences in channel structure. They can be created by the timing of expression of
pumps that create the ionic gradients that determine current flow through the channels.
The best known and perhaps most important example of this is the excitatory action of the transmitters
GABA and glycine early in development (reviewed in
Refs. 34, 469, 470). It has been known for some time that
GABA action was depolarizing and functionally excitatory
in many developing neurons (35, 44, 307, 353, 355, 359,
430, 431, 446). Experiments using the gramicidin perforated patch method of whole cell recording, which does
not disrupt intracellular chloride levels, subsequently
showed that the excitatory action of GABA was not
caused by a unique GABA receptor, but by elevated intracellular Cl⫺ concentrations early in development (468, 505).
The high [Cl⫺]i in immature neurons is maintained by
a Na⫹-dependent Cl⫺ uptake pump (NKCC1 in rat) (505,
539). The switchover to inhibitory GABA action takes
place in rodent cortex and hippocampus during the first
two postnatal weeks and results from expression of the
K⫹-dependent Cl⫺ extrusion pump KCC2 (254, 274, 502,
621). In cortex, the timing of this switch is controlled by
the state of differentiation of the neurons, not by chronological age of the animal (539). In spinal cord neurons, the
timing of the switch is influenced by astrocytes (332).
Interestingly, the switch from excitatory to inhibitory
GABA action occurs at different times in different regions
of the brain, even when strong synaptic pathways connect
the two. So, for example, neurons of the rat visual cortex
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low conductance of the immature muscle resting membrane so that synaptic currents are long enough in duration to allow ACh-triggered activity necessary for muscle
maturation (268). Interestingly, in slow-twitch muscle fibers, this switch is delayed, and in true slow extraocular
muscles, the ␥-form persists into adulthood (412). This
may reflect differences in activity-dependent suppression
of ␥-subunit synthesis due to differences in muscle activity among these types (412). It also may have a functional
role in matching ACh currents to the higher resting resistance of the slow muscle membrane. In fast-twitch muscle, nerve-induced activity suppresses the ␥-subunit synthesis and increases resting Cl conductance (236, 581).
This coordinates the development of the high mature
resting conductance (see sect. IVD3) with the suppression
of the long-open time embryonic ACh channel, which is
no longer required to compensate for the long immature
membrane time constant.
Similar developmental changes occur in the NMDA
receptor. During the development of many neuronal
types, the deactivation kinetics of NMDA currents become much faster (e.g., Ref. 239). [Deactivation kinetics
are a property of the receptor, not of the time course of
glutamate or NMDA persistence (see Ref. 127).] NMDA
receptors are heteromeric ion channels, consisting of an
essential NR1 subunit and one or more NR2 subunits. NR1
subunits are expressed in multiple splice variants, while
NR2 subunits form a multigene family consisting of at
least four members (NR2A, B, C, D). The subunit composition of the receptor has large effects on channel kinetics, especially deactivation times, with NR2B- and NR2Dcontaining receptors showing much slower deactivation
kinetics than NR2A-containing receptors (626; see Ref.
127 for review). The speeding of deactivation kinetics
during early development in most cells results from a
subunit swap, with the NR2B subunit that is present in
immature cells being replaced by the NR2A subunit (182,
246, 593). The exact developmental function of NMDA
receptors containing the NR2B subunit and the long time
course of the currents they mediate is not entirely clear.
The immature subunit composition would clearly favor
temporal summation, and in fact, such summation is observed in neonatal rat LGN in response to spontaneous
activity from retinal ganglion cells (349). It would also, as
in the case of the ACh receptor, be better matched to the
high input resistance and long time constant of immature
cells. In addition, the longer duration excitatory postsynaptic currents in immature cells would be expected to
admit more Ca2⫹ to cells during activity, possibly allowing more effective triggering of gene expression and synapse stabilization (122, 289, 487). But it is not entirely
clear that developmental plasticity in synapse function is
tightly related temporally to the period of immature
NMDA receptor expression (see Ref. 503), or that in cases
where a good temporal relation exists under normal con-
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WILLIAM J. MOODY AND MARTHA M. BOSMA
Physiol Rev • VOL
ple, moving the membrane potential into a range that
opens voltage-gated Na⫹ and Ca2⫹ channels and causes a
rise in [Ca2⫹]i . But at the same time, the GABA reversal
potential may be negative to the glutamate reversal potential, and hence, GABA may reduce glutamatergic excitation. Even in this situation, if the depolarizing action of
GABA is sufficient to remove the Mg2⫹ block of the
NMDA channel, GABA may potentiate NMDA responses
while shunting both NMDA and non-NMDA glutamate
responses. As chloride is pumped out of immature cells
and GABA makes the transition to an inhibitory transmitter, functional inhibition will develop before GABA becomes hyperpolarizing, when the GABA reversal potential
becomes negative to threshold for a particular cell.
The excitatory action of GABA in immature cells
encapsulates four important principles that we discussed
in section I, and which have appeared in many contexts
throughout this review.
1. Optimization
Depolarizing GABA action is necessary for its developmental effects.
2. Coordination
For GABA to act in this way, expression of GABAA
receptors must be coordinated with that of Cl⫺ pumps
that create, and then reverse, the immature Cl⫺ gradient,
and with voltage-gated Ca2⫹ channels that GABA excitation acts on to admit Ca2⫹ to cells.
3. Self-limiting nature of activity
GABA itself appears to participate in triggering the
reversal of the Cl⫺ gradient and its conversion to an
inhibitory transmitter (193).
4. Incompatibility of immature and mature properties
Clearly, excitatory GABA action would be incompatible with mature nervous system function, as evidenced
by the fact that KCC2 knockout mice die at birth from
respiratory failure (254).
D. Nonlinear Developmental Profiles of Channels
That Create Early Periods With Unique
Firing Properties
In addition to making use of channels that are structurally or functionally different from their mature counterparts, immature cells often express mature-type channels in such different patterns that their firing properties
are unique to their stage of development. This is most
often seen either as the transient expression of a partic-
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show strong excitation by GABA at P0, whereas lateral
geniculate neurons are inhibited by GABA at the same
stage (256). Other neurons show long delays in the switchover correlated with substantial late developmental
changes in their function, such as hypothalamic gonadotropin-releasing hormone (GnRH) neurons, which switch
at puberty (224). Of particular note is the late persistence
of excitatory GABA action in temporary neuronal populations, such as the Rohon-Beard neurons of the amphibian spinal cord (505) and Cajal-Retzius cells of the cortex
(400)(see sect. IIP). The switchover in GABA action is
reversible under some circumstances, as indicated by the
reappearance of excitatory GABA responses in neurons
after various forms of traumatic injury (594). Other examples of this “dedifferentiation of channel function” are seen
in certain experimental models of epilepsy (see sect. VI).
GABA itself seems to be involved in the switchover of
the Cl⫺ gradient. In hippocampal neurons, application of
GABAA blockers delays the change and delays the appearance of KCC2 mRNA, whereas depolarizing the cells with
KCl accelerates the switchover and the KCC2 mRNA expression (193).
During this period when GABA exerts a depolarizing
action, it has many trophic effects on neurons and neuronal precursors (see Refs. 34, 469, 470 for reviews).
These include inhibition of DNA synthesis and stimulation of migration in cortical ventricular zone precursor
cells (29, 30, 235, 355). The fact that DNA synthesis in
cortical precursor cells in cortical explants can be stimulated by bicuculline (355) indicates endogenous activation of GABA receptors, possibly by GABA released from
axons of GABAergic cells in the early cortex or subcortical structures (114, 131, 595). These effects rely on the
depolarizing action of GABA and its ability to increase
[Ca2⫹]i via voltage-gated Ca2⫹ channels (see, e.g., Refs.
355, 468), and hence are restricted to the period when the
intracellular Cl⫺ concentration is sufficiently high (see
Refs. 34, 469, 470 for reviews). The high affinity and lower
levels of desensitization of the immature GABAA receptor
(471) are likely to contribute to the ability of immature
neurons and precursor cells to respond to low, nonsynaptically released levels of GABA. Some trophic effects of
GABA may be indirect, given that GABA can stimulate
BDNF expression specifically in immature cells via depolarization and activation of L-type Ca2⫹ channels and
MAPK-dependent CREB phosphorylation (38, 447). Because BDNF can markedly stimulate GABA release, an
interesting positive feedback exists in immature neurons
relating GABA excitatory transmission and the trophic
effects of BDNF (447).
As discussed in Ben-Ari (34), Owens and Kriegstein
(469, 470), and elsewhere, the term excitatory is ambiguous when applied to the actions of GABA in immature
cells. If the Cl⫺ potential is positive to threshold, GABA
may depolarize a cell and directly excite it by, for exam-
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
ular channel type or as large temporal disparities in the
times of functional expression of different channels.
1. Transient channel expression:
disappearing channels
Physiol Rev • VOL
expression corresponds with a period of spontaneous
activity in DRG neurons. Because Nav1.3 has particularly
rapid recovery from inactivation, it may help to induce
spontaneous, repetitive firing in developing DRG neurons
(128, 171). Interestingly, Nav1.3 shows this pattern of
transient expression in a variety of CNS structures (28).
Nav1.3 is also expressed at very early stages in CajalRetzius neurons of the preplate (5), where it might contribute to postnatal activity-dependent cell death in this
temporary neuronal population (405).
The inwardly rectifying cation current Ih is downregulated during the development of cardiac ventricular
myocytes (629) and hippocampal neurons (596). Ih serves
pacemaking functions in many cells (473, 504). As an
inward (depolarizing) current activated by hyperpolarization, Ih can create a situation where there is net inward
current at all potentials near rest, thus ensuring spontaneous, repetitive firing. Thus a developmental downregulation suggests an early role for Ih in pacemaking spontaneous activity. Ventricular myocytes do in fact show
spontaneous pacemaking at early stages, when Ih is
present, and lose it as Ih disappears (629). In the hippocampus, Ih in hilar neurons has been implicated as a
pacemaker for spontaneous, synchronous activity (566).
The experiments of Vasilyev and Barish (596) also illustrate the importance of measuring cell surface area in
developmental studies of ionic currents. In the hippocampus, Ih density shows an early peak, but Ih amplitude does
not. The impact of a current on firing properties is more
closely related to its density, and as cells grow during
development, it is important to know whether changes in
current amplitude keep pace with, fall short of, or exceed
the amount of membrane added. A similar finding was
made for the T-type Ca2⫹ current in Muller glial cells:
current amplitude held constant during early postnatal
development, but because there was extensive cell
growth, current density fell substantially (75). Although
current amplitude and capacitance (a measure of surface
area) are not always measured over the same compartments because they are measured at different frequencies, at least an approximate indication of true current
density should be monitored along with current magnitude in developmental studies where cell size and/or
shape are changing. This can sometimes give valuable
clues as to the mechanism underlying changes in relative
amplitudes of different current types, as discussed above
for the case of starfish oocyte maturation (422).
The current that most often declines or disappears
with development is the T-type, or low voltage activated,
Ca2⫹ current, implying that it plays important developmental roles. Reduction in T-type currents occurs during
the early development of spinal neurons (213, 380, 387),
embryonic skeletal muscle (26, 39, 204), cardiac myocytes
(172, 217, 327), Muller glial cells (75), cortical and hippocampal neurons (94, 584), vestibular neurons (93), neu-
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When a channel functionally disappears during development, the inference is strong that it serves a developmental function during the period when it is present.
We discussed several examples of disappearing channels
above: downregulation of A-currents during starfish oocyte maturation (sect. IIA), the disappearance of Na⫹ and
Ca2⫹ currents during early postfertilization development
of ascidian embryos (sect. IIB), the downregulation of
Na⫹ and Ca2⫹ currents in cochlear hair cells (sect. III),
and the transient disappearance of inwardly rectifying K⫹
currents in immature ascidian muscle (sect. IIL).
Disappearance of Na⫹ currents and consequent loss
of excitability occurs in many cells. Some glial cells, for
example, express functional INa at early stages, but not
later (22, 306; but see Ref. 64). In hippocampal astrocytes,
INa shows a biphasic expression pattern: INa density is
high at P0 and P7, but absent at P4-P5, suggesting a switch
in INa subtype (551). This is supported by the finding that
the inactivation versus voltage curve is 20 mV more negative at P7 than at P0. It is not known whether the gap in
INa expression has a functional significance, but it is
reminiscent of the gap in inward rectifier expression in
developing ascidian muscle, created by the time lag between disappearance of the maternally coded channel
and expression of the zygotic form (208). Another example of loss of INa and excitability is seen in the starburst
amacrine cells of the retina, as discussed in section IIC.
Hair cells express INa at P0-P9, but lose it by P18. The
absence of INa at maturity in these cells is understandable,
since full action potentials are not compatible with the
ability of membrane potential oscillations to follow highfrequency sounds. The early function of the Na⫹ current
probably relates to activity-dependent cell survival in the
auditory brain stem, among other things (e.g., Ref. 639). A
similar pattern is seen in utricular hair cells, where it has
been shown that action potential activity at early stages
releases BDNF (92). In the pacemaker sinoatrial node
cells of the heart, a sodium current is present at early
developmental stages and contributes to pacemaking activity, but is absent at later stages (24). Rat pituitary
melanotropes are spontaneously active early in postnatal
development, before dopaminergic innervation arrives
from the hypothalamus. Secreted dopamine from hypothalamic afferents downregulates the Na⫹ current and
shuts off spontaneous activity (351).
Transient expression of Na⫹ currents during development can also be subtype specific. In DRG neurons, for
example, Nav1.3 is expressed early, peaking at E17, and
then has disappeared by about P15. The timing of Nav1.3
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WILLIAM J. MOODY AND MARTHA M. BOSMA
Physiol Rev • VOL
2. Relative timing differences of the development
of different channels
Transient periods of unique levels of excitability or
firing patterns need not be created by transient channel
expression. Another common method of creating early
periods of heightened excitability is to delay major increases in outward currents relative to the expression of
inward currents. Action potential shortening, as is seen in
Xenopus spinal neurons and ascidian muscle, are examples (see sect. II, K and L). In ascidian muscle, the late
expression of large and rapidly activating Ca2⫹-activated
K⫹ currents both shortens spike duration and decreases
cell responsiveness to slowly depolarizing inputs (208).
Late expression of Ca2⫹-activated K⫹ currents may also
contribute to changing the firing patterns of retinal ganglion cells from bursting during spontaneous retinal
waves to more sustained firing needed for encoding visual
information (510, 604). And in embryonic Xenopus muscle, time lags between two phases of delayed K⫹ current
development relative to Na⫹ current development creates
a window of spontaneous activity (see sect. IIO).
In more extreme cases, late expression of outward
currents helps to eliminate the ability to generate action
potentials entirely, as seen for example in cochlear hair
cells and insect motor neuron somata (see sect. II, I
and M).
There are other cell types in which excitability in the
sense of the ability to generate full action potentials must
be eliminated by increasing expression of outward currents without eliminating or reducing inward currents. In
hair cells, some Ca2⫹ current is retained because the
interaction between Ca2⫹ entry through voltage-gated
Ca2⫹ channels and the subsequent activation of IK(Ca)
underlies the oscillatory behavior on depolarization (173).
Crustacean slow muscle fibers are another example.
These cells contract on depolarization due to Ca2⫹ entry
through Ca2⫹ channels, but must do so in a graded fashion. They therefore must have Ca2⫹ entry graded with
depolarization, which is difficult to achieve with action
potentials. They also have very slow contractile apparatus, which brief action potentials cannot activate. They
therefore eliminate the ability to generate action potentials by expressing large outward K⫹ currents. When
these are blocked pharmacologically or by anoxia-induced intracellular acidification, the ability to generate
action potentials appears (420). Indeed, in the immature
state, the crayfish superficial flexor muscle does generate
full action potentials (Moody, unpublished data), and presumably the late expression of the outward currents eliminates action potentials at later stages (see Ref. 12). Other
cell types in which blockade of outward K⫹ currents
reveals action potential generating ability may pass
through similar immature stages in which action poten-
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ronal cell lines (310, 314), chromaffin cells (70), and others. In cardiac and skeletal muscle, the T-type currents
that are downregulated are of the ␣1G and ␣1H types (39,
172, 327). In skeletal muscle, denervation did not restore
the T-type current (204), whereas in cardiac ventricular
myocytes, “dedifferentiation” in serum-based culture conditions did (165).
The inference that the T-type current is serving some
developmental function has been confirmed in several
cell types. In amphibian spinal neurons, the T-type current
is expressed during the period of spontaneous activity,
and blocking it blocks activity (213). This implies a role
for the current in pacemaking activity, as might be expected from a low-threshold inward current. But it is also
likely to serve a role in mediating Ca2⫹ entry during
activity, because the channel opens when Ca2⫹ driving
force is high and because the overlap of activation and
inactivation curves creates a window current near the
resting potential (20, 21, 39). The idea of Ca2⫹ entry
through steady T-type currents at near-resting potential
has also received strong support from studies showing
that the resting potential of myoblasts is in the range of
voltages where the T-type Ca2⫹ channel window current
exists, and that Ca2⫹ influx by this pathway is essential
for myoblast fusion (41; see sect. IIN). In developing cardiac myocytes, Ca2⫹ influx through the T-type channel
mediates atrial natriuretic factor release (327).
In general, the developmental role of the T-type Ca2⫹
channel is likely to be a combination of three of its
common functions: a low-threshold inward current that
amplifies depolarizing inputs, increases excitability, and
by virtue of its inactivation, creates bursting behavior out
of tonic inputs; a Ca2⫹ entry pathway that operates at high
driving force, and hence can mediate large amounts of
Ca2⫹ influx during activity (386); and a channel whose
inactivation and activation relations overlap near the resting potential, creating window currents and the potential
for steady Ca2⫹ entry at near-resting potentials. These
roles are not trivial to separate with blocker experiments,
and probably use of methods such as action potential
waveform voltage clamp combined with [Ca2⫹]i imaging
will yield clearer results.
Ligand-gated channels are also often expressed transiently during development. This is seen in the auditory
brain stem, where synapses between the MNTB and the
lateral superior olive change from GABAergic to glycinergic during development (303). It presumably also occurs in other situations where the transmitter phenotype
of a presynaptic input changes (see, e.g., Ref. 614; see
also chick spinal cord discussion in sect. IIH). GnRH
neurons migrating from the olfactory placode are spontaneously active and express functional GABAA receptors only during the period of migration; this appears to
be significant developmentally since GABA inhibits migration (191, 313).
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
3. Late appearance of mature, low resting resistance
The resting conductances of a cell have a profound
influence on excitability because they affect the size and
duration of synaptic inputs, the response of the cell to
its own inward and outward voltage-gated currents, the
passive spread of voltage within the cell, and the effective electrical coupling across gap junctions. There is a
strong tendency toward high input resistance in immature neurons and muscle cells. This is seen in the
development of mammalian central neurons (33, 379,
481, 589, 638), insect neuronal somata (155), and vertebrate skeletal muscle (236). Developmental decreases
in resting resistance can be quite large, fivefold or more
in some cases. The coincidence of high resting resistance and recently increased Na⫹ currents may underlie widespread, spontaneous, synchronous activity in
cortical neurons, and the decline in resistance may help
terminate that activity (481; see sect. IIE). In insect
neuronal somata, a fivefold decrease in resting resistance is one factor that eliminates soma excitability
and spontaneous activity during development (155). In
skeletal muscle, the late development of large resting
Cl⫺ conductance in fast-twitch muscle fibers is essential
for their ability to generate single twitches in response to
single excitatory postsynaptic potentials (486).
The apparently simple phenomenon of a decrease
in input resistance can exert complex effects on cellular properties. In cortical pyramidal cells, the 10-fold
decrease in resistance shortens the length constant
and electrically isolates the apical dendrites from the
soma, changing the roles of regenerative responses in
the dendrites in the processing of incoming synaptic
events (638).
Physiol Rev • VOL
E. Changes in the Spatial Distribution of Channels
During Development
By changing the spatial distribution of channels during development, cells may effectively eliminate ionic
currents and truncate their functions in certain regions of
the cell without globally up- or downregulating them.
Although changes in physical location of channels during
development are best known for ligand-gated channels in
muscle, it also occurs for voltage-gated channels in neurons. For example, in hippocampal neurons, the N-type
Ca2⫹ channel is diffusely distributed throughout the cell
early in development, but becomes punctate at presumed
future regions of vesicle release later, upon neuron-neuron contact (13). During these same stages, L-type channels remain restricted to the soma (485).
F. Changes in the Coupling of Channels to
Intracellular Events During Development
As the expression and spatial distribution of channels changes during development, so does the expression
of other molecules involved in second messenger cascades and vesicle release. As a result, the functional coupling between ion channels that admit Ca2⫹ to the cell and
downstream cellular events may change over time. The
result is a change in function of a given channel type even
during periods of relatively constant expression. This is
seen most commonly as changes in the type of Ca2⫹
channel that mediates transmitter release (207, 261, 527,
545) or in the efficiency with which metabotropic transmitter receptors couple with activation of second messenger systems (442, 526). It is not just coupling of ion
channels to subsequent events in the cell, but also coupling of cellular events to channel modulation that can
change with development. For example, voltage-gated
Na⫹ channels in immature cortical neurons are subject to
activity-dependent endocytosis at early stages, but are
protected later when their ␤-subunit is expressed (6).
G. Differences in Intracellular Trafficking
of Channel Subtypes
Although it is clear that the biophysical properties of
channels expressed at early stages may be optimized to
regulate spontaneous activity, it has more recently become appreciated that different channel types, even
within the same family, may also differ substantially in
intracellular trafficking. Thus a cell’s choice of channel
types to express may govern how efficiently that channel
is expressed at the level of the plasma membrane and how
that expression is regulated by events such as glycosylation or the presence of ␤-subunits. Within the Kv1 family
of delayed K⫹ channels, Kv1.4 is much more efficiently
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tials, either spontaneous or evoked, can be generated (see
Ref. 163).
Although differential timing of functional ion channel
development is likely often to be created by direct transcriptional control of channel ␣-subunits, other mechanisms also play important roles. Accessory, or ␤, subunits
show complex patterns of developmental regulation and
regulate the functional properties of channels, their insertion into the membrane, and their susceptibility to activity-dependent regulation (see, e.g., Refs. 6, 84, 489, 490,
491, 522, 534; see Refs. 225, 258, 586 for reviews). Other
less common forms of regulation may exist. In ascidian
embryos, a truncated form of L-type Ca2⫹ channel mRNA
is expressed early in development (458) and can suppress
expression of the full-length form. The downregulation of
this truncated form appears to function as a late, positive
regulator of a rapid rise the developmental appearance of
the fully functional L-type Ca2⫹ channel.
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WILLIAM J. MOODY AND MARTHA M. BOSMA
V. ACTIVITY-DEPENDENT ION CHANNEL
DEVELOPMENT AS PART OF THE ESSENTIAL
TRANSITION BETWEEN IMMATURE AND
MATURE PHYSIOLOGICAL PROPERTIES
Like their mature counterparts (370), developing neurons show both stability and plasticity in their firing patterns: stability in that they can maintain consistent patterns of spontaneous activity for many days during critical
periods of development, and plasticity in that they successfully make the transition out of this early state of
spontaneous activity into their mature firing patterns. Because early patterns of spontaneous activity are likely to
be incompatible with the mature functions of the cell (see
below), the transition between these two states of activity
is critical. The complex sequence with which ion channels
develop in a given neuron is best viewed in the context of
early periods of spontaneous activity followed by the
required transition to the mature physiological state. Because activity-dependent ion channel development is part
Physiol Rev • VOL
of this transition process, it is also best viewed in the
same context. In many cases, the activity-dependent
channel expression is compensatory, the effect of the
change being to reduce or eliminate the activity that
triggered it.
A. Voltage- and Ca2ⴙ-Gated Channels
The apparent compensatory nature of activity-dependent channel development is readily seen in the case of
outward K⫹ currents and inward Na⫹ currents. The ascidian muscle and hair cell examples discussed in section
2⫹
⫹
II, I and L, illustrate this for the Ca -activated K current
[IK(Ca)]. In each case spontaneous activity is eliminated by
the activity-dependent expression of a rapidly activating
IK(Ca). In other cell types, spontaneous firing may change
in pattern during development, rather than be eliminated
entirely, but the same principles may hold. Cerebellar
Purkinje neurons, for example, are spontaneously active
in both the immature and mature states, but the pattern of
activity changes from steady firing to more bursting behavior. It is likely that activity-dependent developmental
expression of a Ca2⫹-activated K⫹ channel participates in
this transition as well (433). IK(Ca) development also depends on early periods of spontaneous activity in mammalian spinal motor neurons (378), although its role in
terminating or modifying the activity is not yet understood.
Similar changes in firing properties during development can be created by activity-dependent expression of
voltage-gated K⫹ currents. Inferior colliculus neurons express high levels of the voltage-gated K⫹ current Kv3.1,
whose rapid kinetics contribute to high-frequency firing
abilities of these cells during auditory processing. During
development, midbrain auditory neurons fire spontaneously at low frequencies (304), and this activity may contribute to Kv3.1 maturation, given evidence that Kv3.1
expression is enhanced by depolarization and Ca2⫹ entry
(344). Activity-dependent K⫹ current development occurs
at other levels of the central auditory system as well, such
as in the chick nucleus magnocellularis (357). Similarly,
activity dependence of the second phase of expression of
a delayed K⫹ current in embryonic Xenopus muscle appears to terminate a period of spontaneous activity (see
sect. IIO).
Activity can be very specific in its effects on K⫹
channel development. In hippocampal neurons, six members of the Kv1 family all appear during postnatal development, in a specific pattern, and contribute to a seven- to
eightfold increase in macroscopic outward current. But
only Kv1.1, Kv1.2, and Kv1.4 show activity dependence,
and for those, block of activity prevents their developmental appearance at early stages, but does not downregulate them in more mature cells (211). Similarly, in
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trafficked to the plasma membrane in a variety of heterologous systems than are Kv1.1 or Kv1.2, which tend to be
retained more in the endoplasmic reticulum (363). Between Kv1.1 and Kv1.2, the expression of Kv1.2 at the
plasma membrane is more subject to modulation by the
formation of heterotetramers and by the presence of
␤-subunits than for Kv1.1 (363). Mutating a single amino
acid (A352) within the pore region (S5-S6 loop) can
greatly increase the trafficking of Kv1.1 to the plasma
membrane (364). This traffic control region interacts with
a glycosylation site in the S1–S2 extracellular linker of the
protein in controlling functional expression. It is intriguing that the same region of the protein that controls
trafficking also determines dendrotoxin (DTX) sensitivity,
so that in general DTX-insensitive K⫹ channels express
better (364). Carboxy-tail sequences also control trafficking of Kv1 family members to the plasma membrane and
may regulate how that trafficking is modified by the presence of ␤-subunits (330).
A recent paper by Blaine et al. (47) implicates carboxy-tail sequences in the Kv2 family as regulators of
channel density control during development of Xenopus
spinal neurons. They found that excess transcripts of
some Kv1 and Kv2 family members could increase functional channel density at any stage of development, but
Kv2.2 specifically could only increase functional channel
density in immature neurons. This suggests that one solution to the problem developing neurons have of determining when the mature channel density set point has
been reached is to switch the subunits that are expressed,
changing to a channel type for which translational or
trafficking control operates around a different channel
density.
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
Physiol Rev • VOL
highly subtype specific, as seen for example in embryonic
dorsal root ganglion neurons (see sect. IIJ).
Calcium currents seem to show more variable activity-dependent developmental effects than Na⫹ or K⫹ currents, with both up- and downregulation by activity evident, sometimes in the same cells (see, e.g., Ref. 164).
This may reflect the somewhat more complex and varied
roles of Ca2⫹ currents in neuronal function in both immature and mature states. In some cases, there is clear
evidence that activity mediated by immature patterns of
Ca2⫹ channel expression triggers later development of
mature Ca2⫹ current expression. This occurs in the
NG108 –15 neuronal cell line, which expresses only functional T-type Ca2⫹ currents in the undifferentiated state,
but during differentiation adds a variety of high-voltageactivated Ca2⫹ current types (101). Blocking the T-type
Ca2⫹ current at early stages greatly suppresses the later
appearance of functional HVA Ca2⫹ currents. As with
other channels, the effects of activity on Ca2⫹ channel
development may be subtype specific (144, 164, 187), even
to the point of selectively stabilizing one form of N-type
Ca2⫹ channel mRNA but not another (528). In DRG neurons, Ca2⫹ currents show similar dependence on the specific patterns of stimulation as do other activity-regulated
molecules (331).
In many cells, inwardly rectifying K⫹ channels provide all or part of the resting conductance. These channels close with small depolarizations, allowing cells to
maintain a high resting K⫹ conductance and yet still
present a high input resistance to depolarizing stimuli. In
embryonic amphibian skeletal muscle, IIR development is
suppressed by blocking spontaneous activity and accelerated by providing activity at abnormally early stages (338,
339). In mammalian skeletal muscle, innervation upregulates and denervation downregulates IIR expression (205),
effects that appear to be secondary to activity-induced
increases in [Ca2⫹]i that stabilize IRK1 mRNA (540).
Chloride channels also contribute to resting conductance, particularly in skeletal muscle, and their development appears to be dependent on innervation-induced
electrical activity (236, 293, 482).
There is some evidence that development of the hyperpolarization-activated cation channel, Ih, which acts as
a pacemaker current in cardiac and other cells (473, 504),
can be influenced by activity (74, 102; see sect. VI).
Regulation of voltage-gated ion channels by electrical
activity need not be limited to the cells that generate the
activity. T-type Ca2⫹ currents and inwardly rectifying K⫹
currents in glial cells show long-term upregulation as a
result of activity in associated neurons (27, 301, 302).
Although activity-dependent control of channel spatial distribution is most commonly associated with ligandgated channels (see sect. VB), it also operates for voltagegated channels. In hippocampal neurons, Kv2.1 channels
are clustered at the soma and proximal dendrite, whereas
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cerebellar neurons, the Kv3.1b splice variant increases
after P8, but not Kv3.1a. Although both are regulated by
basic fibroblast growth factor (bFGF), depolarization prevents the FGF effect on Kv3.1a, but not on Kv3.1b (345),
so it is possible that a suppressive effect of activity contributes to the specific developmental expression of
splice variants of the same channel. Activity can also
show opposite effects on K⫹ channel expression in different cell types. Depolarization, acting via cAMP, upregulates Kv1.5 transcription in cardiac muscle but downregulates it in GH3 cells (328, 427). [Interestingly, this effect in
GH3 cells seems to be an unusual case in which the
effects of activity are not secondary to Ca2⫹ entry (328).]
The effects of activity on K⫹ channel expression are likely
to be due to several mechanisms, including transcriptional (328, 427), mRNA stability (7), or with multiple
posttranscriptional effects probably acting simultaneously in the same cell (66).
Voltage-gated Na⫹ channels also show activity-dependent expression, especially early in development. If
the effects of activity are compensatory, as they appear to
be by upregulating outward K⫹ channel expression, one
would expect activity to downregulate Na⫹ channel expression. That is what is commonly seen. In developing
central neurons (hippocampus and cortex), activity triggered by Na⫹ channel agonists causes a rapid internalization of Na⫹ channel proteins and a downregulation of
␣-subunit mRNAs (132, 133, 197, 317, 472). This phenomenon occurs only at early stages of development (132) and
is specific for Na⫹ channels (472). The loss of Na⫹ channel sensitivity to activity-induced internalization with development parallels the appearance during development
of the ␤1-subunit, implying a protective or stabilizing role
for the ␤1-subunit (6). As is the case for Kv1.5 downregulation in GH3 cells (328), Na⫹ channel internalization
triggered by activity does not seem to be secondary to
Ca2⫹ influx (472). However, a similar endocytotic internalization of Na⫹ channels in chromaffin cells is mediated
by increased [Ca2⫹]i (294). Depolarization of neurons
with KCl could mimic the effects of Na⫹ channel agonists
on Na⫹ channel downregulation, but, oddly enough, KCl
depolarization relies partly on cAMP for its effects,
whereas Na⫹ channel agonists do not (197). Differences
in transduction pathways triggered by different types of
depolarizing stimuli are also seen in other cells (see Ref.
78, sect. IIIA3). Na⫹ currents in developing cortical neurons also show a corresponding upregulation when electrical activity is blocked chronically with TTX (143). Similar activity-dependent downregulation of Na⫹ channels
occurs in skeletal and cardiac muscle cells (77, 105, 452,
538), where there is direct evidence that the effects are
secondary to Ca2⫹ entry. Activity has been reported to
upregulate Na⫹ channel density in a Ca2⫹-dependent
manner in GH3 cells (417). As with outward K⫹ currents,
activity-dependent Na⫹ channel downregulation can be
923
924
WILLIAM J. MOODY AND MARTHA M. BOSMA
Kv2.2 channels are more uniformly distributed (336).
Ca2⫹ entry triggered by glutamate or by kainate-induced
seizure activity declusters Kv2.1 (as well as inducing a
large hyperpolarizing shift in its current-voltage relation), apparently by triggered calcineurin-based channel dephosphorylation of sequences in the carboxy tail
region (411).
B. Ligand-Gated Channels
Physiol Rev • VOL
C. Summary
Developmental changes in the expression of a wide
variety of voltage-, Ca2⫹-, and ligand-gated channels are
dependent on electrical activity. These are summarized in
Table 1. The pattern that emerges from studies of activitydependent channel expression in developing nerve and
muscle suggests two conclusions. First, activity-dependent channel development helps to mediate the essential
transition between immature and mature patterns of
channel expression. As a result, many of the changes are
compensatory, serving to eliminate the very activity that
triggered them. A second conclusion is more speculative.
Activity-dependent expression of channels that eliminate
spontaneous activity may be a monitoring system, by
which the cell detects when spontaneous activity has
successfully triggered the required developmental programs. By making expression of a channel that terminates
activity one of these programs, the system can compensate for variations in the intensity and timing of activity by
extending or truncating the period over which the activity
occurs.
VI. CLINICAL IMPLICATIONS
OF ACTIVITY-DEPENDENT
NERVOUS SYSTEM DEVELOPMENT
Understanding how the time course and mechanisms
by which the intrinsic properties of central neurons develop is essential to understanding both the etiology and
sequelae of pediatric seizure disorders. Immature animals, including humans, are more susceptible to seizures
than adults (251, 269, 416, 553). In humans, seizure susceptibility peaks in the first few months after birth, and
then declines from 5 years through adolescence (553).
Seizure incidence has been reported to be between ⬃2
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During development of the mammalian neuromuscular junction, activity-dependent regulation of ACh receptor expression plays a major role. Before innervation,
receptors are of the fetal form, with a subunit composition ␣2␤␥␦. Innervation initiates a complex set of changes
resulting in the suppression of extrajunctional fetal receptors, stimulates synthesis of receptors in nuclei underlying the synapse, and then triggers a change in subunit
composition to that junctional receptors change to the
␣2␤␧␦ form, suppressing synthesis of the ␥-subunit and
stimulating synthesis of the ␧-subunit (410). Suppression
of synthesis of ACh receptors from extrajunctional nuclei
involves multiple regulatory elements within the first 81
upstream base pairs, at least for the ␦-subunit (603). Suppression results from nerve-stimulated activity, acting via
CaM kinase II, which phosphorylates myogenin and reduces its DNA binding ability (412, 581). Both ␥- and
␧-subunits cluster at the end plate, but synthesis of the ␥
is suppressed in the perinatal period, whereas synthesis
of the ␧-subunit is stimulated. ARIA induces both genes at
the end plate, but electrical activity specifically suppresses ARIA induction of the ␥, but not the ␧, subunit
(412). The ␦-subunit is regulated oppositely in extrajunctional nuclei (suppression by activity) versus junctional
nuclei (enhancement by nerve related factors), and these
two aspects of regulation involve different upstream elements (582). Thus nerve-induced activity is involved in a
very complex process of maturing the composition and
spatial distribution of ACh receptors in skeletal muscle,
and in coordinating the passive properties of the muscle
membrane with the properties of ACh receptors. Activity
stimulates development of the mature low resting resistance, in the form of Cl⫺ channels, and participates in the
spatial restriction and subunit swapping of the ACh receptor so that its open time matches the impedance of the
muscle membrane (268).
Similarly, the speeding of kinetics of the NMDA receptor discussed above in section IVB depends on electrical activity (87, 487). The developmental upregulation of
the NR2A subunit is prevented by blocking activity with
either L-type Ca2⫹ channel or NMDA receptor blockers
(246), and reexpression of NR2B-like properties can be
induced in neurons after the swap to NR2A by blocking
ongoing activity with TTX (290). More details of the mech-
anism of this change in subunit composition have been
discovered using green fluorescent protein-tagged subunits in hippocampal slices (23). They found that the
insertion of NR2B-containing receptors into the postsynaptic membrane does not require activity and that NR2Bcontaining receptors can only replace other NR2B-containing receptors, but not those containing NR2A. In contrast, NR2A-containing receptor insertion does require
synaptic activity, and these receptors can replace NR2Bcontaining receptors.
In the AMPA-type glutamate receptor, the developmental switch to GluR2-containing AMPA receptors,
which eliminates this Ca2⫹ permeability, depends on electrical activity (343). In addition to mediating the subunit
swap, activity can also recruit AMPA receptors rapidly
(within minutes) to the postsynaptic membrane of immature neurons (335).
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
TABLE
1.
925
Activity-dependent development of voltage- and ligand-gated channels
Effect of Activity
Cell
Effect on Activity
Ascidian muscle
1IK(Ca)
1IK(Ca)
1IK(Ca)
1IK(v)
Cochlear hair cells
Spinal motor neurons
Cerebellar Purkinje cells
Xenopus muscle
Speeds IK(v) activation
Xenopus spinal neurons
1IK(v)
Hippocampal neurons
2INa
Cortex, hippocampal
neurons
2INa
DRG neurons
2INa
2INa
1ICa
1Kir
1ICl
Skeletal muscle
Cardiac muscle
Hypothalamic neurons
Xenopus muscle
Skeletal muscle
2ACh channel open time
Skeletal muscle
1 NMDA receptor
deactivation rate
Cortical neurons
Eliminate Ca2⫹ permeability
of embryonic AMPA
receptor
Switch of GABA from
excitatory to inhibitory
action
Cerebellar neurons
Hippocampal neurons
Speeds overall K⫹ current activation. Helps terminated activity by reducing response
to slow depolarization. Shortens action potential duration and reduces Ca2⫹ entry.
Helps eliminates both spontaneous activity and excitability.
Not yet clear.
May help change spontaneous activity to a bursting pattern.
May help terminate spontaneous activity. TTX reduces and Na⫹ channel
overexpression increases IK(v) expression.
Not clear. IK(v) amplitude increase, which is not activity dependent, plays major role
in shortening action potential and reducing Ca2⫹ influx.
Effect on spontaneous activity unclear. Subunit specific: activity affects only Kv1.1,
1.2, and 1.4.
Effect on spontaneous activity unclear. Rapid endocytosis followed by slower
downregulation of transcription, both caused by increased activity. Specific to
early stages when ␤1-subunit is absent. Activity block causes 1INa.
May help terminate spontaneous activity due to negative voltage dependence of
Nav1.8 and 1.9. Subtype specific for Nav1.8 and 1.9, but not for Nav1.3.
Unclear.
Unclear.
Activity increases development of LVA current.
Probably helps reduce aberrant activity created by Na⫹ channel misexpression.
Early lack of resting Cl conductance is impedance matched by long open-time ACh
channels. 1ICl by innervation, via activity, limits muscle action potentials and
contraction following stimulus.
Activity-dependent swap from ␦- to ␧-subunit. Long embryonic open time for
impedance matching to high embryonic Rin. Note activity also increases resting Cl
conductance, so mature short open-time ACh receptor is impedance matched to
low, mature Rin.
Activity dependent swap from NR2B to NR2A subunit. Slowly deactivating
embryonic receptor may aid in summation of EPSPs and increase Ca2⫹ entry, but
relation to developmental plasticity is unclear at present.
Activity-dependent upregulation of GluR2-containing receptors. Likely that Ca2⫹
entry through embryonic receptor occurs under physiological conditions in
immature neurons.
Activity-dependent expression of KCC2 Cl pump, which lowers [Cl]i and converts
GABA action to hyperpolarizing.
Data shown are as discussed in section V. See text for definitions.
and 5 per 1,000 live births, and about one-third of neonates with seizures progress to status epilepticus (416).
The pattern of seizures in the immature brain is different
than in the mature brain, with the majority of early-onset
seizures being neocortical, rather than hippocampal, in
origin (416). In addition, antiepileptic drugs that work
in adults are not necessarily effective in early-onset
seizures (269). The neonatal brain is less prone to
certain types of seizure-induced damage, such as cell
death (251), although more prone to other kinds of
damage (210, 282, 524).
It is almost certain that the increased susceptibility of
the immature brain to seizures is caused in part by the
unique intrinsic properties of developing neurons, in particular their propensity to generate spontaneous synchronized activity. It is equally likely that the different longterm response of the immature brain to early seizure
activity results at least in part from the fact that seizurelike activity disrupts normal activity-dependent developmental processes.
Physiol Rev • VOL
The attribution of heightened early seizure sensitivity
to particular immature neuronal properties has been
problematic because of differences in methods used to
trigger seizures, differences in the time course of development of neuronal properties in various regions of the
brain, and difficulties in measuring certain neuronal properties accurately over time. A recent paper by Khazipov et
al. (283) has attempted to resolve some of these issues by
using relatively noninvasive extracellular recording methods in hippocampus to measure the developmental time
courses of spontaneous activity (GDPs; see above), GABA
inhibition, and seizure susceptibility. Using single- and
multi-unit recording to estimate the functional sign of
GABA action, they concluded that GABA was uniformly
excitatory through P10 and underwent a gradual transition to inhibition by P15. This is a somewhat later transition than previous estimated. Comparing this time course
to that of GDP occurrence and susceptibility to seizures
induced by elevated KCl, they found a close correspondence. GDPs were present in all slices from P0 to P9 and
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1IK(Ca)
926
WILLIAM J. MOODY AND MARTHA M. BOSMA
Physiol Rev • VOL
even subtle changes in the properties of currents measured under voltage clamp can have marked effects on the
firing properties of neurons, especially in complex circuits. These effects are caused by a specific downregulation of HCN1 channel subtype and increased HCN2 subtype in both CA1 and CA3 neurons (74). Other studies
have also implicated seizure-induced changes in intrinsic
neuronal properties as possible mechanisms of seizureinduced hyperexcitability. Long-term postseizure increases in burst generation (147), decreases in IK(Ca) expression (262, 599), increased input resistance (262), upregulation of T-type Ca2⫹ currents, and downregulation of
N-type currents (568) have all been reported. Many of
these changes effectively reverse developmental events
that have been shown to help terminate normal spontaneous activity, such as IK(Ca) upregulation, early developmental prominence of T-type Ca2⫹ currents, and high
input resistance of immature neurons. They thus suggest
a close relation between the disruption of activity and
activity-dependent processes and the aftereffects of seizure activity. Another excellent example of how seizure
activity in one set of neurons can induce independent
seizure foci in another by interfering with normal developmental processes is seen in a recent paper by Khalilov
et al. (282). Using an intact two-hippocampi preparation
in which the two structures can be independently exposed to drugs, they showed that repeated kainate-induced seizures in one hippocampus can induce independent seizures in the other. This effect was due purely to
the propagation of TTX-sensitive action potentials to the
“naive” hippocampus, but could be prevented by blocking
NMDA receptors. The specific requirement for NMDA
receptor activation was indicated by the fact that NMDA
blockers did not prevent acute propagation of the seizures
to the naive hippocampus, but did prevent the establishment of an independent seizure focus there. The establishment of the mirror focus was accompanied by a positive shift in Cl⫺ potential, indicating the possibility that
the incoming activity had delayed the normal developmental reduction in intracellular Cl⫺ concentration that
shifts GABA action from excitatory to inhibitory. This
may be another example of the “dedifferentiation” of
electrical properties created by injury. Seizure activity
can also trigger changes in the spatial distribution of
channels (411).
Other work indicates that this kind of activity-dependent effect of seizures on ion channels may underlie some
instances of the development of resistance of seizures to
antiepileptic drugs. In human hippocampi from patients
that had developed carbamazepine-resistant seizures, the
normal use-dependent block of Na⫹ channels by this drug
had disappeared, suggesting that seizure activity had triggered the modification of Na⫹ channels (497).
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gradually disappeared from P10 to P16, closely following
the GABA switchover. Seizure susceptibility was bellshaped between P6 and P16, with a peak at P11. This
implies that the switch of GABA to inhibition may govern
the decline of seizure susceptibility, whereas the onset
may rely on other factors, such as the emergence of
synaptic circuitry or early developmental changes of
intrinsic neuronal properties. They also found, as have
others, a mixed functional excitatory and inhibitory
action of GABA even at stages when it generates depolarizing responses (see sect. IVC). This work also emphasizes the point that early seizure activity occurs at
the same stages as normal spontaneous activity and
indeed has been shown to disrupt spontaneous GDPs in
hippocampus (281).
Several experiments indicate the early seizure activity has long-term deleterious effects on processes that are
known or likely to be dependent on spontaneous activity.
Hippocampal slices cultured under conditions that trigger
seizurelike activity (picrotoxin) show inhibited growth of
mossy fibers to their normal targets, but increased targeting to other areas (257), reminiscent of improper targeting
of thalamic axons to visual cortex in activity-blocked
brains. L-type Ca2⫹ channel blockers, but not antagonists
of T-type Ca2⫹ or NMDA channels, were protective
against this effect, reflecting the many roles of Ca2⫹ influx
through L-type Ca2⫹ channels during normal activity-dependent development (see sect. IIIA3). [It is interesting
that L-type Ca2⫹ channel blockers can also protect against
long-term behavioral aftereffects of repetitive early seizures, even though they do not block the seizure activity
itself (406).] Repetitive seizures in hippocampus also reduce neurogenesis (385). Other long-term effects are
more subtle. Repetitive hippocampal seizure activity does
not cause substantial acute cell loss, indicating the lower
sensitivity to seizure-induced cell death in the immature
brain, but it does increase in the sensitivity of the hippocampus to later seizure-induced cell death (524).
Some of the most interesting and relevant studies
revolve around the question of how repeated seizures at
early stages can induce independent seizure foci, and how
that phenomenon might relate to activity-dependent development of ion channels. Reactive febrile seizures are
the most common seizure type in children, and it is a
matter of some controversy whether they increase the
later incidence of limbic epilepsy. Two recent studies
indicate that experimental hyperthermia-induced seizures
in rats can lead to long-term effects on neuronal excitability. Tested 1 wk after the seizures, hippocampal neurons
showed a small positive shift in the inactivation versus
voltage curve for Ih (102), resulting in increased postinhibitory rebound. This finding clarified how hyperthermiainduced seizures can increase circuit excitability while
also increasing inhibition. It also emphasizes the fact that
ACTIVITY-DEPENDENT DEVELOPMENT IN NERVE AND MUSCLE
VII. SUMMARY
Address for reprint requests and other correspondence:
W. J. Moody, Dept. of Biology, Univ. of Washington, Seattle, WA
98195 (E-mail: [email protected]).
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