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Annu. Rev. Physiol. 2001. 63:847–69
c 2001 by Annual Reviews. All rights reserved
Copyright MAINTAINING THE STABILITY OF NEURAL
FUNCTION: A Homeostatic Hypothesis
Graeme W Davis1 and Ilya Bezprozvanny2
1Department of Biochemistry, University of California, San Francisco, San Francisco,
California 94143-0448; e-mail: [email protected]; 2Department of Physiology,
University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040;
e-mail: [email protected]
Key Words learning, synaptic plasticity, calcium, synaptogenesis, growth
■ Abstract The precise regulation of neural excitability is essential for proper nerve
cell, neural circuit, and nervous system function. During postembryonic development
and throughout life, neurons are challenged with perturbations that can alter excitability,
including changes in cell size, innervation, and synaptic input. Numerous experiments
demonstrate that neurons are able to compensate for these types of perturbation and
maintain appropriate levels of excitation. The mechanisms of compensation are diverse, including regulated changes to synaptic size, synaptic strength, and ion channel
function in the plasma membrane. These data are evidence for homeostatic regulatory
systems that control neural excitability. A model of neural homeostasis suggests that
information about cell activity, cell size, and innervation is fed into a system of cellular
monitors. Intracellular- and intercellular-signaling systems transduce this information
into regulated changes in synaptic and ion channel function. This review discusses
evidence for such a model of homeostatic regulation in the nervous system.
INTRODUCTION
An increasing body of experimental evidence demonstrates that neurons have the
capacity to respond to perturbations such as inappropriate synaptic function or
altered innervation and thereby maintain their function within a normal physiological range (1). These experiments suggest that neurons have the capacity to
monitor their own activity levels and transduce this information into regulated
changes in excitability. For example, a neuron or muscle that is challenged by
excessive innervation can regulate the function of each impinging synaptic terminal, decreasing the strength of each synapse such that the sum total excitation is
normal despite the presence of abnormal innervation (1–3). The mechanisms that
monitor excitation and maintain the functional properties of neurons and muscle
are by definition homeostatic. These experiments have led to an emerging theory
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of neural homeostasis that may provide a basis for understanding how the stability of neural circuitry is maintained. Homeostatic regulation of neural activity
could maintain the robust function of the nervous system during the restructuring
and refinement of neural circuits that occur during postembryonic development.
Homeostatic mechanisms may also ensure that neurons in all areas of the brain
continue to function appropriately throughout life. Most neural circuits remain
robust throughout life. During this time, most cellular components are recycled
many times. One implication is that synaptic connections, once established, must
be continually maintained (1, 4).
Homeostasis is one of the most basic cellular processes by which a cell responds
to a change in the intracellular or extracellular environment and maintains a constant physiology. Homeostatic processes have been revealed in systems ranging
from the cellular response to changing extracellular osmolarity to the system-level
maintenance of blood pressure (5). In the nervous system, the maintenance of
nerve cell excitation within reasonable physiological limits is a form of electrical
homeostasis ensuring that an individual neuron is neither induced to fire action
potentials excessively nor silenced.
Our ability to learn and adapt to our environment is thought to require changes
in synaptic connectivity and neural excitation (6). It is essential, therefore, that
the homeostatic regulation of neural activity does not preclude activity-dependent
modification of neural circuitry. Rather, homeostatic mechanisms might establish
limits beyond which activity-dependent changes may not reasonably modify cellular activity. As such, homeostatic regulation will ensure the stability of neural
function without impairing our capacity for neural change. Thus whereas synaptic
competition, activity-dependent synaptic plasticity, and neurotrophism encompass
mechanisms that can generate precise change in synaptic structure and function
(7–9), homeostasis is thought to constrain this change within reasonable physiological limits.
The mechanisms of homeostatic regulation in the nervous system remain to be
characterized in any detail. The experimental data suggest that there are many
different types of regulation. Regulatory changes can be cell autonomous or can
involve intercellular-signaling events. Homeostatic changes in ion channel density
and neurotransmitter receptor function have been observed that allow neurons to
modulate excitability cell autonomously. In other examples, trans-synaptic signals
have been implicated in the homeostatic regulation of synaptic function (1, 4). It
is also possible that homeostasis may be expressed at a circuit or system level.
The types of perturbation to which neurons have been demonstrated to respond
in a homeostatic manner are also diverse. Homeostatic compensation has been
demonstrated in response to altered innervation, altered synaptic function, and altered cellular depolarization (1, 4). In addition, it is hypothesized that homeostatic
mechanisms allow neurons and muscle to remain functional during the dramatic
changes in cell shape and size that occur in normal development. The presence
of multiple, redundant types of homeostatic signaling may be a consequence of
the many different perturbations to which a cell must respond. Alternatively, such
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mechanistic diversity may ensure a robust regulatory system. The implicit importance of homeostasis to appropriate neural function suggests that there are links
to neural disease. Homeostatic regulation has been observed as a response to
disease and damage in the nervous system. Ultimately, a thorough understanding
of homeostatic signaling at a cellular and molecular level will be required before
impaired homeostatic systems can be investigated as a cause of neural disease.
EVIDENCE FOR HOMEOSTATIC REGULATION
IN THE NERVOUS SYSTEM
In systems ranging from the invertebrate neuromuscular junction (NMJ) to
synapses in the vertebrate cortex, increasing evidence supports the hypothesis that
homeostatic processes maintain stable levels of neuronal activity. In each experiment, synaptic or neuronal functions are examined before and after experimental
perturbations that alter innervation, excitation, or cell growth. The data demonstrate that neurons and muscle have a remarkable capacity to respond to these
perturbations and return to function within their normal physiological range—an
indication of homeostatic regulation. Evidence for homeostatic regulation in the
nervous system has been the focus of two recent reviews (1, 4). In this section we
highlight several additional experiments and add further discussion.
Homeostatic Response to Altered Post-Synaptic Excitability
at the Vertebrate and Invertebrate Neuromuscular Junction
Two independent genetic manipulations have been used to impair post-synaptic
excitation at the Drosophila NMJ. The Drosophila NMJ is glutamatergic. Electrophysiological analysis of glutamate receptor knockouts reveals a reduction in quantal size (most likely owing to the altered conductance of the channels formed by
the remaining glutamate receptor subunits). Remarkably, impaired post-synaptic
receptor function is precisely compensated for by increased presynaptic transmitter release, resulting in normal muscle depolarization (10). Identical results were
obtained by muscle-specific overexpression of protein kinase A. Increased protein
kinase A activity decreases quantal size (11). Again, presynaptic release precisely compensates for reduced quantal size, and the evoked depolarization of the
muscle remains normal. Thus two independent genetic manipulations that alter
post-synaptic glutamate receptor function demonstrate that presynaptic transmitter
release is modulated in response to changes in post-synaptic excitability. In each
example, it is hypothesized that homeostatic-signaling systems modulate presynaptic release via a retrograde signal from muscle to nerve. Either this retrograde
signal may enhance release, or these effects may be achieved by the repression of
a negative regulator of presynaptic release (12).
A similar homeostatic change has been observed at the vertebrate NMJ in experiments examining neuromuscular function in neuregulin-knockout mice. In
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heterozygous knockout mice, post-synaptic acetylcholine receptor clustering is
reduced, and, as a result, there is a decrease in the post-synaptic sensitivity to
acetylcholine (13). As in Drosophila, there is a compensatory increase in presynaptic transmitter release at these synapses. Thus despite the large safety factor
at the vertebrate NMJ, homeostatic regulatory mechanisms can be revealed. This
raises the possibility that such homeostatic compensation may play a significant
role in the maintenance of the vertebrate neuromuscular synapse during normal
growth and function.
The observed compensatory increase in synaptic efficacy, at both the Drosophila
and vertebrate NMJs, is achieved during development. Therefore, the changes
could be mediated by an increased rate of active-zone insertion. Alternatively, a
portion of active zones at the wild-type synapse might normally be silent during
development (14). Unveiling silent synapses could act as a compensatory response.
Finally, a change in presynaptic release at the wild-type complement of active zones
is also consistent with the observed data.
Homeostatic Response to Altered Post-Synaptic Excitability
at Central Synapses
Neurons of the lobster stomatogastric ganglion show a remarkable ability to regenerate their stereotypic bursting properties after acute isolation from their normal
synaptic circuitry (15, 16). In these experiments, single neurons are isolated from
their surrounding synaptic circuitry and placed in single-cell culture. Remarkably,
these single cells regenerate their endogenous bursting properties in the absence
of patterned synaptic input by modifying the balance of their voltage-gated channel densities. This homeostatic modification of channel density can be blocked
by supplying patterned activity, and it can also be blocked by preventing calcium
entry to the neuron (15–17). The implication is that calcium entry is utilized as a
means to monitor altered activity levels in the neuron. In this case, since cells are
isolated from their surrounding synaptic connections, the source of calcium is
likely to be calcium channels. The ability of calcium to act as an activity sensor is
discussed at length in later sections.
An alternate form of compensation has been observed in vitro at vertebrate
central synapses. Cortical synapses in culture have the capacity to modulate postsynaptic sensitivity to neurotransmitters in response to either increased or decreased excitation (18, 19). In these experiments, increased excitation is achieved
by chronically blocking inhibitory synaptic input. Reduced excitation is achieved
by bathing cultures in tetrodotoxin (TTX). A remarkable feature of the observed
compensation is the demonstration that quantal size not only compensates for altered excitation (increased quantal size compensates for TTX treatment and vice
versa) but that compensation is achieved by factorial scaling of the size of the quantal current (18). These results implicate mechanisms of receptor insertion as a form
of compensation (20). More recently, the activity of brain-derived neurotrophic
factors has been implicated in this homeostatic response (21).
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Homeostatic Response to Altered Innervation at Central
and Neuromuscular Synapses
The homeostatic control of neuronal or muscle function implies that the summed
strength of all synaptic inputs should remain within certain bounds. According
to this hypothesis, increasing the number of synaptic contacts to a single target
should result in reduced synaptic efficacy at all (or a portion) of the synaptic
terminals on a given target, and reducing the number of synaptic contacts should
have the opposite effect. These phenomena have been observed at both central
and neuromuscular synapses (1–3).
At a vertebrate central synapse in vitro, focal recordings from individual boutons (a single active zone) demonstrate that total target innervation is inversely
correlated with the efficacy of transmission at each individual active zone (3).
Cells that receive increased innervation show decreased efficacy at each individual
active zone and vice versa. The apparent compensatory response is achieved by an
altered post-synaptic response to neurotransmitter (3). One possible interpretation
is that the post-synaptic cell senses increased innervation, potentially through altered excitation, and this cell generates a compensatory change in synaptic efficacy.
Alternatively, if quantal size is determined by post-synaptic receptor density, then
the distribution of a fixed number of receptors across various numbers of synaptic
inputs could, in theory, account for this result.
Another test of the homeostatic response to altered innervation was recently
achieved at the Drosophila NMJ (2). These experiments exploited a natural pattern of muscle innervation in which a pair of motoneurons each contacts two
adjacent muscle targets. Innervation from these two motoneurons was biased
onto one muscle target and away from the adjacent muscle target by overexpression of the cell adhesion molecule Fasciclin II (Fas II) exclusively in one of the
two target muscles. The total bouton number was conserved such that one muscle received increased innervation (the muscle overexpressing Fas II) and the
adjacent target received decreased innervation (having normal levels of Fas II
expression) (22). Despite experimentally induced altered innervation (either an
increase or decrease in bouton number), the muscles were normally depolarized,
demonstrating a homeostatic response to altered innervation (Figure 1). At the
target with fewer boutons, there was an increase in quantal size that produced
a compensatory increase in muscle excitability, thereby generating normal depolarization. At the muscle target receiving increased innervation, there was a
decrease in presynaptic release from each synaptic bouton, which allowed, once
again, normal muscle depolarization. Taken together, these results demonstrate that
homeostatic regulation of synaptic function is not only target specific, but it can
be achieved through independent mechanisms at the terminals of a single neuron
(2; Figure 1).
Synaptic competition drives many of the rewiring events that occur during
postembryonic development (8, 9). A remarkable feature of synaptic competition
is the ability of the post-synaptic cell to remain functional despite the pruning
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Figure 1 Homeostatic compensation for altered innervation at the Drosophila neuromuscular junction. (Top) A diagram of the motoneuron innervation to muscle 6 and muscle 7 in
Drosophila. A single synaptic bouton is diagrammatically enlarged. Single boutons at the
mature synapse contain multiple active zones (∼12 on average). (Bottom) Two images of
the neuromuscular synapse are shown, the wild-type synapse at muscles 6 and 7 and an example of altered innervation after the overexpression of the cell adhesion molecule Fasciclin
II only on muscle 6. The neuromuscular synapse is biased toward growth on muscle 6 and
is biased away from muscle 7. At right, the results of quantal analysis are summarized for
each muscle. Despite increased innervation at muscle 6, muscle depolarization is wild type.
There is a compensatory decrease in per-bouton transmitter release resulting in normal total
transmitter release. Despite reduced innervation at muscle 7, the muscle depolarization is
wild type. There is a compensatory increase in quantal size that allows normal muscle depolarization despite fewer synaptic boutons. Thus two independent forms of compensation
occur at the terminals of a single motoneuron contacting neighboring muscle targets.
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and sprouting of presynaptic input(s). An interesting possibility is that synaptic
competition is played out in a background of homeostatic regulation.
Homeostatic Response to Cellular Growth
The physiological changes caused by cellular growth are some of the most drastic
perturbations that an individual cell will confront. During postembryonic development, a muscle cell can achieve a tremendous increase in size and mass (>50-fold
growth in many vertebrate and invertebrate systems). Muscle has a requirement
for homeostatic regulation of depolarization during this growth. As muscle size
increases, input resistance decreases (23, 24). Decreased input resistance causes
decreased depolarization for a given amount of synaptic current. Yet muscle must
receive nearly constant levels of depolarization so that appropriate contractile properties are maintained. Developmental observation of neuromuscular transmission
during a period of 40-fold growth at the crayfish NMJ demonstrates that constant levels of muscle depolarization are maintained by an increase in presynaptic
transmitter release (achieved through growth of the motoneuron terminal) and an
increase in the quantal size (23, 24). Thus compensatory changes are observed
both pre- and post-synaptically to compensate for growth-related changes in muscle excitability. It has been proposed that a signal from muscle to nerve regulates
presynaptic growth and function to compensate for the drop in muscle input resistance that occurs during growth (23–25). Recent experiments at the Drosophila
NMJ provide experimental evidence supporting the presence of a homeostatic,
retrograde-signaling system that couples synaptic development to muscle growth
(1, 10).
Several experiments demonstrate that neurons are able to preserve their unique
response properties during profound cellular growth—a form of homeostatic regulation. An insect giant interneuron, for example, preserves its response properties
to sensory input during an ∼50-fold increase in cell size by precisely coordinating
the growth of dendrite diameter and dendrite length. This type of growth (termed
ISO-electronic growth) alters the physical dimensions of the cell to preserve cellular response properties (26). There appear to be other solutions to this problem.
As the dendrites of a central neuron grow, pre-existing sites of synaptic input
become physically and electrically more distant from the soma. The presence
of voltage-gated channels in the dendrite plasma membrane of vertebrate central
neurons has been proposed as a mechanism to help propagate synaptic inputs made
in distal regions of the dendritic tree to the site of synaptic integration (27, 28). It
is not known whether these dendritic voltage-gated currents change in a coordinated manner during dendrite growth. In other instances, neurons appear to have
evolved to take advantage of the changing response properties caused by growth
to generate new functionality (29).
Homeostasis During Disease and Injury
The hypothesis that homeostatic regulation maintains the stability of neural function in the nervous system implies that this process should be revealed in the
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etiology of neural disease. Myasthenia gravis affects the neuromuscular synapse,
causing a progressive loss of post-synaptic acetylcholine receptors. Decreased
receptor function is compensated for by increased presynaptic release at human
myasthenic muscle (30, 31), a result that parallels experimental observations at the
Drosophila NMJ (10, 11) and at the NMJ of neuregulin-knockout mice (13).
Postpolio syndrome describes the gradual loss of neuromuscular function in
a current population of people who survived polio as children (32). The neuromuscular synapses of these survivors are regenerated synapses that can be smaller
than normal but are able to function at wild-type levels. In some cases, there is
evidence of a compensatory enhancement of presynaptic release at these terminals.
The cause of postpolio (the regression of these regenerated synapses after many
years of nearly wild-type function) is not well understood, but it may include a
gradual loss of compensatory mechanisms that are normally required to maintain
wild-type function at regenerated, postpolio, neuromuscular synapses (32).
The disruption of homeostatic regulation might adversely alter the function
of neural circuits, resulting in seizure-like activity or degeneration. Moreover,
homeostatic mechanisms that normally ensure a balance of synaptic efficacy in
the central nervous system might lead to various clinical syndromes of the injured
central nervous system (1). For example, spinal cord injury leads to the removal of
major classes of descending and ascending inputs. As a result, homeostatic mechanisms controlling synaptic strength might lead to the observed, inappropriate
strengthening of persisting inputs, resulting in debilitating post-traumatic disorders. As another example, lesions of mature axons in a hippocampal slice induce
numerous changes, including the formation of new axon collaterals, an increase in
synaptic connectivity between neurons, and hyperexcitability (33). These results
implicate a homeostatic response to injury that could be deleterious and may be
related to the cause of post-traumatic epilepsy (33). We understand very little about
the underlying mechanisms of the diverse homeostatic regulatory mechanisms that
have been observed. We can only speculate on the relationship between homeostatic signaling and the basis for a broad spectrum of other neurological disorders
and diseases.
Model for Homeostatic Regulation
The types of perturbations to which neurons and muscle are known to respond in
a homeostatic manner include changes in cell growth, innervation, and excitability. Each of these perturbations ultimately impacts post-synaptic depolarization.
Thus it seems likely that neurons and muscle are endowed with the capacity to
monitor levels of activity or depolarization to initiate a compensatory response. It
is also possible that neurons and muscle can monitor cell growth and innervation
independently of the effects of these parameters on cellular depolarization. This is
suggested by the observation that perturbations producing the same effects on postsynaptic depolarization do not always initiate the same compensatory response.
For example, there are different responses to decreased innervation vs decreased
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post-synaptic receptor sensitivity at the Drosophila NMJ. Furthermore, increased
innervation and increased post-synaptic receptor sensitivity will both increase postsynaptic depolarization, but increased receptor sensitivity is not compensated for,
and the muscles become super excited (1, 2, 11).
The experiments and developmental observations made to date suggest a model
of homeostatic regulation in the nervous system (Figure 2). Information about
cell activity, cell size, and innervation is fed into a system of cellular monitors.
Cellular monitors are likely to reside in the soma so that summated activity or
size can be monitored. Important components may also be localized at synaptic
sites to achieve specificity. Information regarding activity, size, or growth is then
transduced from various monitors to intracellular signals (potentially requiring
transcriptional regulation) that act on effectors such as post-synaptic transmitter
receptors or ion channels in the plasma membrane. Modulation of presynaptic
release via retrograde signaling, as demonstrated at the Drosophila NMJ, will require trans-synaptic signaling to receptors and effectors at presynaptic terminals.
The mechanism by which various monitors are coupled to compensatory signaling may be continuous, or a cell may establish thresholds beyond which changes
Figure 2 A model for homeostatic regulation at the Drosophila neuromuscular junction.
A homeostatic regulatory system that assures proper muscle depolarization will include a
system of post-synaptic monitors of muscle depolarization. It is possible that muscle size
and synapse sizes are monitored simultaneously through their respective effects on muscle
depolarization. It is equally likely that there will be independent systems that can monitor
muscle size and synapse sizes independent of each other and independent of muscle depolarization (thin versus thick arrows). The assimilation of this information into meaningful
trans-synaptic signals will likely include both positive and negative regulators.
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in activity, size, or innervation are not tolerated. The next sections describe
evidence for cellular monitors that may transduce activity or growth into meaningful chemical signaling within or between cells.
CELLULAR MONITORS OF CELL MASS AND GROWTH
The connection between cellular growth (increased cell mass) and other cellular
processes is a well-established feature of the developmental program. Experiments
at the intersection of cell cycle control and embryonic development demonstrate
that cells have the capacity to monitor cell mass and control both cellular growth
and cellular proliferation (34). One example is the presence of a cell mass checkpoint during progression through the cell cycle. Cells must attain a certain mass to
progress through the cell cycle (35). If cells in culture are limited in their growth,
they stop proliferating, and synchronous proliferation begins upon the addition of
nutrients or growth factors. Progress through the cell cycle can be driven experimentally by activation of cell cycle regulators (34). However, when division occurs
without cellular growth, the cells continue to decrease in size until catastrophe.
The systems that monitor cell size can be coupled to intercellular signaling and
regulatory events, which demonstrates that monitors of cell mass can be coupled
to other cellular regulatory systems, including intercellular signaling (34). Thus
it seems plausible that monitors of cell mass may also be coupled to homeostatic
systems that regulate neuronal and muscle excitability during growth. The presence of cell mass monitors raises the issue of the extent to which differences in
neuronal size and complexity are impacted by cell-autonomous monitors of growth
vs extrinsic factors that influence, for example, dendrite outgrowth and branching.
It is almost certain that both cell-autonomous and exogenous factors are involved
(36).
CELLULAR MONITORS OF ACTIVITY
Intracellular calcium levels can provide a sensitive readout of cellular activity
in both neurons and muscle (37–39). Activity-induced calcium oscillations can
be generated by calcium entry through neurotransmitter receptors, voltage-gated
calcium channels, and calcium release from intracellular stores. Each source of
calcium can provide temporal information about changes in activity and spatial
information from different subcellular localization and diffusion within the cell. It
has been demonstrated in a number of systems that information can be encoded in
the frequency, amplitude, duration, and number of calcium oscillations (39–42).
There are many questions related to calcium-dependent monitors of neural
activity. How are calcium transients reliably encoded in the intracellular-signaling
machinery (what are the calcium sensors)? If homeostatic regulatory machinery
acts downstream of calcium sensors within the cell, how is flexibility achieved
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such that each cell can establish different calcium-sensitive responses or a similar
homeostatic response to a very different calcium signal? For example, a tonicfiring neuron has different requirements for homeostatic regulation compared with
a phasic-firing neuron. Furthermore, over time the properties of a cell may change
and the homeostatic system that monitors activity must, therefore, be adaptable.
The hypothesis that calcium-dependent signaling could be the basis for a homeostatic monitor of neuronal activity was originally proposed in experiments that
modeled the changes in ion channel density observed in stomatogastric neurons
of the lobster after acute isolation in cell culture (15, 43). A series of calciumsensitive frequency filters were modeled that were sensitive to different frequencies of calcium oscillation. By coupling information from the calcium filters to
ion channel densities, the authors were able to effectively model the homeostatic
regulation of ion channel density that was observed experimentally. The use of
calcium frequency filters takes advantage of information encoded in the timing
of calcium oscillations and is therefore more elaborate than invoking calcium set
points beyond which changes in calcium concentration are not tolerated.
CamKII
Calcium-calmodulin-dependent protein kinase II (CamKII) has many of the required features of a calcium sensor of neural activity. CamKII can act as a frequency monitor for calcium spikes (38, 39). The frequency response of this enzyme
is dependent on the properties of calmodulin (CaM) trapping and autophosphorylation (39, 44). The properties of autophosphorylation also allow this enzyme to
retain information of previous activity. For example, if the threshold for autophosphorylation is met during an initial stimulus and only a portion of the holoenzyme
subunits are autophosphorylated, then the response to subsequent low-frequency
stimuli may be increased (39, 45). Furthermore, CamKII is demonstrated, in vitro
and in vivo, to have functional output that is relevant to the modulation of neuronal
excitability, synaptic function, gene expression, and cell shape (46–48).
There are several ways that the frequency response properties of CamKII might
be modulated to accommodate different cellular set points as a homeostatic-activity
sensor. CamKII activation is sensitive to a number of cellular variables including
CaM concentration, phosphatase activity, enzyme localization, and the subunit
composition of the holoenzyme (37, 44, 46). Modulation of any of these variables will potentially modulate CamKII function. The subunit composition of the
holoenzyme may be a particularly potent parameter for altering the CamKII activity as an activity sensor. Neuronal CamKII consists primarily of two subunits,
alpha and beta. These subunits can form homomeric and heteromeric enzymes
composed of 6–12 subunits. The subunit composition influences the frequency
response properties of the enzyme (39, 44). Several experiments indicate that subunit composition may be a modifiable feature of the kinase. Increased expression
of the alpha subunit but not the beta subunit has been observed after long-term
potentiation in the freely moving rat (49). Altered subunit composition may also
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change the subcellular targeting of CamKII, and this could be a potent means of
modulating kinase sensitivity and function (50).
Calcineurin
The serine/threonine phosphatase calcineurin is another example of a calciumsignaling molecule that has recently been implicated in signaling systems that can
generate oscillation-specific changes in gene transcription (40, 51). This is most
clearly demonstrated in experiments examining the signal transduction cascade of
calcium, calcineurin, and NF-AT in lymphocytes and more recently in hippocampal neurons (40, 41, 52). Several important features of this signaling system are
worth highlighting. It can mediate calcium oscillation-specific changes in gene expression that include both changes in transcriptional selectivity and changes in the
magnitude of the transcriptional response. Signaling via calcineurin and NF-AT
is cell type specific, depending on the NF-ATc family members expressed within
each cell. Finally, this signaling system is responsive to cellular context because
the transcriptional response can be strongly influenced by convergent signaling
systems including ras and protein kinase C (40). This last point is particularly
important because it means that a calcium signal can be interpreted by the cellular
context in which the signal is delivered.
Calcium signaling and CamKII signaling have essential functions during synaptic and neuronal development. Two recent studies are particularly relevant to
the topic of homeostatic regulation. In Caenorhabditis elegans, synapse number
at central neurons remains constant during normal larval development. A genetic
analysis demonstrates that the maintenance of synapse number during development
requires voltage-gated calcium channels and CamKII (47). These results implicate
a system for maintaining synapse number and thereby maintaining post-synaptic
function that is sensitive to both voltage and calcium signaling through voltagegated channels.
Calcineurin, likewise, has functional output that is relevant to the regulation
of neuronal excitability (53, 54). Post-synaptic calcineurin has been implicated
in muscle-to-nerve retrograde-signaling systems that modulate synaptic strength
at the vertebrate NMJ, in vitro (55). More recently, calcineurin modulation of
inhibitory synaptic function has been implicated in the altered neuronal excitability
after long-term potentiation (56).
Calcium Channels
The decoding of neural activity via calcium signaling is not achieved solely in
the properties of the second messenger and transcriptional regulatory systems.
Some of the selective properties of a calcium sensor for neural activity may be
established by the properties of the voltage-gated channels themselves. L-type
calcium channels provide a source of calcium influx capable of triggering calmodulin mobilization to the nucleus and activation of CREB-mediated transcription
(48, 57). L-type calcium channels may be preferentially activated by synaptic
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potentials [excitatory post-synaptic potentials (EPSPs)] as opposed to action potentials. This is suggested by experiments monitoring the L-type calcium current
in response to simulated EPSP or action potential waveforms (57a). The differential activation of L-type calcium channels is linked to the observation that L-type
channels are activated at relatively negative potentials and have slow activation
kinetics. Both features favor activation by slow, low-amplitude EPSPs as opposed
to action potentials. One can imagine that information regarding both synaptic
and action potential activity might be necessary for a neuron to accurately achieve
homeostatic regulation. Action potentials provide information about the summed
total cellular depolarization. EPSPs can provide information about the localized
sources of depolarization within the dendritic tree.
In conclusion, calcium entry into a cell via calcium channels or transmitter
receptors can be transduced into changes in calcium and second-messenger signaling that allow a cell to decode the voltage activity of a neuron into chemical
signaling. There is the potential for this signaling to distinguish information about
summed neuronal depolarization from information about local regions of synaptic
activity in the dendrites. The responses downstream of calcium sensors can be
cell type specific and context dependent within a given cell type. These are essential features of a system capable of monitoring neuronal activity and generating
a homeostatic, compensatory response to altered activity or innervation. Many
questions remain. How does a cell establish its own particular activity set points?
Is this a cell-autonomous property linked to the genetic phenotype of a cell or is it
influenced by early activity-dependent events? If early activity-dependent events
participate in establishing the set points for the homeostasis of neuronal activity,
is there a critical period for determining the calcium sensitivity (or set points) that
will maintain cellular activity within a particular range? Can these properties be
modulated?
Specificity of Homeostatic Synaptic Regulation
The specificity of homeostatic regulatory mechanisms has yet to be explored in
any depth. A series of experiments at the Drosophila NMJ demonstrated that
homeostatic regulation of synaptic function can be target specific at the terminals
of a single neuron (2). Every other experiment has used cell-wide perturbation of
activity or innervation, and, as a result, our current understanding of homeostatic
signaling points to cell-wide regulatory change (4, 19). In theory, however, some
forms of synaptic regulation must be synapse specific if homeostatic regulation is
going to maintain the stability of neural circuitry as opposed to generating change
(thereby functioning as another expression of synaptic plasticity).
For a cell to regulate its own excitability, it requires a mechanism to monitor
summed, total excitation. One possibility is that a cell can monitor some aspect
of action-potential-induced depolarization, potentially via calcium-dependent signaling (15, 57). If a cell monitors summed depolarization in this manner, how
might a homeostatic regulatory system be established such that specificity could
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be achieved? Two candidate solutions to this problem draw on models for synapsespecific activity-dependent plasticity (Figure 3).
One possibility is that activity monitors are present in the cell soma, at a central
location capable of integrating action-potential-induced activity. This would allow
homeostatic signaling to include a transcriptional response at the nucleus. A homeostatic signal could be sent throughout the entire dendritic tree. If this homeostatic
signal required a synaptic cofactor that was sensitive to local synaptic activity such
as CaMII or calcineurin, then the a cell-wide homeostatic signal would be active
only at sites of inappropriate activity (Figure 3A). Synaptic microdomains of elevated calcium have been observed, mediated by signaling via metabotropic glutamate receptors and inositol-1,4,5-triphosphate receptors (58, 59). Because homeostatic regulation is expected to respond to persistent and inappropriate synaptic
activity, these local sites of elevated calcium signaling will not require synaptic
“memory” of previous activity or “synaptic tagging,” both of which have been proposed as mechanisms for synapse-specific long-term synaptic plasticity (60, 61).
A second possibility is that the entire homeostatic-signaling mechanism is localized post-synaptically at each synapse. Information about sum total excitation
could be conveyed to every synapse via action potential back propagation. In this
model, each synapse would be endowed with a mechanism for comparing the activity of back propagating action potentials with local synaptic activity (Figure 3B).
There is evidence that modulation of synaptic strength via correlated activity might
be highly sensitive to the timing of synaptic and action-potential-mediated depolarization (62), and this could conceivably be utilized to mediate homeostatic
regulation of synapses in this manner. However, purely Hebbian mechanisms may
not be sufficient to account for homeostatic synaptic regulation because synapses
that participate in firing a post-synaptic cell, but do so inappropriately, should be
downregulated according to a homeostatic hypothesis.
SIGNALING AT THE SYNAPSE
The evidence for homeostatic regulation of synaptic and neuronal function implies
the presence of elaborate intracellular- and intercellular-signaling mechanisms.
Signaling from the site of activity integration to sites of synaptic input is essential.
At the synapse, there is evidence for modulation of transmitter receptor function
or insertion. There is also evidence for trans-synaptic signaling systems that can
modulate presynaptic release.
Trans-Synaptic Signaling
Nerve growth factors and neurotrophins are among the most intensively studied
trans-synaptic signaling molecules. Neurotrophins in particular have been implicated as both survival factors and as mediators of activity-dependent synapse modification (7). Alternatively, biochemical and cell-biological evidence is
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Figure 3 Synapse-specific homeostatic signaling. A neuron with two sources of synaptic input is diagrammed. (A) Monitors of summed excitation may be located in the soma.
Depolarization is transmitted to the soma via passive or active dendritic propagation. Homeostatic regulatory signals are then sent back to the dendrites in a uniform manner, but they
only generate regulatory changes at synapses with inappropriate synaptic activity [increased
synaptic excitation (right)]. Sites of inappropriate synaptic activity may be recognized by
the homeostatic signals owing to localized calcium-dependent signaling, potentially involving the activity of Cam kinase or calcineurin. (B) An alternate model proposes that
information of summed excitation is monitored via back propagating action potentials.
Activity sensors at each synapse (synapse-specific monitors) could achieve homeostatic
change through the comparison of synaptic vs action potential activity at each individual
synapse.
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accumulating to suggest a model of trans-synaptic signaling that is achieved via
a trans-synaptic scaffold of proteins that spans the synaptic cleft from the postsynaptic density to the presynaptic cytoskeleton.
Biochemical data have linked proteins of the pre- and post-synaptic densities
via a trans-synaptic, asymmetric neuroligin-neurexin junction (63, 64). Neurexins
have a single transmembrane domain and a short carboxy tail with protein 4.1 and
CASK-PDZ domain-binding sequence motifs (65). Proteins with similarities to
neurexins have been shown to mediate axon-glia interactions (66, 67). The subcellular localization of neurexins within central neurons remains to be determined.
However, neuroligin-1 is localized postsynaptically at central synapses and has
been shown to be a beta-neurexin ligand (68–70).
Three neuroligins have been identified in the rat, and two neuroligins have
been recently identified in mice (71). All three neuroligins possess an extracellular domain that shares homology with acetylcholinesterase, although this domain
does not have enzymatic activity (68). All of the neuroligins have a cytoplasmic
domain with a PDZ-binding motif capable of binding synaptic adapter proteins including post-synaptic density protein (PSD)-95 (72). Thus the neuroligin-neurexin
asymmetric junction is linked to a large network of synaptic proteins through the
binding of modular adapter proteins such as CASK and PSD-95 via PDZ-mediated
interactions.
Biochemical data have been assembled that describe a core trans-synaptic protein scaffold around the neurexin-neuroligin asymmetric junction that is hypothesized to participate in the organization of the synapse (Figure 4A). This model
assumes an asymmetric junction with presynaptic neurexin and post-synaptic neuroligin. Presynaptic neurexin interacts with an evolutionarily conserved protein
complex consisting of CASK, MINT1, and Veli (63). CASK, MINT1, and Veli
are modular adapter proteins that contain multiple protein interaction domains including PDZ and SH3 domains. Significantly, both CASK and MINT1 are linked
biochemically to the presynaptic calcium channel (64). The CASK SH3 domain
has been shown to interact with a proline-rich sequence in the presynaptic calcium
channel (64). The carboxy terminus of the apha1a and alpha1b calcium channel
subunits also binds to the first PDZ domain of MINT1. Post-synaptically, neuroligin interacts with PSD-95 (72). Many other constituents of the post-synaptic
density interact with PSD-95 including CamKII, nitric oxide synthase, and potassium channels (73). Thus an extensive trans-synaptic protein complex is linked
biochemically to presynaptic calcium channels (64).
This extensive, trans-synaptic protein complex could serve to regulate the localization or function of presynaptic calcium channels. Because transmitter release is
exquisitely sensitive to the function and most likely the localization of the presynaptic calcium channel, this trans-synaptic protein complex may have a potent
influence on synapse organization and function. This model is supported by genetic analysis of an analogous Lin-10/Lin-2/Lin-7 protein complex in C. elegans.
The Lin-10/Lin-2/Lin-7 complex is necessary and sufficient for basolateral localization of the epidermal growth factor receptor tyrosine kinase Let-23 and is
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necessary for post-synaptic glutamate receptor localization in C. elegans (74, 75).
Until recently, however, there has not been experimental evidence supporting a role
for the neurexin-neuroligin trans-synaptic complex in either synapse formation or
modulation.
An elegant series of recent experiments demonstrated a role for the neuroliginneurexin interaction in synapse formation (71). In these experiments, neuroligin
expression was demonstrated to be sufficient to induce presynaptic differentiation
in vitro. Neuroligin-induced synapse formation was analyzed both at the light level
and ultrastructurally. This synaptogenic activity is mediated by specific sequences
in the esterase domain of neuroligin, and evidence suggests that this signaling
is mediated through interaction with presynaptic beta-neurexin (71). Among the
synaptic proteins that are assembled by the neuroligin-neurexin interaction are
synapsin and the modular adapter protein CASK/lin2. These data provide the first
evidence of a cell-contact-mediated signaling event that is sufficient to drive
synapse formation in the central nervous system. It remains to be determined
whether similar signaling may occur at a mature synapse. The function of this
complex, in vivo, also remains to be clarified. A neuroligin knockout is remarkably healthy (68). Neuroligins have widespread expression, however, and it is
possible that different neuroligins have partially overlapping functions (68, 71).
A recent result by Hsueh et al (76) offers a further glimpse of possible signaling
from this extensive trans-synaptic protein complex. The modular adapter protein
CASK/Lin2 is concentrated at central synapses and binds to neurexin and syndecan
proteins at the plasma membrane as well as binding the cytoplasmic proteins Mint
and Veli. Recent work demonstrated that CASK can enter the cell nucleus and bind
to specific DNA sequences (called T elements) in a transcriptional coactivation
complex with Tbr-1 (76). Among the T-element-containing genes that may be
regulated by the CASK/Tbr-1 complex is reelin, a gene implicated in cerebrocortical development. Thus an integral element of the trans-synaptic protein complex
can signal to the nucleus and modulate transcription. Parallels can be drawn to
cadherin signaling via beta-catenin from the cell plasma membrane to the nucleus
(77), suggesting that this scenario may become a more common aspect of synaptic
signaling and regulation. The mechanism by which CASK nuclear translocation
is initiated and the role of this signaling in synaptic regulation remain unclear.
The generality of such a trans-synaptic signaling scaffold is suggested by the
recent demonstration of a similar system at the vertebrate NMJ (78). In this system,
biochemical data link synaptic alpha 4-beta 2-gamma 1 laminin to a presynaptic
protein complex that includes a calcium channel subunit (Figure 4B). A potential trans-synaptic protein complex can be achieved through the synaptic basal
lamina that traverses the neuromuscular synaptic cleft. Thus biochemical data at
both central and neuromuscular synapses implicate a network of protein-protein
interactions that may unify the pre- and postsynaptic densities.
A role for trans-synaptic adhesion in synaptic regulation is not unique to the
neurexin-neuroligin junction. Homophilic cell adhesion molecules with the potential to signal across the synapse have been implicated in the mechanisms of
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synapse stabilization, growth, and activity-dependent plasticity (22, 79–81). Cell
adhesion-dependent changes in synaptic morphology are demonstrated to be necessary, in some systems, for activity-dependent changes in synaptic function (82).
However, signaling via cell adhesion molecules has not been demonstrated to
directly influence the mechanisms of either transmitter release or post-synaptic
transmitter detection (Figure 4C).
The complexity and extent of the synaptic signaling complex are yet to be completely realized. Forward genetic studies have begun to elucidate new elements
of the synapse that may have escaped traditional biochemical techniques owing
to their extreme size. These proteins are among a growing number of proteins
that define a perijunctional region of the synapse, just adjacent to the active zone
(Figure 4D). Perijunctional proteins include Piccolo, Bassoon, Still-life, Highwire, and Futsch (83). The Highwire protein (5233 amino acids) has recently been
demonstrated to control presynaptic growth (83, 84). Mutations in highwire show
a dramatic synaptic overgrowth phenotype, suggesting that highwire may represent
a repressor of synapse elaboration (84). The Futsch protein is also extremely large
(5327 amino acids). It is associated with the synaptic microtubule cytoskeleton
and is necessary for synaptic microtubule organization and normal synaptic growth
(85, 86). Among the constituents of the periactive zone are molecules implicated in
synaptic vesicle endocytosis. Dynamin and dynamin-associated protein (DAP160)
are localized to the periactive zone in a honeycomblike lattice that surrounds active
zones in the Drosophila neuromuscular bouton (87, 88). The function of a potential
periactive-zone protein complex remains to be determined. However, since highwire and futsch are potent regulators of synaptic growth and function, signaling via
proteins in the periactive zone may be important during homeostatic regulation.
Regulation of Post-Synaptic Neurotransmitter Receptors
An altered post-synaptic response to neurotransmitters is implicated in many of
the known examples of homeostatic regulation. A variety of different mechanisms
could account for altered post-synaptic sensitivity to neurotransmitters, including
altered receptor insertion, localization, or altered function of existing receptors.
Rapid, activity-dependent cycling of α-AMPA-type glutamate receptors appears
to be a potent mechanism for altering synaptic function during acute synaptic plasticity (20). Green fluorescent protein-tagged receptors are delivered to dendritic
spines and clusters after tetanic stimulation, and this receptor trafficking requires
activation of the NMDA receptors (89). Agents that block processes of exocytosis and endocytosis have effects on synaptic function that are consistent with a
mechanism by which receptors are trafficked to and from the synaptic membrane
(90, 91). Most recently, it has been shown that the insertion of α-AMPA-type receptors requires CamKII activity and a PDZ protein interaction (92). In principle,
intracellular-signaling systems that are coupled to the mechanisms of receptor cycling could represent a potent mechanism for homeostatic regulation of synaptic
strength.
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CONCLUSION
The mechanisms of neural homeostasis are complex and may comprise diverse,
interrelated signaling systems. Neurons and muscle are capable of responding
in a homeostatic manner to diverse types of perturbation that include altered cell
size, innervation, and excitation. The mechanisms of compensation are equally
diverse, including regulated changes to synaptic size, presynaptic release, postsynaptic transmitter sensitivity, and the balance of voltage-gated channels. The
complexity and diverse nature of homeostatic regulation may assure that neurons
and muscle have a robust system with which to regulate excitability. Ultimately,
the role of homeostatic signaling during neuronal development, the maintenance
of neural function, and the etiology of neural disease will require an in-depth
understanding of these homeostatic regulatory events at a molecular and cellular
level. Given a limited molecular understanding of neural homeostasis, a forward
genetic approach in model systems such as C. elegans and Drosophila may provide
initial insight into these processes.
ACKNOWLEDGMENTS
We thank Kurt Marek, Suzanne Paradis, and Peter Clyne for critical comments on
earlier versions of this manuscript. The writing of this review was supported in
part by the BWF and National Institutes of Health grant NS39313-01 to GWD and
grant NS39552 to IB.
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Annual Reviews
AR114-COLOR
Figure 4 Synaptic organization and trans-synaptic signaling. (A) The constituents of a neuroliginneurexin trans-synaptic complex are diagrammed. Presynaptic neurexin interacts with the evolutionarily conserved protein complex consisting of CASK, MINT, and Veli (adapter complex)
that, in turn, binds to the presynaptic calcium channel. (B) A trans-synaptic complex that parallels the neuroligin-neurexin complex has been identified at the vertebrate NMJ. Synaptic laminin
interacts with a complex that includes the presynaptic calcium channel alpha subunit. (C ) A periactive zone (perijunctional) complex is diagrammed for the Drosophila NMJ. Within this region
directly adjacent to the active zone (gray shading) are cell adhesion molecules, including integrins and Fasciclin II, capable of signaling across the synapse. PDZ-containing molecules in the
post-synaptic density (PSD), including discs-large, may organize the post-synaptic density in a
manner analogous to vertebrate central synapses. (D) Additional molecules have been localized
to the perijunctional region, including proteins involved in endocytosis [Dynamin and DAP160
(87)]. Recently a number of very large proteins have been identified that are present within the
perisynaptic region, including Highwire and Futsch.