Download 13-1 CHAPTER 13 SYNAPSES The nervous system consists of

CHAPTER 13
SYNAPSES
he nervous system consists of billions
of neurons, each one an individual
cell, receiving signals from some
other cells and generating signals of its own
to be sent to other cells. We consider here
how these signals are transferred from one
neuron to another. In most cases, there is a
gap between neurons that must be bridged in
order for transmission to continue
throughout the nervous system. In some
cases, there appears to be no gap between
possess a swelling at their ends. The
boutons, whether from myelinated or
unmyelinated fibers, are always found in
close proximity to a soma, axon, or dendrite
of another cell or to another bouton.
At the site of the termination of a fiber,
the specializations of the terminal and the
cell it contacts are called collectively a
synapse. Synapses on somas are termed
axosomatic synapses; those on dendrites are
termed axodendritic; and those on other
axons or boutons are axoaxonic. The fiber's
bouton is called the presynaptic element
and the structure it contacts is the
postsynaptic element. A schematic
diagram of a synapse is shown in Figure 131A. The pre- and postsynaptic elements are
separated by a space 15-200 nm wide,
known as the synaptic cleft. At the
synapse, the membrane of the postsynaptic
Figure 13 -1A. A schematic diagram of a synapse indicating element
the pre- is slightly thickened, and there is
T
and p ostsyna ptic elemen ts with sy naptic sp ecialization s.
the neurons. Transmission between cells
connected in this way is believed to occur by
purely electrical events. How these two
kinds of transmission occur is the subject of
this chapter.
Anatomy of a synapse.
If we follow a primary afferent fiber
along its course, we find that the fiber may
branch many times, becoming smaller each
time. If the fiber is myelinated, then near its
termination the myelin disappears and there
is a swelling of the axon, called the bouton
terminaux, end bulb, terminal, synaptic
knob, or just bouton; with this swelling, the
fiber simply ends. Unmyelinated fibers also
Figur e 13-1 B. A electron microg raph a syna pse
show ing the pre- and po stsynaptic elements with
synaptic specializations. Note the accumulation of
mitocho ndria an d presence of syna ptic vesicles in
the presynaptic membrane. The actual points of
synap tic conta ct are ind icated by the a rrow s.
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often an accumulation of some electrondense (appears dark in electron micrographs)
material near the thickened membrane. On
the presynaptic side, there is normally an
accumulation of mitochondria in the bouton
and, in electron micrographs, a large number
of spherical or irregularly shaped structures
are seen near the synaptic region. These are
called synaptic vesicles. All of these
structures except the synaptic cleft (you’d
need a higher power to see that) are visible
in the electron micrograph of Figure 13-1B.
It is believed that transmission from one
cell to another at a synapse like the one just
described (a chemical synapse, as opposed
to an electrical synapse) is accomplished by
release of a substance, the transmitter
substance, from the synaptic vesicles into
the synaptic cleft by the process of exocytosis. The identity of the transmitter substance
is unknown for most synapses. Many
candidate transmitter substances have been
suggested; however, we can be certain a
substance is a transmitter substance only if it
meets all of the following criteria:
1. The substance must occur naturally
in presynaptic terminals, and either
the precursors and enzymes for its
formation or an adequate, specific
transport system for its uptake into
the terminal must exist,
2. The substance must be released from
the terminals by nerve stimulation,
3. A mechanism must exist for rapid1
inactivation of the released
transmitter substance, i.e., it must be
degraded or taken-up again by the
terminal,
4.
A synaptic action must be identified
for the substance, and local
application must produce effects
"exactly" like those of synaptically
released transmitter substance,
5.
Drugs must produce similar effects
upon actions of the substance and
natural transmitter substance.
No one of these criteria is sufficient by
itself to define a transmitter substance. For
example, a compound, present in nerve
terminals, could not be a transmitter
substance unless it was released and unless it
influenced the postsynaptic cell. It is also
possible that a compound serves as a
transmitter substance in one neuron, but
serves a different purpose in another one.
Table 13-1 contains a list of some of the
substances that have been suggested as
chemical transmitter substances, their
presumed actions2, locations of highest
concentration within the central nervous
system, modes of action (we will have more
to say about this later), and agents that block
their actions.
It is difficult to establish the validity of
all five criteria at synapses within the central
nervous system because the cells involved
can rarely be seen; because only small
1
How rapidly the transmitter substance
must be hydrolyzed or removed from the
synaptic is determined by the duration of
action of the natural transmitter substance.
As we shall see, some transmitter substances
have only short actions; others act for long
times; some do both at different places.
13-2
2
Some care should be exercised in
attributing single actions to transmitter
substances. Acetylcholine, for example, is
usually thought of as excitatory, but there
are some cases in which it is known to be
inhibitory.
Table 13-1
Known and Putative Transmitter Substances in the Mammalian Nervous System
Presumed
action
Locations of maximum
concentration
Mode of
action
Acetylcholine
Excitation,
inhibition
Interpeduncular, dorsal raphe and
caudate nuclei, nucleus
accumbens, ventral horn of spinal
cord
Ionotropic,
metabotropic
(cGMP‡)
Curare, atropine
Glycine
Inhibition
Spinal cord, medulla, pons
Iono tropic
Strychnine
(-amino butyric acid
Inhibition
Cerebellum, cerebral cortex, spinal
cord, retina
Iono tropic
Bicuculline
Norepinephrine
Excitation,
inhibition
Pons, medulla
Metabo tropic
(cAMP†)
Pro panolol,
phentolamine
Dop amine
Excitation,
inhibition
Putamen, caudate, locus ceruleus,
hypothalamus
Metabo tropic
(cAMP†)
Phenoxybenzam ine
Serotonin (5-HT)
Excitation,
inhibition
Amygdala, hypothalamus, septum,
striatum
?
LSD !
L-Glutamate
Excitation
Temporal cortex, basal ganglia,
cereb ellum, amygd ala
Iono tropic
?
L-Asp artate
Excitation
Substantia nigra, occipital cortex,
thalamus, cerebellum,
hypothalamus
Iono tropic
?
Epinephrine
?
Thalamus, hypothalamus
Metabo tropic
(cAMP†)
Pro panolol,
phentolamine
Substance P ?
Excitation
Substantia nigra, trigeminal
nucleus, dorsal horn of spinal cord,
limbic system
Metabo tropic
(?)
?
Enkephalins ?
Inhibition
Globus pallidus, caudate, nucleus
accumbens, hypothalamus
?
Naloxone
Endorp hins?
Inhibition
Pituitary, striatum, spinal cord
?
Naloxone
Histamine
Inhibition
Hypothalamus, thalamus
Metabo tropic
(cAMP†)
Ethanolamine,
butamide
Substance
Blo cking agents
Othe rs: Ta urine, ne urotensin, carnosine , angiotensin II, hyp othalamic releasing factors, serine, proline, N -acetylL-aspartate, adenosine, P-tyramine, tryptamine
? Peptides
† cA MP = cyclic ad enosine mo nophosp hate
‡ cG MP = cyclic guanine m onophosphate
! LSD = lysergic acid diethylamide
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Table 13-2
Acetylcholine
Norepinephrine
(
-Aminobutyric acid
Glycine
Glutamate
Aspartate
Dopamine
Serotonin
Substance P
Enkephalins + Endorphins
Histamine
Status of Putative Transmitter Substances
1. Present in presynaptic
terminals–precursors and enzymes present
%
%
%
L
%
%
%
%
%
%
%
2. Released from terminals by nerve
impulses
%
%
%
x
%
%
%
%
?
?
%
3. Rapid inactivation mechanism
%
%
%
?
?
%
?
%
%
?
?
4. Known action–local application mimics
natural transmitter substance
%
%
%
%
?
%
?
?
?
?
?
5. Pharmacologically similar to natural
transmitter substance
%
%
%
%
?
%
%
?
?
?
?
Criterion
Key: % = Property demonstrated
L = Labeled substance is taken up by synapses in vitro or in vivo, but it is not know
that synapses normally contain it
x = Exogenous, labeled substance is released, but release of endogenous substance has
not been shown
? = Property not examined experimentally or results hard to interpret
quantities of transmitter substance are
released and even these are rapidly degraded
if they are not protected from enzyme action;
and because it is impossible to know if the
putative transmitter substance is being
applied near the postsynaptic membrane.
Thus, acetylcholine (ACh), norepinephrine
(NE) and dopamine (DA) have been
identified as transmitter substances at
synapses in the peripheral nervous system,
ACh at the neuromuscular junction, at all
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autonomic ganglia, and at some sympathetic
and all parasympathetic postganglionic
synapses, NE at most sympathetic
postganglionic synapses, and dopamine at
sympathetic ganglionic synapses. Table 132 shows the validity of all five criteria for
these substances and for (-aminobutyric
acid (GABA), an inhibitory transmitter
substance in the central nervous system.
The remaining compounds of Table 13-2
meet one or more of the five criteria. These
compounds must still be considered as
putative transmitter substances though some
people ignore the deficiencies and call them
transmitter substances.
Figure 13-2. A reciprocal syn aptic
relationship between two dendrites. Note the
accumu lation s of synap tic vesicles on wh at is
presumed to be the presynaptic side of the
synap ses.
accumulation of synaptic vesicles on what is
presumed to be the presynaptic side of each
synapse. The function of this arrangement is
unknown. The physiology of these new
synaptic arrangements has not been studied
in detail yet, but it can be presumed for now
that they behave like other chemical
synapses. Their presence certainly broadens
the possibilities for interactions between
neurons in the central nervous system.
Another type of synaptic arrangement
that has received a great deal of attention is
the electrotonic synapse or electrical
synapse, the substrate for which is thought
to be the gap junction. A schematic diagram
of a gap junction (sometimes called a
connexon) is shown in Figure 13-3. The
membranes of the two cells involved come
extremely close or may actually fuse
together. X-ray diffraction studies suggest
that membrane ionic channels (perhaps
sodium channels) of the two cells are in
register such that there are small conduits
between the two neurons by which their
cytoplasms could communicate. Gap
junctions are most frequently seen in
dendrodendritic, dendrosomatic, and
somatosomatic synaptic arrangements, but
Several other types of connections
between cells have been discovered. These
junctions, thought to be substrates for
chemical transmission, occur
between two dendrites
(dendrodendritic synapses), a
dendrite and an axon
(dendroaxonic synapses), a
dendrite and a soma (dendrosomatic synapses), and any part of
a neuron and a node of Ranvier
(nodal synapses). In some cases,
synapses have been described in
which a single element is both preand postsynaptic to a second
Figure 13-3. A schematic diagram of what is thought to be the
element. This arrangement, a
structure of an electrical synapse. Note that the sodium channels of
reciprocal synaptic arrangement, is the the membranes of the two cells are in register, forming a
illustrated in Figure 13-2. Note the chan nel betw een the two cells.
13-5
they do occur in other types of synapses.
Such junctions have been found in the
retina, olfactory bulb, cerebellar cortex,
lateral vestibular nuclei, inferior olive and
elsewhere, but they are also found outside
the nervous system. A role for gap junctions
in the control of cellular proliferation has
been suggested.
The majority of the synapses in the
vertebrate central nervous system are of the
axosomatic and axodendritic types and of
the chemically transmitting type. It is
therefore a small wonder that chemical
transmission is the most thoroughly
understood. There are now many reports of
gap junctions and presumed electrotonic
coupling between neurons in vertebrates,
especially in mammals. Yet, two important
morphological questions still remain
unanswered: (1) Is every structure that looks
like a chemical synapse really a chemical
and not an electrical synapse, or for that
matter a synapse at all? (2) Is every gap
junction an electrical synapse and not a
chemical synapse, or for that matter a
synapse at all? These questions are made
important by the observations that vesicles
(possibly synaptic vesicles) are found in
conjunction with both chemical synapses
and gap junctions and that gap junctions are
characteristic of epithelia, in general, and not
limited to the nervous system, which is
epithelial in origin. It is not clear that
answers to these questions are even possible.
Physiology of a chemical synapse.
An action potential, initiated in an
afferent axon, arrives at a bouton and
hypopolarizes it. Boutons hypopolarize in
the same way as axons. At this point the
action potential itself can go no farther, but
the hypopolarization of the bouton somehow
causes some of the synaptic vesicles in the
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region to fuse with the presynaptic
membrane whereupon the fused membrane
breaks and spills the contents of the vesicles
into the synaptic cleft. The release of
transmitter substances depends upon several
factors, including the magnitude of the
hypopolarization, the number of available
vesicles, and, importantly, the concentration
of calcium in the extracellular fluid.
Reduced calcium blocks synaptic
transmission. Likewise, increased manganese, a calcium inhibitor, leads to depression
or block of transmission. Calcium appears
to be necessary for hypopolarization-release
coupling. Hypopolarization leads to opening
of voltage-gated Ca++ channels and the entry
of Ca++ into the terminal. Once inside, Ca++
promotes fusion of the vesicles with the
terminal membrane and release of the
transmitter substance. The released
transmitter substance diffuses across the
cleft in a fraction of a millisecond and
interacts with the postsynaptic membrane,
changing its permeability and, ultimately,
the membrane potential at that point on the
postsynaptic membrane. The action of the
transmitter substance is terminated by its
removal from receptors on the postsynaptic
membrane. Some transmitter substances are
then degraded, e.g., acetylcholine, whereas
others are taken up by the presynaptic
terminal, e.g., norepinephrine and other
amine transmitter substances. This entire
process, from presynaptic spike to the
termination of the postsynaptic response,
frequently requires only 10-20 msec.
Most chemical transmitter substances act
by producing changes in the transmembrane
potential of the postsynaptic cell. Some
produce their effects noticeably more slowly
At ganglionic synapses of the sympathetic
nervous system acetylcholine has both a fast
action (4 to 7-msec latency and a 200-msec
duration) and a slow action (200 to 300msec latency and a 5-sec or longer duration).
Both effects occur on the same postsynaptic
cell! The rapid-onset, briefer effects of
acetylcholine at skeletal muscle are
apparently the consequence of changed ionic
conductances, resulting from conformational
changes in the membrane. These
Figure 13-4A . M odel of ion otro pic synap tic
conformational changes result from the
transmission. A transmitter substance binds to a
interaction of the transmitter substance with
receptor and opens a channel, changing
receptors3 in the postsynaptic membrane.
membrane conductance and, therefore, membrane
This is called ionotropic transmission, and
potentia l.
it is illustrated schematically in Figure
13-4A.
The longer latency and duration of
norepinephrine effects on sympathetic
postsynaptic structures have been
explained by invoking a second
messenger, in this case, cyclic
adenosine monophosphate (cAMP).
The model proposed for this kind of
transmission, called metabotropic
transmission, is shown schematically
in Figure 13-4B. According to the
model, the transmitter substance
Figure 13-4B. Models of metabotropic synaptic transmission.
interacts with the receptor on the
Here the second messenger is shown as cAMP, but cGM P or
postsynaptic membrane, activating
ano ther substance or e ven several different substances could
adenylate cyclase and producing
serve as w ell.
cAMP. The cAMP activates a protein
than others. For example, the interval
kinase, phosphorylating a protein. It is the
between the arrival of the presynaptic spike
phosphorylation of the protein which
at the synapse and the change in membrane
produces the change in membrane potential,
potential, the synaptic delay, is shorter at
either through a change in membrane ionic
the neuromuscular junction, where
conductance or through stimulation of an
acetylcholine is the transmitter substance,
electrogenic pump. The process is reversed
than at sympathetic postganglionic synapses,
by dephosphorylating the protein and
where norepinephrine is the transmitter
substance. Surprisingly, acetylcholine acts
3
A term used here in the sense of a
faster at the neuromuscular junction than at
molecule or molecules that bind specifically
the parasympathetic junctions at the heart.
the transmitter substance.
13-7
hydrolyzing cAMP. Often associated with
metabotropic transmission is an increase in
membrane resistance, not a decrease as in
ionotropic transmission.
It has also been suggested that the longer
latencies and durations of the muscarinic
effects of ACh and the effects of dopamine
and norepinephrine may be partly the result
of having long diffusion distances between
the site of release at the presynaptic terminal
and the site of action, i.e., that the synapses
differ from the classical 15- to 200-nm cleft
variety. These have sometimes been called
nonsynaptic interactions, but the current
trend is to call them loose synapses. Longer
synaptic delays can readily accommodate
longer diffusion times. Of course, this
usage makes transmitter substances subtly
merge with neurohormones.
Table 13-1 shows that glycine, GABA,
L-glutamate, and L-aspartate are probably
ionotropic transmitter substances.
Norepinephrine, dopamine, serotonin,
epinephrine, histamine, and probably
substance P are metabotropic. Acetylcholine
is sometimes ionotropic (at nicotinic
cholinergic synapses; those also activated by
nicotine), and sometimes metabotropic (at
muscarinic cholinergic synapses; those also
activated by muscarine). The second
messenger at metabotropic (muscarinic)
cholinergic synapses is thought to be cyclic
guanidine monophosphate (cGMP).
The excitatory postsynaptic potential.
The postsynaptic cell can either
hyperpolarize or hypopolarize in response to
the transmitter substance. It is possible to
study the postsynaptic events by puncturing
the soma of a cell with a microelectrode to
pick up the changes in membrane potential
that result from activity in a presynaptic
axon. The arrangement of the cell and the
electrode is shown in Figure 13-5 along with
13-8
some sample records. If we stimulate a
peripheral nerve at weak intensity while
recording from a motoneuron, we see in the
record a hypopolarization with a latency of
1-2 msec, followed shortly by a
repolarization of the cell. This response is
the excitatory postsynaptic potential, or
EPSP, shown in Figure 13-5B. It has a
Figure 13-5. A. The method of recording the
postsynaptic potential with a micropipette. B-E.
EPSPs elicited in a motoneuron by stimuli to a
peripheral nerve a t increasing strengths. Note
that the critical firing level is achieved and that
the action potential is initiated in E. (Eccles JC,
Eccles RM , Lundberg A: J Physiol (Lond)
136:52 7-546, 195 7)
decay time-constant of about four msec and,
like the generator potential, is a local or
nonpropagated event. The EPSP is in fact a
generator potential; it is sufficiently
important to warrant special consideration
and a name of its own. The amplitude of the
EPSP varies with the strength of the
stimulus (that is, with the number of fibers
stimulated), as shown in Figure 13-5C-E,
and if it hypopolarizes the membrane to or
beyond its critical firing level, the
motoneuron will discharge an action
potential (Fig. 13-5E).
The neuromuscular junction: an example
of excitatory transmission.
We can use transmission at the
neuromuscular junction as an example of
excitatory transmission because it displays
many of the important features of such
transmission. It is also of historical interest
because it was in the neuromuscular junction
that most of the early studies of synaptic
transmission were done. It is easily
accessible, and the postsynaptic cell (in this
case a striated muscle cell) is large and
easily penetrated by recording electrodes.
The neuromuscular junction or motor endplate is morphologically much like any other
synapse except that it is larger. The axon of
the motoneuron loses its myelin sheath near
its termination and expands greatly, forming
a bouton that is 10 :m or so in diameter. It
contains synaptic vesicles, known to contain
the transmitter substance, acetylcholine, in
its terminal. The postsynaptic element in
this synapse is a skeletal muscle cell whose
membrane is specialized at the end-plate by
numerous deep infoldings. Only the peaks
of these folds are near the motoneuron
terminal, but the depths of the folds are in
contact with the fluid of the synaptic cleft.
The structure of the neuromuscular junction
is shown in Figure 13-6.
Figure 13-6. Structure of the neuromuscular
junc tion. T he terminal of the motoneuron is
expa nded ov er the syn aptic cleft. M uscle
mem bra ne is deeply info lded und er the term inal.
It is possible to remove the muscle and
its nerve from an organism and put it into a
bath of Ringer's solution (a balanced ionic
solution, the ionic constituency of which is
similar to that of blood). The nature of such
a preparation is shown in Figure 13-7.
When a microelectrode is used to penetrate
the muscle, a resting membrane potential
Figure 13 -7. Recording setup for the end-plate
potential. M uscle is bathed in Ringer's solution
containing curare, and motor axon is placed on
stimulating electrodes. A recording microp ipette
penetrates the muscle membrane at 1-mm
intervals away from the end-plate. Sample records
show the nature of the recording at each site.
(Vr) of about -70 mV is recorded as
described in Chapter 3.
13-9
When the axon of the motoneuron is
stimulated, it can be excited to discharge a
spike that conducts down to the terminal.
Hypopolarization of the terminal by the
action potential opens the voltage-gated Ca++
channels, Ca++ enters the terminal, the
synaptic vesicles fuse with the terminal
membrane, and acetylcholine is released into
the synaptic cleft. The acetylcholine
diffuses across the synaptic cleft from
presynaptic to postsynaptic in less than 100
:sec and interacts with the acetylcholine
receptors on the folded postsynaptic, muscle
membrane. The acetylcholine receptor is
believed to be a pentameric glycoprotein
composed of 4 types of transmembrane
polypeptides. Two acetylcholine molecules
Figure 13 -8. The spike
and the end -plate
potential. A. The spike
recorded by a
transmembrane
micropipette from the
muscle. B. The end-plate
potential recorded after
the spike has been
blocked w ith curare.
bind to the pentamer with weak
cooperativity and cause a conformational
change. The binding of the acetylcholine
opens the channel which has an effective
diameter of 0.65 nm, and it is nonselective,
i.e., it is permeable to small ions–Ca++, Na+,
K+ and Cl-. Because the channel is
nonselective, the contribution that any ion
makes to the total current is a function of its
driving force and concentration. As a result
the total ionic current is comprised mainly of
Na+ current because of its large
electrochemical gradient at the resting
membrane potential and its high external
concentration. Inward Na+ current
13-10
hypopolarizes the membrane and, when the
membrane potential crosses the critical
firing level, an action potential is initiated in
the muscle membrane. In Figure 13-7, the
instant when the stimulus is applied to the
nerve is signaled by the stimulus artifact (a
nearly instantaneous spread of stimulus
current from stimulating to recording
electrodes) and then, after a suitable time for
conduction along the axon and for synaptic
delay, the membrane hypopolarizes, leading
to the action potential.
If the preparation has been bathed in a
solution containing the drug curare, a
substance used experimentally as a muscle
relaxant and used by South American
Indians as a poison that is applied to
arrowheads, the stimulus to the nerve leads
to a change in potential, called the end-plate
potential. The end-plate potential looks and
behaves much like EPSPs in nerve cells; an
example is shown in Figure 13-8B for
comparison with the uncurarized spike in
A4. Like the EPSP, the end-plate potential is
graded and non-propagated, as shown by the
decreasing amplitude as the potential is
recorded further from the end plate (reading
traces toward the right in Figure 13-7). As
the electrode is moved farther and farther
along the muscle membrane away from the
end-plate, the potential drops in amplitude
because it conducts electrotonically. As in
other synapses, the receptor region of the
postsynaptic membrane contains no voltagegated channels and therefore does not
discharge spikes, but the end-plate potential
has only to bring the adjacent membrane to
critical firing level to initiate an action
potential there. Normally, in the absence of
curare, the end-plate potential is more than
4
Recordings in this figure were obtained
using the setup in Fig. 13-7.
large enough to bring the membrane to the
critical firing level; an action potential is
initiated in the muscle fiber for each spike in
the motoneuron connected to it.
Acetylcholine acts to open the ionic
channels in the postsynaptic membrane for
only 1-2 msec; the remainder of the endplate potential is simply due to the passive
properties of the muscle membrane. After
1-2 msec, the acetylcholine is removed from
the receptor and hydrolyzed by the enzyme
acetylcholinesterase, which is found on the
postsynaptic membrane mainly in the region
of the synaptic cleft. Acetylcholinesterase is
capable of hydrolyzing about 10
acetylcholine molecules per msec.
Therefore, most of the transmitter substance
is hydrolyzed, and the products are taken up
again by the motoneuron terminal, but some
of the acetylcholine escapes from the cleft
and is carried away by the blood. There is
no danger that this escaped transmitter can
re-excite the muscle because it is only
effective in changing the membrane
potential when applied to the membrane
within the cleft, i.e., there are no active
receptors on the muscle membrane except in
the cleft.
Within the motoneuron terminals,
acetylcholine is stored in the synaptic
vesicles, each vesicle containing about
10,000 molecules of acetylcholine. Because
the transmitter substance is stored in this
fashion and because the entire content of a
vesicle is released or none of it is released, it
is reasonable to assume that the end-plate
potentials must be made up of some multiple
of the potential change caused by a single
vesicle's contents. Actually, when
recordings are made from a nerve-muscle
preparation (Fig. 13-7) at rest, small,
spontaneous hypopolarizations are seen in
the membrane potential. These have a time-
course and configuration reminiscent of the
end-plate potential, and they are termed
miniature endplate potentials or MEPPs.
Pharmacologically and physiologically, it
has been demonstrated that MEPPs have the
same properties as the end-plate potential
and that they are caused by spontaneous
release of small quantities of acetylcholine.
MEPPs tend to have the same amplitude or
multiples of their smallest amplitude, so it is
surmised that they are caused by release of
nearly equal-sized packets of acetylcholine,
called quanta. It seems reasonable to
assume that a quantum is the amount of
transmitter in a single vesicle. It also seems
reasonable that the end-plate potential is
always composed of integral multiples of a
MEPP.
Figure 13-9. The surface of a motoneuron soma
studded with boutons terminaux. (Schadé JP,
Ford D H: Basic Neurology. Amsterdam, Elsevier,
1965)
MEPPs occur spontaneously at irregular
intervals with a low rate of occurrence at the
resting end-plate. The motoneuron spike
increases the rate of occurrence of MEPPs
for a short time, 1-2 msec, during which
200-2,000 quanta, depending upon the
particular nerve-muscle preparation, are
released. Each quantum opens up to 2,000
channels and each channel can admit as
13-11
many as 20,000 Na+ ions. The potential for
change in the membrane potential of the
muscle is enormous and therefore always
more than enough to cause a spike in
normal, healthy muscle.
Because the process of transmission at
the neuromuscular junction contains so
many different steps, the possibilities for
interference with the process are numerous.
Curare has already been mentioned as a
blocker; curare competes with acetylcholine
for the receptor sites, but is incapable of
activating them. Other competitive
blockers, such as decamethonium or
succinylcholine, not only compete, but
activate the receptor. Their paralyzing effect
is due to the tenacity with which they bind
the receptor and the difficulty with which
they are removed from the receptor and
hydrolyzed.
The toxin of botulinus bacteria, found in
some spoiled food, is an extremely powerful
neuromuscular blocker that works by
preventing the release of the transmitter
substance from the motoneuron terminals.
Low Ca++ concentrations in the extracellular
fluid also prevent release of transmitter
substance. Elevated Mg++ or Mn++ levels
also block release, but they work by
competition with Ca++.
Neuromuscular blocks can also be
created by interfering with the action of the
ACh-degrading enzyme
acetylcholinesterase. Cholinesterase
inhibitors, such as neostigmine, block the
removal and hydrolyzation of acetylcholine;
thus, the muscle membrane stays
hypopolarized for too long a period and the
muscle cannot relax. This is the principle of
action of many insecticides and nerve gases.
Prolonged hypopolarizations lead to
convulsions, then to paralysis and death,
usually caused by paralysis of the
13-12
diaphragm.
The disease myasthenia gravis is
characterized by muscle weakness after
repeated activation of the neuromuscular
junction, but not for a single activation.
Patients typically are strong in the morning,
but become progressively weaker as the day
goes on. The problem with the myasthenic
appears to be threefold: (1) there is an
abnormality of the immune system such that
antibodies are formed against the
acetylcholine receptor, and the number of
receptors is reduced; (2) there is a decreased
ability to resynthesize acetylcholine from the
acetate and choline taken up into the
terminals; and (3) there is increased
hydrolysis of acetylcholine. With repeated
activation of the synapse, the vesicular
stores of acetylcholine are depleted, not
replenished as they normally would be, and
after a while the junction fails to transmit.
In addition, the reduction in the number of
receptors means that less of the
acetylcholine available can be bound.
Administration of anticholinesterase drugs
like neostigmine is sometime effective in
treatment of myasthenia, probably because
they make the acetylcholine remain in the
cleft longer, increasing the likelihood that it
will bind to a receptor and activate the
muscle.
Synaptic transmission between neurons.
Synaptic transmission between neurons is
basically the same as at the neuromuscular
junctions. Transmitter substance release is
triggered by terminal hypopolarization and is
dependent upon Ca++. The release process is
quantal in nature, and transmitter release
occurs spontaneously. Synaptic
transmission is terminated by removal of the
transmitter substance from the synaptic cleft
through reuptake or hydrolysis. One
fundamental difference is that in synaptic
transmission between neurons, an EPSP in
the postsynaptic neuron, caused by a single
spike at a single synapse, seldom is large
enough to trigger a spike. In general, the
EPSPs caused by a single presynaptic action
Figure 13-10. Spatial and temporal
summation of EPSPs. A. EPSPs elicited by
stimulation of two fibers afferent to a
motoneuron both separately and
simulta neously. N otice the a lgebraic
summ ation. B. EPSPs elicited by a single
stimulus to a fiber afferent to a
motone uron an d tw o stimuli applied in
rapid succession (2 msec apa rt).
potential are small, only 1-2 mV of
hypopolarization, and cannot bring the
postsynaptic cell to critical firing level. For
the postsynaptic cell to be excited to
discharge requires spatial and temporal
summation, the same two phenomena
discussed previously. Figure 13-9 shows a
sketch of the soma of a motoneuron, literally
encrusted with boutons from afferent fibers
of various sources, to show how extensive
neural interconnections are. Estimates of the
density of synapses on motoneurons have
indicated that boutons cover 40-50% of the
somatic and 50-80% of the dendritic
surfaces. If we stimulate more than one of
these afferent fibers with a single stimulus,
then each active fiber will release its
transmitter substance onto the membrane of
the motoneuron and cause its own EPSP,
and we see the algebraic sum of them. In
Figure 13-10A are illustrated the EPSPs
elicited in a motoneuron by two action
potentials in two different afferent fibers,
when stimulated separately and when
stimulated together. The response to
simultaneous stimulation is clearly seen to
be the algebraic sum of the two single
responses. This is an example of spatial
summation.
Like all generator potentials, EPSPs can
show temporal summation. If the same
afferent axon is stimulated twice in rapid
succession, the response to the first stimulus
is not yet over before the response to the
second begins. The changes in potential
again sum, but because they do not start at
exactly the same time (2 msec apart), the
sum is a bit irregular in shape (Fig. 13-10B).
This is an example of temporal summation.
The membrane potential can be brought to
firing level by summation, spatial or
temporal or both. Any number of EPSPs,
from a variety of types of presynaptic
neurons, can be summed by a single
postsynaptic cell.
13-13
Synapses
that require a
lot of
summation to
reach firing
level are called
integrative
synapses, and
they make up
the bulk of the
synapses in the
nervous
system. A few
synapses
require only
one
presynaptic
action
potential to
Figure 13-11. An IPSP elicited
bring the
by a single stimulus applied to
postsynaptic
a peripheral nerve at
membrane to
increasing strengths from top
to bottom.
critical firing
level, and
these are called obligatory synapses. An
example of an obligatory synapse is the
neuromuscular junction. A single action
potential in a single "-motoneuron causes a
postsynaptic action potential in every
extrafusal muscle fiber in its motor unit (a
motoneuron plus all the muscle fibers it
innervates is a motor unit). Generation of
the action potentials in the "-motoneurons
themselves requires considerable
summation, and therefore synapses on
motoneuron somata or dendrites are
integrative. Not all neurons behave exactly
like motoneurons, but most use this same
basic mechanism for transmission at
chemical synaptic junctions with other cells.
The inhibitory postsynaptic potential.
Another difference between neuronal and
neuromuscular synapses is the possibility of
13-14
inhibition at neuronal synapses. Inhibition is
not seen in mammalian neuromuscular
junctions. With an appropriate stimulus, the
response of the motoneuron can be an
hyperpolarization, beginning 3-4 msec after
the stimulus, followed by a return to the
resting potential, again with a decay timeconstant of about four msec. This response
is called the inhibitory postsynaptic
potential, or IPSP, because it drives the
membrane 1-4 mV away from the critical
firing level and therefore reduces the
frequency or, alternatively, the probability of
firing of the postsynaptic cell. Figure 13-11
shows that as the stimulus strength increases
(from top to bottom), so does the amplitude
of the IPSP. Like the EPSP, the IPSP is a
nonpropagated event. IPSPs can sum either
spatially or temporally to hyperpolarize the
cell to an even greater extent than a single
IPSP. IPSPs are never seen in mammalian
muscles.
Figure 13-12. T he effectiv eness of an IPSP in
reducing EPSPs. A. The EPSP by itself. B. The
IPSP by itself. C. The EPSP and IPSP initiated at
the same time. D. A mu ch larger EP SP by itself.
E. The EPSP in D with the IPSP in B.
Ionic mechanisms of postsynaptic
potentials. It appears that the excitatory
transmitter substances responsible for the
EPSP act at the postsynaptic membrane by
increasing the permeability of the membrane
to all small ions, including sodium,
potassium, calcium and chloride ions; there
is an increase in net flux of ions, with all
ions moving down their electrochemical
gradients. The major contributor to the
change in potential is sodium current
because of the large driving force
(membrane potential minus equilibrium
potential) on sodium ions and the large
change in sodium conductance. It is also
apparent that the change in the membrane's
permeability to sodium is much larger than
the change for potassium, because the
potential that the membrane is seeking
during the EPSP, the equilibrium potential
of the EPSP, is 0 to +30 mV, the exact value
depending upon what synapse is being
studied. Recall that the resting membrane's
permeability to sodium is only 1/30th of that
to potassium, making the resting potential
very near the potassium equilibrium
potential. If the membrane is suddenly made
30 times more permeable to sodium ions, the
membrane potential will shift to a level
halfway between the sodium and potassium
equilibrium potentials, about -15 mV. In
fact, during the EPSP the membrane
potential shifts farther, to 0 to +30 mV, so
the relative change in sodium permeability
must make the permeability ratio much
greater than 1:30, in fact, greater than 1:1.
Apparently, chloride plays no major role in
this process, but any chloride cur-rent would
tend to hold the membrane near ,Cl-, i.e.,
near Vr.
The IPSP, on the other hand, is produced
by increased permeability of the membrane
to chloride or potassium or both. If, in the
Figur e 13-1 3. Cu rrent flow at syna pses.
Excitatory and inhibitory synapses are
indicated on the soma and proximal dendrites
and currents initiated at each, flowing through
the postsynaptic membrane and the region of
the axon hillock, where the spike is thought to
be initiated.
postsynaptic cell, Vr=,Cl-, then chloride
current will be zero, and chloride will make
no contribution to the hyperpolarization. If
Vr is less negative than ,Cl-, then the driving
force on chloride will move it inward,
creating an outward current. Under this
circumstance, an increase in chloride
conductance will hyperpolarize the
membrane. On the other hand, if Vr is more
negative than ,Cl-, then the driving force on
chloride will move it outward, creating an
inward current. Under this circumstance, an
increase in chloride conductance will
actually hypopolarize the cell. Vr is always
less negative than ,K+, so an increase in
potassium conductance always results in
hyperpolarization. Chloride and potassium
are nearly in electrochemical equilibrium,
and therefore their driving forces are small,
but then the amplitude of the IPSP is also
small.
It is important that the inhibitory effect
of the IPSP is not due simply to the
hyperpolarization, driving the membrane
13-15
to hypopolarize the cell to the same
level as the original EPSP, as shown in
E. This happens because the IPSP
results from an increased membrane
conductance for K+ and Cl-. This
means that the membrane resistance
(R=1/g) is decreased. The inward Na+
current of the EPSP therefore produces
a smaller voltage drop across the
smaller membrane resistance (V = iR,
Figure 13 -14. The com bination of EP SPs and IP SPs to
R is reduced) and a smaller EPSP. The
generate differ ent pa tterns of sp ike discharge. Inset sho ws a
IPSP inhibits both by virtue of the
neuron with three synaptic junctions--two on the soma and
decreased membrane resistance and the
one on a proximal dendrite. Two of the synapses are
hyperpolarization. The
excitatory; one is inhibitory. A. Transmembrane potential
hyperpolarization forces a greater
recorded with the micropipette, with different temporal
arrangements of a single postsynaptic potential at each
amount of hypopolarization to achieve
synapse (indicated by letters under trace). For the purpose of
critical firing level, and the decreased
illustration, E PSPs and IP SPs are show n larger than normal;
membrane resistance reduces the size
they can cause the membrane potential to cross the critical
of the EPSP. For this reason, inhibition
firing level (CFL). B. The spike trains that would be recorded
always makes itself felt. Equal
from the a xon of the cell as gen erated b y the syna ptic
potential patterns in A.
excitatory and inhibitory presynaptic
inputs to a cell always result in
away from the critical firing level, but also
inhibition of its discharge. And it is for this
includes another process. If the effect were
reason that increasing Cl- conductance
simply due to the hyperpolarization, then
inhibits even though Cl- is in
summation between EPSPs and IPSPs
electrochemical equilibrium and changing it
would still be linear, IPSPs summing with a
conductance produces no voltage change in
negative sign. The maximum change in
the cell.
voltage of the EPSP is 8-10 mV, whereas
The postsynaptic membranes at all
that for the IPSP is 2-4 mV; yet an IPSP can
synapses are electrically inexcitable; the
reduce the amplitude of an EPSP by more
action potential is initiated somewhere else
than its own amplitude, that is, they do not
on the membrane. Most people think that
sum algebraically. This is shown in Figure
the spike in most neurons is initiated in the
13-12. When the appropriate pathways to a
region where the axon is connected to the
cell are stimulated, an EPSP and an IPSP are
soma, the axon hillock. The axon hillock is
initiated in the cell, as shown in A and B. If
thought to have an electrical threshold about
the EPSP and the IPSP are initiated at the
half that of the soma and dendrites, so that
same time, the resulting change in potential
the spike is initiated there first. Figure 13is a small hyperpolarization as shown in C,
13 shows a drawing of the neuron showing
not the small hypopolarization that would be
the axon hillock, synaptic junctions on the
expected if there were algebraic summation.
soma and dendrites, and the currents that
An EPSP (D) larger than the IPSP (in terms
flow when the synapses are active. EPSPs
of amplitude) must be added to the response
and IPSPs are not propagated, but spread
13-16
electrotonically into the region of the
hillock. This means that, for synapses
producing equal changes in membrane
potential at the synapse, the ones closer to
the hillock have a greater influence on the
firing of the cell. However, synapses on
dendrites tend to generate particularly large
EPSPs, somewhat offsetting their greater
distance. Inhibitory synapses, synapses that
produce IPSPs, also tend to be located closer
than excitatory synapses to the axon hillock
(the spike-generating region). This
arrangement may also add to the great
influence of IPSPs on the neuron membrane.
The firing pattern of the neuron is
completely determined by the sum of its
synaptic bombardment, both excitatory and
inhibitory. This is especially important in
cells with integrative synapses. It was
pointed out in the earlier discussion of
generator potentials that there is a linear
relationship between generator potential
amplitude and the frequency of discharge in
the receptor or its nerve. The EPSP is a
generator potential, and, like any good
generator potential, its amplitude is related
to discharge frequency in a linear way. The
hypopolarization at the axon hillock is
increased by summation of EPSPs from
different synapses and decreased by
summation of IPSPs. As a result, the firing
frequency increases or decreases. Figure 1314 shows a hypothetical arrangement of
synapses on a cell and some different
configurations of synaptic potentials at the
axon hillock (A)5 and the resulting patterns
5
The spikes have been omitted from
trace A for clarity. Obviously, they would
be superimposed on top of the traces in an
actual recording. Also the postsynaptic
potentials are shown larger than normal for
illustration.
of discharge in the axon hillock (B). Shown
are two excitatory synapses, one on the soma
and one on a dendrite, and one inhibitory
synapse on the soma. Each pattern in A was
generated by some combination of inputs
over the three synapses (indicated by the
letters: a, b and c). The same synapses are
involved in generating each pattern; only the
order and timing are changed. Even small
changes result in noticeably different
patterns of spike discharges, with great
consequences for behavior.
If the precise timing required to produce
spatial and temporal summation is altered,
the precise firing patterns of interneurons
and motoneurons required to produce even
the simplest of movements are no longer
possible. In fact, the real impact of certain
demyelinating diseases such as multiple
sclerosis is not due to destruction of neurons
or even blockage of conduction; they still
conduct (at least in the early stages of the
disease), although at reduced velocities after
the myelin is removed. The slowed
conduction in a demyelinating disease
means that some impulses do not arrive on
time at synapses on motoneurons.
Considering the time constant of an EPSP, a
slowing of conduction that produces even a
0.5-msec delay in the arrival of an impulse
at the synapse can have devastating effects
on movement. The timing of the arrival of
impulses is also important in sensory events.
Humans use small differences in the time of
arrival of a sound at the two ears to localize
the source of sounds with low frequencies.
This difference in arrival time can be as little
as 30 :sec. Clearly, very close timing of
impulses is essential to this behavior.
Rectification6. In the initial discussion
6
Here the term rectification is used in the
engineering sense of a lower resistance to
13-17
of the initiation of an action potential in
axons, it was noted that, with electrical
stimulation, once the critical firing level is
reached, the action potential propagates in
both directions away from the point of
stimulation. The direction normally taken
by action potentials is the orthodromic
direction; the reverse is the antidromic
direction. If the action potentials can travel
down an axon both ways, why is there a
"normal" direction? The answer lies in the
synapse. When the action potential reaches
a synapse it can go no further, but it can
cause a release of transmitter substance in a
presynaptic element. There is usually no
transmitter mechanism in the postsynaptic
element; therefore, synapses act as rectifiers,
allowing transmission in only one direction.
Modulatory role of transmitter
substances. The term neuromodulator has
been coined to describe certain functions of
transmitter substances (or putative
transmitter substances). A transmitter
substance acts as a neuromodulator when it
alters the synaptic action of other neural
inputs by means other than itself producing
direct excitation or inhibition. In other
words, it acts by means other than eliciting
EPSPs or IPSPs. Neuromodulators can
change the release of a transmitter substance
from presynaptic terminals. This can be
accomplished by way of autoreceptors,
which when bound by a transmitter
substance, modulate further release of that
substance, or it can occur when one
transmitter substance modulates the release
of another. Norepinephrine at some
synapses in the autonomic nervous system
can inhibit its further release. When
enkephalin is released into sympathetic
transmission in one direction than in the
opposite direction.
13-18
ganglia by preganglionic neural input, it can
inhibit the release of acetylcholine within
that ganglion.
In some cases, the postsynaptic potential
elicited by a given transmitter substance can
be altered by, or contingent upon, the
postsynaptic action of a neuromodulator.
For example, a brief exposure to dopamine
released synaptically into sympathetic
ganglia enhances the muscarinic
hypopolarizations induced by acetylcholine
for hours, even though the dopamine causes
no change in the membrane potential or
resistance of the postsynaptic cell. Similar
effects of dopamine have also been
described in the caudate nucleus and
hippocampus. A shorter potentiation of both
excitatory and inhibitory responses of
Purkinje cells in the cerebellar cortex is
induced by norepinephrine released by axons
originating in the locus ceruleus.
It has been suggested that these longer
lasting changes in neural activity produced
by neuromodulators may play a role in
slowly developing and enduring behavioral
changes such as learning and memory. The
effects of muscarinic antagonist drugs on
learning and monoamines on sleep/waking
and learning may indicate that this
suggestion has some credence.
Physiology of an electrotonic synapse.
In known examples of electrotonic
synapses in invertebrates, the anatomical
substrate of transmission is a gap junction in
which the joined membrane is of lower
resistance than surrounding membrane, i.e.,
the cell-to-cell resistance is less than the
cell-to-extracellular fluid resistance, and it is
electrically inexcitable, i.e., it does not
generate action potentials. An impulse
propagates into the region of the junction,
and the resulting current flows across the
frequencies of up to 100/sec
and presumably is used by
the fish for guidance or
perhaps communication. The
recording arrangement is
shown in A. Histologically,
these motoneurons have been
shown to be interconnected
by thick dendritic or somatic
processes, as shown. The
recordings in B-I are made
from neurons 1 (marked 1),
from neuron 2 (marked 2),
and from the current applied
to the cells (marked i). An
hyperpolarizing current was
Figure 13-15. E lectro tonic spre ad b etw een spina l neurons in an electric
applied to neuron 1, and
fish. A . Rec ord ings a re made simulta neo usly o f the m emb rane potentia ls
responses were recorded
of two neurons while either one is hypopolarized or hyperpolarized
from both neurons in Figure
through an intracellular electrode. B-G. The responses of both cells are
13-15B. Both cells were
show n to hyperp olarization of neuron 1 (B) or neu ron 2 (C ),
hypopolarization of neuron 1 below (D) and exceeding its critical firing
hyperpolarized. A similar
level (F), and hypop olarization of neuron 2 below (E) and exceeding its
result occurred when an
critical firing level (G). H. An impu lse is initiated by a brief stimulus to
hyperpolarizing current was
neuron 1, and it spreads to neuron 2. I. The same as in H except that
applied to neuron 2 (Fig. 13neuron 2 is strongly hyperpolarized; this fails to block spread of the
15C). An hypopolarizing
spike from neuron 1 to neuron 2. (Bennett MV L, Pappas GD, Aljure E et
al.: J Neurophysiol 30:180 -208, 1967 )
current, applied to either cell,
hypopolarized both or, in
junctional membrane, out of the presynaptic
some cases, caused both to discharge action
cell and into the postsynaptic cell. That
potentials (Fig. 13-15D-G). Notice that the
current must again flow out of the
latency of the discharge was longer in the
postsynaptic cell (according to Kirchhoff's
cell that did not receive the current injection
current law), this time through electrically
directly. This is due to the slower rate of
excitable membrane, causing an
rise of the electrotonic potential farther from
hypopolarization, which, if large enough,
the current source, causing a delay in
can cause the postsynaptic cell to discharge.
reaching the critical firing level (Fig. 13Usually, though, the resulting
15F,G). The sort of reciprocal relationship
hypopolarization is small, of the order of 1-2
shown in Figure 13-15 is just what one
mV.
would expect for such an electrotonic
Figure 13-15 shows recordings made
synapse. Current flows as easily from
intracellularly from two spinal motoneurons
neuron 1 to neuron 2 as from neuron 2 to
that drive the electric organ of the electric
neuron 1, i.e., the junction is not rectifying.
fish, Gnathonemus. The electric organ emits
There are a few examples in invertebrates of
electrical impulses of 0.3-msec duration at
electrotonic synapses that do rectify. This
13-19
can be the result if the two cells have greatly
different membrane resistances, membrane
areas, or voltage thresholds, the latter being
the voltage at which the synapse begins to
transmit.
Chemical and electrotonic synapses
compared and contrasted.
Inhibition. It should be clear that
chemical synapses can produce either
hypopolarizations
(excitation) or hyperpolarizations
(inhibition) in the postsynaptic cell. As far
as we know, axons do not carry propagated
hyperpolarizations in any nervous system,
and therefore simple hyperpolarizing
postsynaptic potentials will not occur at
electrical synapses. There is the possibility
of transmission of hyperpolarizing afterpotentials at electrical synapses, especially if
transmission at the junction were rectified in
the proper direction. If the polarity of
rectification is such that hypopolarizations
pass more easily from pre- to postsynaptic
and hyperpolarizations from post- to
presynaptic, a large hyperpolarizing afterpotential in the postsynaptic cell would then
produce a feedback inhibition of the
presynaptic cell with little feedback
excitation (Table 13-3). Such a possibility
has been suggested for synapses in Aplysia.
The advantages of chemically mediated
inhibition are that it can be larger in size,
i.e., a greater hyperpolarization; longer in
duration; and not limited in its site of
application. Electrically mediated inhibition
would occur more rapidly, because of the
lack of synaptic delay, but this need not be a
13-20
big advantage. The CNS could easily
produce small time compensations.
Synaptic delay. Transmission at a
chemical synapse requires mobilization of
synaptic vesicles, exocytosis, diffusion of a
transmitter substance (in some cases over
long distances), reaction of the transmitter
substance with postsynaptic receptor sites,
production of changes in membrane
permeability, and a change in membrane
potential, produced either directly or through
a second messenger. All of these steps take
time. This time is called the synaptic delay,
and it is measured as the time between
arrival of the impulse at the presynaptic
terminal and the start of the postsynaptic
response. In mammals, the ionotropic
synaptic delay is of the order of 0.1-0.3
msec. At the neuromuscular junction, most
of the delay consists of the time required for
release of the chemical transmitter
substance. Diffusion time and onset of
permeability changes apparently contribute
little to it.
The process of electrical transmission
occurs with minimal delay, usually less than
0.05 msec. It is this short delay that gives
electrical synapses their usefulness as neural
synchronizers. The electrical interconnection of neurons causes them to tend to
fire synchronously. This is presumably of
advantage when rapid movements or highfrequency events, such as electric organ
discharges, are being controlled. What other
advantages it may confer on a system are not
known.
Table 13-3
Properties of Single Chemical and Electrical Synapses
Property
Chemical synapses
Electrical synapses
1. Rectification
Always
Sometimes, usually not
2. Amplification
Yes
No
3. Delay
Yes
No
4. Inhibition
Yes
Yes
5. Summation
Yes
Yes, but over shorter time
6. Influenced by membrane
potential
Yes
No
Rectification. Because of the locations
of synaptic vesicles and receptors for
transmitter substance at chemical synapses,
the latter are, of necessity, rectifying
junctions, i.e., they allow transmission in
only one direction, as we have already
discussed. In cases of reciprocal synapses,
there is a mechanism for removing
rectification, but it is not known how
pervasive this mechanism may be. It does
exist in the retina and the olfactory bulb. As
we have already mentioned, most electrical
synapses appear to be nonrectifying;
however, the study of rectification requires
intracellular recording and stimulation of
both the pre- and postsynaptic elements of
the synapse, which is seldom possible in
vertebrates.
Summation. The processes of spatial
and temporal summation in chemical
synapses are general integrative properties of
neurons and fundamental to operation of the
nervous system. They are also properties of
electrical synapses. The major difference
between summation by chemical and by
electrical mechanisms is the longer timecourse of chemical summation. The
postsynaptic potentials at chemical synapses
typically last 10 msec or longer, whereas
those at electrical synapses seldom outlast the
duration of the presynaptic spike, i.e., about 1
msec. Therefore, summation can occur over
a period 10 times (or more) longer at
chemical synapses.
Amplification. At chemical synapses,
there can be an effective amplification of the
transmitted signal such that the electrical
energy of the postsynaptic response is greater
than that of the presynaptic response. This
can occur if the resistance of the postsynaptic
membrane is higher than that of the
presynaptic membrane or if the change in
membrane permeability, brought about by a
single presynaptic spike, is extremely large.
This may manifest itself as an increase in the
number of action potentials discharged by the
postsynaptic cell. Amplification has been
observed for neurons in the dorsal horn of the
spinal cord that are connected to cutaneous
primary afferent neurons (Tapper DN, Mann
MD: Brain Res 11:688-690, 1968). It
probably also occurs at the synaptic junctions
between receptors and other cells that do not
generate action potentials themselves and
neurons that do generate action potentials,
e.g., bipolar and ganglion cells in the retina.
13-21
Figure 13-16. Demonstration of the
equilibrium potentials of the EPSP and
IPSP. A . The influence of ch ang es in
membrane potential (indicated at the end of
each trace), induced by passing current
through an intracellular electrode, on the
EP SP reco rded fro m a fr og sy mpa thetic
gangion cell is shown. The resting potential
for this cell was -80 mV, and the
equilibrium potential for the EPSP (A5) was
-10 mV . (Nishi S, Koketsu K: J Cell C om p
Physiol 55:15-30, 1960) B. The influence of
membrane potential on the IPSP recorded
from a motoneuron in the cat. The resting
membrane potential for this cell was -74
mV, and the equilibrium potential for the
IPSP was -81 mV (not shown). (Coombs JS,
Eccles JC, Fa tt P: J Physiol (Lond)
130:326-373, 1955)
No such amplification has ever been seen in
an electrical synapse.
Influence of membrane potential.
Because the postsynaptic potentials at
chemical synapses result from changes in
permeability of the postsynaptic membrane
to sodium, potassium, chloride, or other
ions, their amplitude and polarity are greatly
affected by the polarity and magnitude of the
membrane potential. An example of the
influence of membrane potential upon both
13-22
EPSPs, these recorded from a frog
sympathetic cell, and IPSPs, recorded from a
cat motoneuron, is shown in Figure 13-16.
In Figure 13-16, A8 and B4 show the normal
configurations of the EPSP and IPSP, when
initiated with the cell at resting membrane
potential. If the cell is hypopolarized, the
IPSP gets larger (Fig. 13-16, B4-1) because
the driving forces get larger as the membrane
potential gets further removed from the
equilibrium potentials of the ions whose
permeability is changed, i.e., chloride and
potassium. The EPSP, on the other hand,
gets smaller as the membrane is
hypopolarized (Fig. 13-16, A8-6), until it
disappears at about -10 mV (Fig. 13-16, A5)
and is replaced by a negative-going potential
(Fig. 13-16, A4). The value of the membrane
potential at which the EPSP disappears is
called the equilibrium potential for the
EPSP, ,EPSP, and it is determined by the
equilibrium potentials for the ions whose
conductances change during the EPSP, i.e.,
primarily Na+ and K+, with a weighting factor
related to the amount of conductance change,
as indicated in equation 5 of Chapter 3. If the
permeabilities for both Na+ and K+ change,
then the equilibrium potential for the EPSP is
somewhere between the sodium equilibrium
potential, ,Na+, and the potassium
equilibrium potential, ,K+. The squid giant
synapse has a reversal potential of +20 mV,
the cat motoneuron, 0 mV, and the
neuromuscular junction, -15 mV, indicating
that different relative permeability changes
for Na+ and K+ ions occur at different
synapses. The relative change in potassium
conductance is larger for the neuromuscular
junction than for either the cat motoneuron or
squid giant synapse. With further
hypopolarization, a new driving force
develops, but this time in the opposite
direction, moving the membrane back toward
,EPSP (Fig. 13-16, A4-1).
One can see that the IPSP decreases in
amplitude and reverses (in this case, at about
-81 mV) to a hypopolarizing potential as the
membrane is hyperpolarized (Fig. 13-16,
B4-7), whereas the EPSP gets larger (Fig.
13-16, A5-7). The IPSP gets smaller either
because iCl- and iK+ exactly balance each
other (if both ions are involved) or because
ix = Vm - ,x = 0 (if only one ion, x, is
involved). At the equilibrium potential for
the IPSP, the amplitude of the IPSP is zero
because there is no net membrane current.
As the equilibrium potential is exceeded
(Fig. 13-16, B5-7), a net current (two ions)
or new driving force (one ion) develops, but
it is in the opposite direction, so the polarity
of the IPSP reverses. The EPSP gets larger
with membrane hyperpolarization, primarily
because the driving force on Na+ increases
as the membrane potential moves further
from the equilibrium potential of the EPSP.
Figure 13-17. The anatomic arrangement of an
axoaxonic synapse showing the pre- and
postsyna ptic axons. Also show n is the axosomatic
synapse of a group Ia afferent fiber on the
motoneu ron. (Eccles JC: The Understanding of the
Brain. New York, M cGraw -Hill, 1973)
The postsynaptic potential at an
electrical synapse is due to a flow of current
through the membrane resistance with no
concomitant change in membrane
permeability, although an EPSP may lead to a
permeability change in adjacent, electrically
excitable membrane. Because the electrical
EPSP is a simple ohmic voltage change (iR
drop), it is not influenced by membrane
potential, and therefore it has nearly the same
size at any membrane potential. This is
shown in Figure 13-15, H and I. (Of course,
if the cell is near critical firing level, the
EPSP may have a disproportionate effect, i.e.,
the cell may discharge.)
Presynaptic inhibition.
Inhibition of impulse discharge mediated
by IPSPs is called postsynaptic inhibition,
because the effect is exerted directly on the
postsynaptic cell. Postsynaptic inhibition
reduces the cell's excitability to all synaptic
inputs. Another mechanism for producing
inhibition, called presynaptic inhibition,
involves effects exerted on a presynaptic
axon terminal.
To illustrate this inhibition, let us
examine the primary afferent fibers of group
Ia. These enter the spinal cord and go,
among other places, to the ventral (anterior)
horn, where they make synaptic contacts on
motoneurons that innervate the muscle from
which the afferent fibers originated. (This, as
we shall see in Chapter 15, is the anatomical
basis of the monosynaptic, tendon tap reflex.)
On the boutons of the Ia afferent fibers there
are synapses, i.e., synaptic terminals on
synaptic terminals. The presynaptic terminals
on the group Ia terminals come from
interneurons that are driven by group Ia
afferent fibers from another muscle. This
arrangement is shown in Figure 13-17. The
synapse between the two axons, the
axoaxonic synapse, is excitatory in that the
presynaptic (interneuronal, in this case)
action potential produces an EPSP in the
terminal of the group Ia afferent fiber.
13-23
from a more positive
level of membrane
potential and partly
because the
hypopolarization
(previous to the spike)
increased the K+
conductance and
partially inactivated the
Na+ conductance
Figure 13-18. Effect of membrane polarization level on the action potential. B.
(accommodation) in the
Action poten tial initiated with memb rane at resting potential. A. Spike
configuration w hen cell was prev iously hyperpolarized b y 10 mV . When spike
membrane. The
is initiated in a hypopolarized membrane, the spike is reduced in amplitude.
increased K+
Examples are shown for 10 mV (C) and 20 mV (D) hypopolarization.
conductance and Na+
Horizontal line through each record indicates the current passed through the
conductance
membrane to change membrane potential before spike was initiated; values on
right ordinate. Membrane potential is indicated on left ordinate. (Eccles JC:
inactivation reduced the
The Ph ysiology of Nerve Cells. Baltimore, Johns Hopkins Press, 1968)
ratio of conductances
and therefore the
If the group Ia afferent fiber terminal
positive overshoot potential as predictable
membrane is maintained in a slightly
from equation 5 of Chapter 3. The spike is,
hypopolarized condition and then stimulated
therefore, smaller both because it starts closer
to initiate an action potential, the action
potential will be smaller than one that is
initiated when the membrane is at its resting
potential, Vr. This result is illustrated in
Figure 13-187. Trace B shows the action
potential initiated at Vr = -65 mV. The
smaller spikes in C and D were obtained
when the membrane started at hypopolarized
values, Vm = -55 mV and -50 mV. The trace
in A shows a larger than normal spike
initiated when Vm = -70 mV, i.e., the
Figure 13 -19. A collateral inhibitory circuit. Spike
membrane was hyperpolarized. (Actually,
initiated in neuron A invad es the collateral to
these records were made in a motoneuron,
excite the inhibitory interneuron that produces
but the same thing would presumably
IPSPs in neuron B.
happen in the axon terminal.) The spike in
C and D is reduced partly because it arises
to zero and because it does not overshoot as
far. This phenomenon is the basis for the
7
The horizontal line through each spike
presynaptic inhibitory action. Activity at the
indicates the amount of current passed
axoaxonic synapse partially hypopolarizes the
through the membrane to change the
terminal so that, when an action potential
membrane potential before the spike was
comes down the Ia afferent fiber into that
initiated. Calibrate against the right
terminal, its amplitude is reduced. Because
ordinate.
13-24
the amount of transmitter substance released
by a bouton is proportional to the amplitude
of the action potential in it, less transmitter
substance is released, resulting in a smaller
EPSP and less excitation of the postsynaptic
cell, in this case the motoneuron. Some
measurements indicate that a 15-mV
reduction in the amplitude of the presynaptic
spike will reduce the amount of transmitter
substance released to 1/10 of its original
value.
It is usually said that presynaptic
inhibition has no direct effect on the
postsynaptic cell, but this is not entirely true.
The EPSP initiated in the Ia bouton causes
the release of a small amount of transmitter
substance that raises the level of excitability
of the motoneuron slightly. It is possible
that this slight increase in excitability may
offset a small amount of the decrease in
transmitter output caused by the spike in the
group Ia afferent fiber. In any case, the
increased excitability of the motoneuron will
add to the excitatory synaptic activity from
other uninhibited boutons on the same cell.
This could give the nervous system a rather
subtle way of modulating excitability in
certain pathways, a possible function of this
"presynaptic inhibitory circuit" that has
received little attention.
Pre- and postsynaptic inhibition not only
differ in their mechanisms but also in their
consequences for the system. With
postsynaptic inhibition, the postsynaptic cell
is silenced or at least reduced in its excitability to all inputs no matter what their
source. The consequence for the muscle is
that it relaxes because there is no alternate
pathway to it. With presynaptic inhibition,
the excitation of the postsynaptic cell (in this
case, the "-motoneuron) through one
synapse is reduced, but all other synapses
perform normally or perhaps even
supranormally (see previous paragraph). For
the motoneuron, this means that transmission
through group Ia afferent fibers is reduced,
but transmission through polysynaptic and
supraspinal pathways is still possible.
All types of primary afferent fibers
receive presynaptic inhibition from one
source or another. The terminals of
pyramidal tract fibers in the brain stem have
been shown to be hypopolarized in the same
Figure 13 -20. Circuit for Rensha w inhibition. Spike
(A) generated in the axon at the top of the figure
invades the axon collateral, exciting the Renshaw
cell. The Renshaw cell discharges a train of spikes
(B) in response to a single presynaptic spike (an
example of synaptic amplification). The train of
spikes in the Renshaw cell produces summed IPSPs
in the motoneuro n (C). (Eccles JC: The Physiology
of N erve C ells. Baltimo re, Joh ns H opkins press,
1968)
manner. The significance of the latter effect
is unknown. Presynaptic inhibition may be
found to be more wide-spread as information
accumulates in the future. Postsynaptic
inhibition has been found in every structure
of the central nervous system, and our ideas
of its importance and ubiquity seem to be
increasing. The function of presynaptic
inhibition on primary afferent neurons may
be to modulate sensory inputs to the spinal
cord at the earliest possible point, before they
can influence spinal cord activity. In this
way, the central nervous system can eliminate
13-25
unwanted sensory information. By reducing
some sensory inputs, presynaptic inhibition
may be useful in certain kinds of contrast
enhancement.
Collateral or recurrent inhibition
A special case of postsynaptic inhibition
is recurrent inhibition, the circuit for
which is shown in Figure 13-19. The output
of a neuron, neuron A, conducts along its
axon and out one axon collateral to excite an
interneuron that inhibits another neuron of
the same type as neuron A, in this case
neuron B. Many people draw this circuit
showing that the inhibitory interneuron
inhibits neuron A, making neuron A inhibit
itself. Although this is possible, there is no
evidence that it occurs. The evidence does
suggest that neurons inhibit other neurons of
the same type. Thus, neuron A inhibits
neuron B and, similarly, neuron B inhibits
neuron A. Thus, the inhibition may more
appropriately be termed collateral inhibition. This is a type of feedback
inhibition, in which the output of a neuron
is used to inhibit at an earlier point in the
pathway.
Collateral inhibition has been found in
the spinal cord and in nearly every major
nucleus in the central nervous system,
notably in the cuneate and gracile nuclei,
thalamic nuclei, cerebellar nuclei, cerebellar
cortex, and cerebral cortex. One theory
suggests that collateral inhibition in the
thalamus may play a role in synchronizing
thalamic activity to produce the cortical
alpha rhythm (see Chapter 20). It is not
known whether this theory can stand
empirical tests nor what this kind of
inhibition might be doing elsewhere.
A special case of collateral inhibition is
Renshaw inhibition. This form of
inhibition involves the same circuit as in
Figure 13-19, in which neurons A and B are
13-26
"-motoneurons, whose axons innervate
skeletal muscles. The Renshaw circuit is
shown in Figure 13-20. The axon collateral
that activates the inhibitory interneuron is
short, remaining within the ventral horn of
the spinal cord and releasing acetylcholine at
its terminal. (Acetylcholine is also released
at the muscle.) The inhibitory interneuron,
called a Renshaw cell in honor of its
discoverer Birdsey Renshaw, discharges a
burst of spikes (B) in response to a single
motoneuron spike (A), releasing a transmitter
substance, perhaps glycine, at terminals on
other "-motoneurons. This leads to a large,
summed IPSP in these motoneurons (C).
Again, there is no evidence that an "motoneuron inhibits itself through Renshaw
inhibition. It has been speculated that
Renshaw inhibition may serve to limit
motoneuron firing rates. It is unlikely that
this is an important control mechanism for
normal motor activity; motoneurons do not
discharge at high rates anyway and, at least
during walking, this kind of inhibition is
suppressed. It is possible, however, that this
kind of inhibition may play an important role
in preventing or limiting certain kinds of
pathological or seizure discharges. What else
it might be doing for an organism is not
known.
Summary.
Synapses are functional connections
between cells. Transmission from one cell to
another at most electrical synapses is just like
transmission along the membrane of one of
the cells. Transmission at a chemical synapse
involves release of a transmitter substance
from the presynaptic element by
hypopolarizing its membrane (usually by an
action potential). The transmitter substance
can cause an increase in the permeability of
the postsynaptic membrane to small ions,
resulting in an EPSP, that is an
hypopolarizing potential with a decay time
constant of about four msec and an
amplitude of 1-10 mV. The transmitter
substance (a different substance usually) can
also cause an increase in permeability to
chloride and to potassium ions, resulting in
an IPSP that is an hyperpolarizing potential
with a decay time constant of about four
msec and an amplitude of 1-4 mV.
Neuromodulators are transmitter substances
which can alter the effectiveness of other
transmitter substances in changing the
membrane potential of a cell, without
themselves producing any EPSP or IPSP in
the cell. EPSPs drive the membrane
potential toward the critical firing level,
exciting, and IPSPs drive the membrane
potential away from the firing level,
inhibiting. Postsynaptic potentials exhibit
spatial and temporal summation. EPSPs do
not add algebraically to IPSPs, because the
IPSP's increase in conductance reduces the
hypopolarization produced by the EPSP's
ionic current; the IPSP normally
predominates. Inhibition by IPSPs is
postsynaptic inhibition. Presynaptic
inhibition involves an hypopolarization of
the presynaptic element at a synapse,
reducing the spike amplitude in it and thus
the amount of transmitter released by the
spike. Presynaptic inhibition reduces
transmission through one pathway afferent
to a cell, but not alternative pathways.
Postsynaptic inhibition reduces the
excitability of the cell itself and thus the
effectiveness of all pathways afferent to the
cell. Both chemical and electrical synapses
are capable of rectification, inhibition, and
summation. Chemical synapses are capable
of amplification, they have a finite synaptic
delay, and they are influenced by changes in
postsynaptic membrane potential. Electrical
synapses have not been observed to amplify
input signals. They have essentially no
synaptic delay, and they are not influenced by
changing the membrane potential of the
postsynaptic cell. Recurrent or collateral
inhibition involves the use of the output of a
neuron to inhibit, through an interneuron,
other neurons of the same type. Renshaw
inhibition is a special case of recurrent
inhibition involving the output of "
motoneurons and inhibition by Renshaw
cells.
Suggested Reading:
1. Bennett MVL: Similarities between
chemically and electrically mediated
transmission. In Carlson FD [ed]:
Physiological and Biochemical Aspects
of Nervous Integration. Englewood
Cliffs NJ, Prentice-Hall, 1968.
2. Curtis DR, Johnston GAR: Amino acid
transmitters in the mammalian central
nervous system. Ergebn Physiol 69:97188, 1974.
3. Horcholle-Bossavit G: Transmission
electrotonique dans le systeme nerveux
central des mammiferes. J Physiol
(Paris) 74:349-363, 1978.
4. Krnjevic' K: Chemical nature of synaptic
transmission in vertebrates. Physiol Rev
54:418-540, 1974.
5. Libet B: Nonclassical synaptic functions
of transmitters. Fed Proceed 45:26782686.
6. McGeer RL, Eccles JC, McGeer EG:
Molecular Neurobiology of the
Mammalian Brain. New York, Plenum
Press, 1978.
7. Pappas GD, Waxman SG: Synaptic fine
structure-morphological correlates of
chemical and electrical transmission. In
Pappas GD, Purpura DP [ed]: Structure
and Function of Synapses. New York,
Raven Press, 1972.
8. Schmidt RF: Presynaptic inhibition in
the vertebrate central nervous system.
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Ergebn Physiol 63:19-101, 1971.
9. Tapper DN, Mann MD: Single
presynaptic impulse evokes postsynaptic
discharge. Brain Res 11:688-690, 1968.
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