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Muscle 1
Clearly, the presynaptic terminals are carrying on a
rather hostile conversation through the postsynaptic
cell, and there must be some molecular pathway that
conveys the signal from one contact to another through
the cytoplasm. One hypothesis is that depolarizing
synaptic potentials open voltage-gated Ca 2+ channels,
and Ca 2+ -dependent proteolytic enzymes are recruited
to demolish the nonactive terminals, ultimately leading
to their withdrawal. A variety of proteolytic enzymes
have been discovered in the nerve terminals and
somata of developing neurons. This hypothesis was
tested at the mammalian NMJ by decreasing extracellu-
lar Ca 2+ or blocking specific Ca 2+ -activated proteases,
and both manipulations were able to slow down the
process of synapse elimination (Connold et al., 1986).
Once again, there are important similarities
between synapse elimination and heterosynaptic
depression (above). First, it is possible to prevent
heterosynaptic depression by injecting the muscle cell
with a Ca 2+ chelator that sops up free Ca 2+ , suggesting
that a rise in postsynaptic calcium is necessary for
depression to occur. Second, it is possible to cause
synaptic depression by momentarily raising postsy-
naptic calcium. This was accomplished by loading
muscle cells with molecules of “caged” calcium, which
can release the calcium into the cytoplasm when it is
exposed to ultraviolet light (Figure 9.26A). Therefore,
the synaptic responses at one muscle cell are recorded
while a second neighboring muscle cell is exposed to
a brief pulse of UV light, and synaptic transmission is
depressed by 50% within seconds (Figure 9.26B) (Lo
and Poo, 1994; Cash et al., 1996). Interestingly, this rise
in postsynaptic calcium is only effective within 50 mm
of the synapse, and stimulation of the synapse protects
it from depression (Figure 9.26C).
Since synaptic activity leads to the depression and
withdrawal of neighboring synapses, it follows that the
active synapse must somehow be protected. Although
the signaling pathways that lead to AChR loss and het-
erosynaptic depression are not fully understood, there
is evidence that two kinases, PKA and PKC, are
involved (Figure 9.25C). For example, PKC activators
can produce synaptic depression in the absence of stim-
ulation. In contrast, the PKC activator has no effect
when the neuron is stimulated (Li et al., 2001). There
are probably several molecular changes that attend
synapse elimination at the nerve-muscle junction. The
removal of AChRs, a decrease in ACh release, and loss
of adhesion between pre- and postsynaptic cells (see
below), all conspire to weaken the connection.
Muscle 2
50 µm
Caged calcium release (<50
1.5 nA
2 min
2 nA
30 ms
FIGURE 9.26 Synapse depression depends on postsynaptic
calcium. A. A whole-cell recording is made from an innervated
myocyte (Muscle 1), while the intracellular calcium was elevated in
a second nearby myocyte (Muscle 2). Calcium was elevated by first
filling Muscle 2 with caged calcium and then using UV light
to release the calcium from its “cage”. B. Baseline nerve-evoked
synaptic currents (downward deflections beneath each dot which
represent the stimuli) are first recorded from Muscle 1 (black).
When intracellular calcium is elevated in Muscle 2 by exposure
to UV light, the nerve-evoked synaptic currents (red) become
depressed within seconds. Depression is greatest when the muscles
are within 50 mm of one another. C. A summary of three conditions
shows that synaptic currents decline by 50% when calcium is ele-
vated (red bar), but the effect can be abolished by stimulating the
nerve during UV-evoked uncaging (blue). (Adapted from Cash et
al., 1996)
Calcium signaling seems to play an important role
in the stabilization of developing synapses, but how
does calcium get into the neuron? One important
pathway is through neurotransmitter receptor-
coupled channels. As we learned in Chapter 8, NMDA-
sensitive glutamate receptors (NMDAR) are highly
expressed in the central nervous system during synap-
togenesis. These receptors become active when
glutamate and membrane depolarization are present
at the same instant (Figure 9.27A). When NMDARs are
depolarized, a magnesium ion is expelled, and the
open channel permits Ca 2+ to rush into the postsynap-
tic neuron.
To find out whether NMDA receptors are involved
in activity-dependent synapse plasticity, these recep-
tors have been blocked in a number of developing
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