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terminals decrease their transmitter release as they
are eliminated (Kopp et al., 2000). In summary, the
strength of one synapse at the nerve-muscle junction
apparently decreases with time, and it seems plau-
sible that this must be the one that is eventually
Control: No stimulation
Experimental: LP stimulation
Te st SN-evoked
Te st SN-evoked
The postsynaptic cell probably plays an active role
in causing extra synapses to withdraw. At the NMJ,
postsynaptic AChR clusters can disappear before
nerve terminals withdraw from the muscle surface.
Thus, presynaptic terminals may be forcibly evicted
from their territory when the postsynaptic cell re-keys
the locks (Role et al., 1987; Balice-Gordon and Licht-
man, 1993). To demonstrate that the loss of functional
AChRs is sufficient to produce synapse elimination, a
small fraction of receptors were blocked by locally
applying a-Btx. Over a number of days, the presynap-
tic terminal that is in contact with the inactivated
region gradually withdraws (Balice-Gordon and
Lichtman, 1994). However, it is essential that only a
small fraction of neighboring receptors are blocked. If
all the receptors are blocked, then the nerve terminal
does not retract. It is also clear that motor axons can
compete for existing receptors. One motor terminal
will grow into the endplate region occupied by a
second motor terminal as it is withdrawing (Walsh and
Lichtman, 2003). These observations emphasize once
again that synaptic competition occurs within very
small dimensions.
To examine whether heterosynaptic depression and
receptor turnover are related, simple dual innervated
nerve-muscle cultures were examined (Figure 9.25B).
Electrical stimulation of one neuron led to a depression
of the excitatory response evoked by the unstimulated
neuron. When the AChR density under each synapse
was examined before and after stimulation, the
unstimulated synapse was found to have lost more
than 30% of its AChRs (Li et al., 2001). These experi-
ments do not have the temporal resolution to decide
whether receptor loss caused the reduction in synapse
strength or whether either phenomenon leads to
synapse withdrawal. However, they suggest how this
process may proceed. Taken together with observa-
tions from in vivo recordings (Colman et al., 1997;
Kopp et al., 2000), the higher release probability and
greater quantal content of some competing axons may
prevent the reduction of postsynaptic AChRs and
maintain the synaptic area.
FIGURE 9.24 Synaptic activity depresses less active inputs in
vivo. The lumbrical muscle in the rat foot is innervated by two phys-
ically separate motor nerve roots, LP and SN. A. In control animals,
stimulation of the SN motor nerve root (red) elicits a robust con-
traction of the lumbrical muscle (bottom). B. If the LP motor nerve
root (blue) is repetitively stimulated during development (top), then
the SN nerve root stimulation elicits a much weaker contraction of
the lumbrical muscle (bottom) when it is subsequently tested.
(Adapted from Ridge and Betz, 1984)
Synaptic terminals do not battle each other directly
but carry on their competition through an independ-
ent agent, the postsynaptic cell. It is a bit like choosing
the winner of a boxing match by judging who punches
the referee harder. The contribution of the postsynap-
tic cell to heterosynaptic depression can be demon-
strated by activating it directly with transmitter. When
a muscle cell is activated focally with a puff of ACh
from the tip of a pipette, then the size of synaptic
responses declines by about 50% (Dan and Poo, 1992).
Of course, this begs the question of whether a
depressed synapse is necessarily an eliminated
synapse. Furthermore, we have already learned that
the rate of synapse elimination in vivo does not occur
within minutes, but over a period of days (Figure 9.7).
If synaptic depression really is the first hint of a dying
connection, then one might expect to record a synap-
tic response that gradually becomes weaker during
development. This can be observed at the mammalian
NMJ by measuring the average number of ACh
packets that are released by each synapse, called the
quantal content . Even at birth, one synapse is about
twice as strong as the second, but over the next week
one of the synapses becomes about four times stronger
than the other (Colman et al., 1997). That is, it releases
four times as much transmitter. It has also been found
that release probability varies dramatically between
competing axons, and it is possible that presynaptic
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