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electrical activity. If the amount of synaptic transmis-
sion is too low during development, then postsynap-
tic neurons can cease protein synthesis, become
atrophic, and may even die. Paradoxically, too much
excitatory activation has been shown to kill neurons by
loading their cytoplasm with calcium (Nicholls and
Wa rd, 2000; Duchen, 2000). In this section, we discuss
the relationship between innervation, synaptic activity,
and neuron survival, and ask what trophic signal is
being provided by afferent terminals.
Many of the original studies involved removing
centrally projecting axons to see whether the central
target developed properly in their absence. For
example, Larsell (1931) removed on eye in tree frog
larvae and found that its target, the contralateral optic
tectum, had many fewer cells than expected. However,
these studies were not able to discriminate between
effects on neurogenesis or migration versus effects on
neuron survival.
One of the best studied cases of afferent regulated
survival is the nucleus magnocellularis (NM) in the chick
central auditory system (Figure 7.31). Just before
taking up her studies of NGF (above), Rita Levi-Mon-
talcini had been studying the effect of cochlear nerve
fibers on the survival of NM neurons and other brain
stem nuclei. These studies have fascinated students of
biology because they were performed with very little
equipment in the countryside of Italy while World War
II raged around her. In spite of these privations, Levi-
Montalcini (1949) was able to show that the period of
normal cell death is elevated when the cochlea is
removed. Although there was little sign of degenera-
tion at E11, the age at which auditory nerve fibers first
activate NM neurons, there was a dramatic loss of cells
by E21. Subsequent studies showed that about 30% of
NM neurons are lost following cochlear ablation, and
the effect of denervation is much reduced in adult
animals (Parks, 1979; Born and Rubel, 1985). In fact,
neuron survival can change from being dependent
upon afferent innervation to being completely inde-
pendent over the course of a few days (Figure 7.32).
When the cochlea is removed in P7 gerbils, about 50%
of the postsynaptic cochlear nucleus neurons are lost.
However, when the cochlea is removed just two days
later, at P9, there is no neuronal cell loss (Tierney et al.,
Survival in other peripheral and central neurons
also depends, in part, on afferent connections during
development (Linden, 1994). However, surgical
removal of the afferent population does not really tell
us much about the trophic signal. Does the synapse
provide a survival factor such as NGF? Does the neu-
rotransmitter itself enhance survival? To address this
question, intact afferent pathways were treated with
E2 ablation
P14 ablation
Adult ablation
Days after Ablation
FIGURE 7.31 Afferent innervation regulates neuron survival in
a chick central auditory nucleus. A. Auditory neurons from the
cochlea innervate the nucleus magnocellularis (NM) in the chick
auditory brain stem. The removal of a cochlea (right) completely
denervates NM neurons on the ipsilateral side. B. When a cochlea is
removed at embryonic day 2 (E2), about 30% of NM neurons are lost
during the ensuing two weeks, although cell death does not begin
until E10. When the cochlea is removed at posthatch day 14, about
25% of neurons die within two days. In adults, cochlear ablation
results in the loss of only about 5% of NM neurons. (Adapted from
Parks, 1979; Born and Rubel, 1985)
agents that block neuronal activity (Maderdrut et al.,
1988; Born and Rubel, 1988). In the chick ciliary gan-
glion, cell death is increased when transmission is
blocked, although neurogenesis and migration
proceed normally. Similarly, action potential blockade
in the cochlea for 48 hours is sufficient to increase
normal cell death in the chick NM. Therefore, synaptic
activity seems to play a critical role in postsynaptic
neuron survival.
What is it about synaptic activity that promotes
neuron survival? One possibility is that synaptic trans-
mission provides a positive survival signal. Alterna-
tively, synaptic transmission may evoke action
potentials, and the associated voltage-gated currents
may affect survival. To distinguish between these two
possibilities, brain slices containing the chick NM and
its auditory nerve afferents were placed in vitro and
provided with two different stimulation protocols
(Figure 7.33). Although the experimental period was
too brief to observe dying neurons, denervation of NM
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