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Neurotrophins, such as NT-3, are produced in the
developing retina, and they are transported antero-
gradely down retinal ganglion cell axons to the optic
tectum (von Bartheld et al., 1996). Since the survival
of optic tectum neurons depends on both axonal
transport and electrical activity by retinal axons, it
seems possible that NT-3 mediates this afferent regu-
lation (Catsicas et al., 1992). Of course, if neu-
rotrophins provided an anterograde signal, then the
target neurons would be expected to have Trk recep-
tors at the synapse. In fact, an electron microscopic
study of TrkB and TrkC receptors shows that they
are located at postsynaptic profiles in the developing
(and adult) central nervous system (Hafidi et al.,
It is also interesting to consider that membrane
depolarization, which is often found to enhance the
survival of cultured neurons, actually promotes the
expression of survival factor receptors. In a sympa-
thetic neuron cell line, membrane depolarization
causes the cells to produce TrkA receptor, and this
allows NGF to become an effective survival factor
(Birren et al., 1992). In fact, some neurons depend on
sufficient levels of cytoplasmic calcium even before
they become dependent on neurotrophins (Larmet
et al., 1992). Thus, synapses may be employing more
than one mechanism in keeping neurons alive, and
these may include activation of ionotropic and
metabotropic receptors, postsynaptic depolarization
(and calcium homeostasis), and activation of neu-
rotrophin receptors.
rored by a diversity of cytoplasmic mechanisms for
dying. However, all forms of normal cell death require
either the production or activation of proteins that can
do damage to the neuron, such as caspases. Given the
danger of keeping death machinery in place, neurons
also express a broad range of regulatory proteins
which ensure that apoptosis occurs only under the
appropriate conditions.
Despite the wealth of candidate mechanisms that
have been shown to mediate cell death in a few model
systems, the process remains poorly understood in the
CNS. Perhaps there are CNS trophic factors that have
yet to be discovered. Alternatively, the survival of CNS
neurons may be distributed among the many afferents
and targets to which they connect, each one contribut-
ing a survival signal. This would make it difficult to
detect the involvement of any single factor through a
loss-of-function experiment.
As new trophic factors and intracellular mecha-
nisms are put forward, we must be cautious of evi-
dence supporting a role for each individual factor in
supporting neuron survival. There are a number of
interesting methods for sustaining neurons that have
been removed from the body and placed in culture.
However, some of these methods do not duplicate
the strategy used by developing neurons to survive
their natural environment, just as parachutes and life
preservers are relevant to our survival only in specific
situations. Conversely, the failure to observe an effect
in genetically altered animals should not remove a
factor from the list of candidates because CNS survival
may depend on several, functionally overlapping
The role of electrical activity in cell survival points
out the tremendous plasticity of the developing
nervous system. Small perturbations of synaptic activ-
ity can have a profound impact on the number of cells
and the amount of postsynaptic membrane on which
the synapses form (see Chapter 9). It is not too difficult
to imagine that these mechanisms are necessary to
optimize the diverse kinds of neural circuitry found
within each animal.
Naturally occurring cell death claims up to 80% of
the neuroblasts and differentiating neurons and glia in
the developing brain. Depending on the particular
group of neurons, survival may rely on target-derived
trophic factors, synaptic activity, hormonal signals,
and other cues. The diversity in survival factors is mir-
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