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nerve-muscle cultures are exposed to these proteins,
there is an increase in the rate of spontaneous synap-
tic events and an increase in the amplitude of evoked
synaptic currents (Figure 8.14). BDNF exerts its effect
at the synaptic terminal through a calcium-dependent
process, whereas CNTF seems to act at the soma. It
takes approximately 10 minutes for BDNF or CNTF to
effect transmission, and neurotransmission remains
altered for hours after these compounds are removed.
These effects may depend on local protein synthesis at
the synapse (Stoop and Poo, 1996; Zhang and Poo,
2002).
Several intracellular signals are also involved in the
transition from growth cone to terminal. By observing
the giant growth cones produced by cultured Aplysia
bag cells, one finds that microtubules extend toward
the site of contact with a target, and filamentous actin
begins to accumulate (Forscher et al., 1987). A similar
transformation can be produced by raising cAMP
levels within the growth cone. The cytoskeleton reor-
ganizes and neurosecretory granules invade the
growth cone's lamellapodia, resulting in a presynaptic-
like morphology. Activation of a second intracellular
signaling pathway, protein kinase C (PKC), results in
the rapid appearance of new calcium channels at the
edge of the grow cone (Knox et al., 1992).
Calcium, PKC, and cAMP may work in tandem to
support the accumulation of secretory vesicles and ion
channels at the site of contact. In fact, the contact-
evoked increase in calcium (Figure 8.9) may actually
be a result of cAMP signaling. When an identified snail
motor neuron is manipulated into contact with its
normal target in vitro, it exhibits an increase in calcium
(Funte and Haydon, 1993). This rise is mimicked by a
membrane permeable analog of cAMP and is pre-
vented by injecting an inhibitor of cAMP-dependent
protein kinase (PKA) into the motor neuron. How are
these intracellular signals activated during growth
cone differentiation? Certain neurotransmitter recep-
tors can produce a Ca 2+ influx, and some of these have
been shown to inhibit growth cone motility (Mattson
and Kater, 1989). Cell adhesion molecules are also
capable of transducing cell surface signals to produce
an elevation of internal Ca 2+ (Doherty et al., 1991).
Load with FM4-64
Unload
0 mins
28 mins
53 mins
Bassoon-labeling
PSD-95-labeling
Post-
fixation
FIGURE 8.12 Early appearance of the presynaptic marker,
Bassoon, at a new release site. FM 4-64 is used to label sites of vesicu-
lar release, and it can be unloaded by stimulating the synapses in the
absence of the dye. A new release site (i.e., presynaptic bouton)
appears between 0 and 28 minutes (arrowhead), and this site is
retained at 53 minutes. The neurons are then fixed, and immunohis-
tochemistry is performed on the same region. The new bouton is asso-
ciated with an aggregate of Bassoon, but not with the postsynaptic
density protein, PSD-95. Scale bar is 3 mm (Friedman et al., 2000)
range from the induction of new synapses to the
upregulation of neurotransmitter release. For example,
the addition of BDNF can increase the number of
synapses, both in cultures and in vivo (Vicario-Abejon
et al, 1998; Marty et al. 2000; Alsina et al., 2001).
Members of the neurotrophin family of growth factors
(BDNF and NT-3) and CNTF are also able to potenti-
ate the release of ACh by presynaptic terminals. When
RECEPTOR CLUSTERING
SIGNIFIES POSTSYNAPTIC
DIFFERENTIATION AT NMJ
The aggregation of neurotransmitter receptors
beneath the presynaptic terminal is the most obvious
hallmark of synaptogenesis. Is receptor clustering a
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