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ment of neurotransmission soon after the initial contact
is made (Figure 8.8). In fact, the presynaptic release
site (called the active zone) is preassembled and
shipped down that axon (Ahmari et al., 2000; Shapira
et al., 2003). Dense core vesicles are found to contain
most, if not all, of the proteins that are necessary for
synaptic vesicle release. These include presynaptic
cytoskeleton-associated proteins (Piccolo and Bassoon)
and a regulator of vesicle fusion (Rim). It is estimated
that a new active zone can be established by the inser-
tion of only two to three of these vesicles. To determine
how quickly these proteins accumulate at a presynap-
tic contact, new active zones were labeled with the
FM4-64 method shown in Figure 8.7 and then counter-
stained for pre- and postsynaptic marker proteins
(Friedman et al., 2000). Within 45 minutes of detecting
a new release site, about 90% of them have already
accumulated Bassoon. In contrast, less than 30% of the
postsynaptic sites are labeled for the postsynaptic
density protein, PSD-95 (Figure 8.12). Thus, presynap-
tic sites display rapid molecular development, which
seems to precede postsynaptic maturation.
Cell adhesion molecules (above) may explain some
aspects of development, but it seems necessary to
invoke an asymmetric signal—that is, a signal that pro-
vides different instructions to the growth cone and the
postsynaptic membrane. Two signaling systems have
now been identified that exhibit this sort of asymmetry,
and each one can recruit synaptic vesicles as well as the
associated transmitter-release machinery (Figure 8.13).
When pontine neurons are grown in vitro, their axons
come to a halt and accumulate synaptic vesicles when
they contact their postsynaptic target neurons, cerebel-
lar granule cells (Figure 8.13A). The growth cones of
these axons express the cell surface protein, b-neurexin,
which serves as a receptor for neuroligin, a ligand that is
expressed in the developing cerebellum. This signaling
system is sufficient to induce presynaptic differentia-
tion. When pontine axons contact nonneuronal cells that
are expressing neuroligin-1 or -2, they stop growing and
accumulate presynaptic protein (e.g., synapsin) and
synaptic vesicles (Figure 8.13B). This effect can be
blocked with the addition of soluble neurexin to the
culture media (Scheiffele et al., 2000; Dean et al., 2003).
Granule cells also release the soluble factor that can
induce presynaptic differentiation, Wnt-7a . Pontine
axons that express the Wnt receptor, Frizzled , accumu-
late synapsin when grown in the presence of Wnt-7a -
transfected cells. There is now evidence that Wnt
supports synapse differentiation in other systems (Hall
et al., 2000; Krylova et al., 2002; Packard et al., 2002).
Many of the trophic factors that support target inva-
sion and neuron survival (Chapters 6 and 7) also play
an important role during synapse formation; these
Nectin-1 I-Afadin Nectin-3 N-Cadherin
FIGURE 8.11 A schematic showing the nectin-afadin adhesion
system during the formation of a synapse in developing hippo-
campal pyramidal neurons. The nectin-afadin system organizes
adherens junctions cooperatively with the cadherin-catenin system.
Nectin is an immunoglobulin-like adhesion molecule, and afadin is
an actin filament-binding protein that connects nectin to the actin
cytoskeleton. During development, nectin-1 and -3 localize at both
the puncta adherentia junctions (i.e., mechanical anchoring sites)
and at synaptic junctions. This changes during development such
that nectin-afadin comes to be localized around the synaptic active
zone. The cadherin-catenin system is likely to co-localize with the
nectin-afadin system at each stage. D, dendritic trunks of pyrami-
dal cells; SV, synaptic vesicles; A, actin filaments. (Adapted from
Mizoguchi et al., 2002)
When cadherins were blocked in a hippocampal
culture, neither the postsynaptic spines nor the presy-
naptic terminals were as differentiated as in control cul-
tures (Togashi et al., 2002). The nectins are another
family of Ig-like CAMs that are connected to the
cytoskeleton by the actin filament-binding protein, l-
afadin. The nectin-afadin system is co-localized with
the cadherin-catenin system during synapse formation
in the hippocampus. Initially, these proteins are found
at the site of contact between growth cone and postsy-
naptic neuron, a close apposition of membrane called
an adherens junction (see EM of neonatal synapse in
Figure 8.2). As the synapse matures, the adhesion mole-
cule gradually become localized adjacent to the synapse
(Figure 8.11). As with the cadherin system, blockade of
nectin-1 function has been shown to affect the size and
number of synapses (Mizoguchi et al., 2002).
Although the growth cone has some ability to
release neurotransmitter, there is a dramatic improve-
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