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innervation pattern, similar to the ocular dominance
columns in mammalian visual cortex. The segregation
of afferents into stripes was blocked completely in the
presence of NMDAR antagonists (Figure 9.27B). This
effect is reversible: when the NMDAR blocker is
removed, the fibers from each eye became segregated.
Interestingly, exposing the midbrain to NMDA leads to
a sharpening of the borders between eye-specific stripes
(Cline et al., 1987; Cline and Constantine-Paton, 1990).
In the mammalian superior colliculus (SC), NMDA
blockade prevents the elimination of retinal projec-
tions that grow to the wrong topographic position
during the first few postnatal weeks (Chapter 6). These
studies, and many others like them, show that the
NMDAR plays a fundamental role in activity-depend-
ent maturation of synaptic connections (Scherer and
Udin, 1989; Simon et al., 1992). One can observe the
influence of NMDA receptor activity by recording
the receptive field of individual SC neurons (i.e., the
portion of visual space that activates the neuron).
When the hamster SC is treated with an NMDAR
blocker during development, the single neuron recep-
tive field sizes are more than 60% larger than normal
(Huang and Pallas, 2001). In fact, the receptive fields
can attain normal values even when a portion of the
superior colliculus is eliminated at birth, forcing the
retinal axons to innervate fewer postsynaptic neurons.
This ability is also prevented with a NMDAR antago-
nist. Therefore, NMDAR blockade commonly inter-
feres with synapse elimination in the central nervous
system, leading to less specific afferent projections. It
is also significant that NMDARs play an important role
in one neural analog of learning called long-term poten-
tiation (see BOX: Remaining Flexible).
there is a greater number of presynaptic sites com-
pared to wild-type flies (Wang et al., 1994). The oppo-
site effect was produced in the frog optic tectum by
causing CaMKII to be expressed constitutively in post-
synaptic neurons (Zou and Cline, 1996). Retinal axons
make simpler arborizations when CaMKII is highly
expressed, suggesting that connections are being elim-
inated more rapidly than normal. In dissociated cul-
tures of cortical pyramidal neurons, the number of
connections per neuron can be modified by transfect-
ing cells with a constitutively active form of CaMKII
(i.e., catalytically active in the absence of calcium). The
transfected neurons display a net loss of presynaptic
contacts and a reduction in the number of presynaptic
partners (Pratt et al., 2003). Thus, CaMKII participates
in decisions about the number of connections to be
made, making it a good candidate for the synapse
elimination mechanism.
At the fly nerve muscle junction, there is an expan-
sion of terminal boutons in the mutant, ether-a-go-go ,
which displays increased synaptic activity and an
increase in bouton number (Figure 9.28A and B). As we
learned in Chapter 8, discs large (DLG) is a clustering
protein at the Drosophila nerve-muscle junction. One
of the synaptic proteins that DLG regulates is the cell
adhesion molecule, FasII. To test whether CaMKII sig-
naling can influence the clustering of DLG and FasII,
mutant flies expressing a constitutively active form of
the kinase were examined (Koh et al., 1999). In these
flies, DLG was apparently displaced from the synap-
tic region. Since DLG can be phosphorylated by
CaMKII, these results lead to a model in which activ-
ity mediates synapse stability by modifying the level
of adhesion (Figure 9.28C). An influx of calcium may
activate CaMKII, leading to phosphorylation of DLG
and declustering of FasII. Taken together with the
results from flies in which CaMKII is inhibited, it
appears that the activity of this enzyme controls
synaptic sprouting and stabilization.
There are several other protein kinases that may
play a similar role during synaptogenesis. One kinase
that is partially dependent on intracellular calcium
and phospholipid metabolites is protein kinase C
(PKC). When mice are genetically engineered to be
deficient in a neuron-specific form of PKC, synapse
elimination is decreased in the cerebellum. About 40%
of Purkinje neurons are innervated by more than one
climbing fiber, while normal Purkinje cells are all
innervated by a single axon (Kano et al., 1995). Other
enzymes, such as protein kinase A (PKA), are activated
by a rise in cAMP. A role for the cAMP and PKA sig-
naling pathway has been suggested by single-gene
mutant flies, named dunce , due to their poor learning
abilities. The cAMP levels are persistently increased in
dunce flies, leading to a decrease in FasII expression
Since calcium plays an important role in develop-
mental plasticity, it is reasonable to ask what calcium
interacts with in the cytoplasm. There are a broad
range of calcium-binding proteins in the nervous
system. One of these, called calmodulin , is a major con-
stituent of the postsynaptic density. Together with
calcium, it serves to activate a cytoplasmic kinase
called Ca 2+ /calmodulin-dependent protein kinase II
(CaMKII). Once activated, the CaMKII becomes
autophosporylated, and its activity then becomes inde-
pendent of Ca 2+ and calmodulin binding.
To test the role of CaMKII, transgenic fruit flies were
engineered to express an inhibitor of this enzyme
during development. The motor nerve terminals of
these transgenic animals have numerous sprouts, and
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