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Abstract:
Neuronal activity controls the structural development of
local circuitry in many regions of the developing CNS. This complex
process has a number of functionally distinct, but not mutually
exclusive phases. Work in our laboratory, concentrated on the
development of the superficial visual layers of the rodent superior
colliculus (sSC), has implicated the N-methyl-D-aspartate subtype
of glutamate receptor (NMDAR) in at least three of these phases.
Thus when the first synapses are forming, when synaptic densities
are low and when sensory receptor organs are still completing their
differentiation, increases in the "spontaneous" activation of young
CNS neurons are necessary for the continued structural and
biochemical maturation of neurotransmission. I will briefly
describe one mechanism through which NMDAR activation controls
local protein translation and the consequences of this control in
modulating dendritic levels of Ca++/Calmodulin Dependent Kinase II.
A second competitive sorting phase of local circuit maturation that
depends on the temporal pattern of action potential activity is
known to dominate the differentiative process once young afferent
can actually drive their target neurons. However, it is likely that
elements of this competitive mechanism operate before significant
spike activity is evident in developing neuropil. I will present
some recent data suggesting that early, low level, chronic
activation of NMDARs on target neurons early in neuropil
differentiation actually suppresses development of glutamatergic
differentiation in the sSC through a mechanism similar to that
proposed for some forms of long-term depression. A final phase of
activity-dependent control in many local circuits involves a
down-regulation of a relatively permissive state for synaptic
sorting and changes in efficacy. Much data suggest that
down-regulation of NMDAR currents plays an important role in this
process, that such regulation is, itself, activity-dependent and
that the change involves a subunit change in the NMDAR complex. I
will present a recent study indicating that the NMDAR subunit
change is only one component of this mechanism and that a more
activity-sensitive and rapid down-regulation in synaptic NMDAR
currents can be effected by an abrupt increase in the activity of a
phosphatase known to alter the gating properties of the receptor
irrespective of its subunit composition.
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