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Abstract:
The BCM theory suggests that synaptic modifications with the
properties of LTP and LTD can account for experience-dependent
shifts in neuronal selectivity in the cerebral cortex. However, a
key assumption is that the LTD-LTP crossover point (now associated
with a critical level of postsynaptic NMDAR activation and Ca2+
flux) must adjust depending on the history of integrated
postsynaptic activity, an example of what has been termed
metaplasticity. The LTD-LTP crossover point, or qm, can be probed
by examining the synaptic modifications that occur in response to
tetanic stimulation delivered at different frequencies. To test the
hypothesis that the value of qm depends on the activation history
of the cortex, we compared the frequency-response functions in
visual cortex of animals reared in complete darkness with that of
normally reared animals. In accordance with theoretical
predictions, it was found in visual cortex of light-deprived rats
that LTP is enhanced, and LTD is diminished, over a range of
stimulation frequencies. As a test of the hypothesis that the value
of qm actually adjusts to a change in cortical activity, visually
deprived rats were exposed to light for various times. The data
suggest that qm "slides" as cortical activity increases.
A number of different mechanisms could contribute to the sliding
threshold. One that we have examined in detail is
activity-dependent changes in NMDAR subunit composition. NMDA
receptors in vivo are heteromeric ion channels composed of NR1 and
NR2 subunits. The subtype (A-D) of the NR2 subunit confers distinct
functional properties to the receptor. NR2B-containing receptors
predominate in the neonatal forebrain and, over the course of
development, these are replaced or supplemented with
NR2A-containing receptors. This subunit switch alters the channel
properties such that the synaptic NMDAR-mediated currents shorten
in duration. It has been previously reported that the developmental
shortening of NMDAR currents in visual cortical neurons is
postponed when animals are deprived of vision. These data suggest
that the NR2A/B subunit composition of synaptic NMDARs in
dark-reared (DR) animals differs from light-reared (LR) controls.
We tested this hypothesis and then examined the effects of brief
light exposure (LE) in DR animals. Our results show that new NMDA
receptors, with a higher NR2A/B ratio, are inserted into synaptic
membrane within 1 hr of the onset of visual experience.
The experience-dependent increase in the NR2A/B ratio, and the
concomitant shortening of synaptic NMDAR currents, are likely to
have a significant impact on the properties of synaptic plasticity.
Shortening NMDAR currents would be expected to make LTD more
likely, and LTP less likely, in response to a given amount of
synaptic activation. Thus, we hypothesize that one molecular
mechanism for the experience-dependent modifications of synaptic
plasticity in visual cortex is the regulation of NMDAR subunit
composition.
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