Molecular Determinants of Visual Cortical Plasticity

Project: Research project

Project Details

Description

DESCRIPTION: Cyclic GMP is a vital second messenger in the CNS. It has been
shown to have specific actions at presynaptic and postsynaptic sites that
induce dramatic short-term alterations in synaptic efficacy. The central
hypotheses of this proposal, that these actions act synergistically to affect
information flow through visual cortex and that similar actions play a role in
longer lasting forms of plasticity, will be tested with four specific aims. In
the first aim, the mechanism by which cGMP enhances NMDA receptor responses
will be studied. Electrophysiological measurements will be used to confirm that
elevation of cGMP decreases receptor desensitization. Recombinant NMDA receptor
subunits, including those that change in postnatal development, will be used to
determine whether cGMP causes direct phosphorylation of one or more subunits.
Finally, the small depolarization induced in some cortical neurons by cGMP will
be studied to determine how these actions combine to increase selectively the
proportion of the glutamate response passing through the NMDA receptor. The
second aim will study the mechanism by which cGMP can dramatically inhibit
cortical GABAergic responses at the presynaptic terminal. A combination of
electrophysiological measurements and calcium imaging studies will be carried
out to test the hypothesis that elevation of cGMP levels leads to inhibition of
both plasma membrane voltage-dependent calcium channels and the endoplasmic
reticulum InsP3 receptor calcium channel. In addition, cGMP-mediated effects on
the downstream mobilization of synaptic vesicles will be tested.

The third aim will study the mechanism of cGMP-induced membrane depolarization
in cortical neurons. Past work has shown that this can occur through
cyclic-nucleotide gated cation channels. Bcng channels, responsible for the Ih
current in many cell types, are also regulated by cyclic nucleotides. The
development and distribution of these channels in different cortical cells will
be studied. The effects of cGMP and cAMP on these cannels will be studied to
determine how activation can alter synaptic responses of cortical cells.
Finally, actions of cGMP will be studied using stimulus paradigms that cause
longer lasting forms of synaptic plasticity. Such experiments will test the
hypothesis that the short-term modulation studied mechanistically in this
proposal are also important for longer lasting potentiation or depression of
cortical synaptic responses. This proposal is a coherent program that will
explain actions of a vital second messenger at the molecular level and show how
it affects the physiology of individual cells and cell assemblies within visual
cortex.
StatusFinished
Effective start/end date3/1/973/31/05

Funding

  • National Eye Institute
  • National Eye Institute
  • National Eye Institute
  • National Eye Institute: $367,875.00
  • National Eye Institute: $367,875.00
  • National Eye Institute: $408,750.00
  • National Eye Institute: $367,875.00
  • National Eye Institute: $263,350.00

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