Mechanisms of Ethanol Action on NMDA Receptors and LTP

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DESCRIPTION (provided by applicant): N-methyl D-aspartate receptors (NMDARs) are ionotropic glutamate receptors required for induction of LTP in area CA1 of the hippocampus. In the 1980's, it was discovered that ethanol inhibits these receptors and blocks LTP. The mechanism(s) by which ethanol inhibits NMDARs and LTP have not been elucidated. We have previously shown that PKC activators induce tyrosine phosphorylation and potentiation of the NMDAR. Phosphorylation is also required for LTP induction. We hypothesized that the inhibitory action of ethanol may be a result of reduced tyrosine phosphorylation of NMDAR subunits leading to endocytosis of NMDARs. In order to test these hypotheses, we will use the hippocampal slice preparation, immunoprecipitation, and western blotting to evaluate tyrosine phosphorylation of NMDA subunits following in situ ethanol exposure. Additionally, we will study NMDAR function and LTP induction utilizing electrophysiology. Biochemical methods will be employed to evaluate the surface expression of NMDARs. We hope that these studies will contribute to the understanding of alcoholism by enhancing our knowledge of how ethanol affects cognition.