CELLULAR AND MOLECULAR STUDIES OF ETHANOL AND MEMORY

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The amnestic effects of acute ingestion of ethanol are well documented in both human and animal studies. However, the molecular and cellular mechanisms which underlie this amnestic effect are unknown. To address this question, the P.I. proposes to examine the effects of ethanol on long-term potentiation (LTP) a form of synaptic plasticity that is widely thought to serve as a cellular substrate of memory. The specific focus of the proposed studies will be to examine the effects of ethanol on electrophysiological and biochemical correlates of LTP. Ethanol has previously been shown to inhibit induction of LTP in area CA1 of the rat hippocampal slice. Previous work has provided contradictory evidence concerning the concentration of ethanol required to block LTP. Moreover, little is known about the brain regional specificity of ethanol's effects on LTP. Therefore, the P.I. will perform dose-response and brain regional analyses of the effect of ethanol on LTP. The potential molecular targets underlying ethanol's effects on LTP differ in their alcohol concentration sensitivities. Moreover, at least one of these targets of ethanol, the NMDA-receptor, are required for induction LTP in some brain regions but not in others. Thus the dose response and brain regional analyses should help to identify constraints on the molecular targets involved in ethanol inhibition of LTP. There have been no studies of the effects of ethanol on the maintenance of LTP after it has been induced. Thus the P.I. also proposes to examine the dose dependency of ethanol's effects on the maintenance of LTP. Given that different molecules appear to participate in maintenance and induction, such studies may also provide new information about the molecular targets of ethanol's effects on LTP. In addition to these electrophysiological analyses, the P.I. also proposes to examine the effects of ethanol on protein phosphorylation. The focus of these analyses will be on the synapsins, synaptic vesicle-associated proteins that are substrates for Ca2+/calmodulin-dependent protein kinase. Synapsin phosphorylation has clearly been shown to play a role in regulation of transmitter release, and ethanol has been reported to modulate release in a number of different neuronal systems. Moreover, synapsin phosphorylation is correlated with LTP induction and LTP is due, at least in part, to increased transmitter release. Therefore the P.I. proposes to examine the effects of ethanol on synapsin phosphorylation produced by chemical and electrical inducers of LTP.