Chronic ethanol abuse results in brain damage and neuronal dysfunction. Studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing this neuronal dysfunction. Nevertheless, we still know little regarding the mechanisms underlying ethanol neurotoxicity nor the morphological or functional basis of the mnemonic deficits associated with chronic ethanol abuse. A major objective of this proposal is to begin to characterize the nature and mechanisms underlying the mnemonic deficit resulting from ethanol neurotoxicity. Chronic ethanol treatment has been shown to result in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Long-term potentiation is now considered to be a significant physiological mechanism whereby the hippocampus and other brain regions encode or index experimental representations and evidence indicates that chronic ethanol treatment may profoundly alter the properties of long-term potentiation in the hippocampus. A major objective of this proposal is to characterize the manner in which chronic ethanol treatment disrupts long-term potentiation in the hippocampus using extracellular and intracellular physiological recording techniques. We also propose to begin to characterize the nature of the mechanisms whereby chronic ethanol treatment disrupts long-term potentiation. A considerable amount is known regarding the induction of long-term potentiation in the hippocampus. The induction of long-term potentiation requires activation of an n-methyl-d-aspartate (NMDA) receptor complex which leads to a calcium transient localized to restricted locations in the postsynaptic membrane. This calcium transient likely leads to a specific activation of one or more calcium-sensitive enzyme systems. This molecular cascade in some way results in an increase in the strength of synaptic transmission which can last for hours to days. A major hypothesis to be investigated in this proposal is that chronic ethanol treatment disrupts long-term potentiation through a mechanism that includes alterations in one or more of the steps involved in this molecular cascade. Our studies will focus upon basic chronic ethanol actions upon glutamatesynaptic transmission, intracellular calcium regulatory processes and protein kinase activity. We will utilize electrophysiological, biochemical, autoradiographic and immunocytochemical techniques as well as studies of gene expression to characterize the manner in which chronic ethanol treatment disrupts the induction of long-term potentiation. In view of corollary evidence indicating a role for glutamate synapses and intracellular calcium regulation in excitotoxicity in a variety of disease states, the results of our studies may also have more global implications for the mechanisms whereby ethanol produces neuronal toxicity and dysfunction.
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