CHRONIC ETHANOL NEUROTOXICITY AND LONGTERM POTENTIATION

慢性乙醇滥用会导致脑损伤和神经元功能障碍。 对实验室动物的研究提供了令人信服的证据， 乙醇诱导这种神经元功能障碍的特异性。 尽管如此，我们仍然对潜在的机制知之甚少， 乙醇的神经毒性，也没有形态学或功能基础， 与慢性酒精滥用相关的记忆缺陷。 一个主要目标 这一建议的目的是开始描述 这是乙醇神经毒性导致的记忆缺陷的基础。 慢性乙醇治疗已被证明会导致显着的损失， 海马神经元、树突状结构和存活功能的改变 神经元和突触连接的丢失或重排。 长期 增强作用现在被认为是一种重要的生理机制 海马体和其他大脑区域编码或索引 实验陈述和证据表明，慢性乙醇 治疗可能会深刻地改变长时程增强的性质， 海马体 该提案的一个主要目标是描述 慢性乙醇处理破坏长时程增强的方式 在海马体中使用细胞外和细胞内生理 记录技术。 我们还建议开始描述 慢性乙醇治疗破坏长期 增强作用 关于诱导， 海马体的长时程增强 长期的诱导 增强作用需要激活N-甲基-D-天冬氨酸（NMDA）受体 复合物，导致钙瞬变定位于限制 位于突触后膜。 这种钙瞬变 导致一种或多种钙敏感酶的特异性激活 系统. 这种分子级联在某种程度上导致了 突触传递的强度可以持续数小时到数天。 一 在这项建议中要研究的主要假设是， 乙醇处理通过一种机制破坏长时程增强， 包括在涉及该分子的一个或多个步骤中的改变 级联。 我们的研究将集中在基本的慢性乙醇行动， 谷氨酸突触传递，细胞内钙调节过程 和蛋白激酶活性。 我们会利用电生理学， 生物化学、放射自显影和免疫细胞化学技术以及 研究基因表达以表征慢性炎症的方式 乙醇处理破坏了长时程增强的诱导。 在 一种推论证据表明谷氨酸突触的作用， 细胞内钙调节在多种疾病兴奋性毒性中作用 美国，我们的研究结果也可能有更多的全球影响 乙醇产生神经毒性的机制， 功能障碍

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.