ARND--IMPACT ON SYNAPTIC PLASTICITY MECHANISMS

描述：(改编自《调查者摘要》)学习 残疾是最微妙但最普遍的缺陷之一 对儿童进行产前酒精暴露。这些学习缺陷， 可能直到孩子到了学龄期才会变得明显，可能发生在 没有其他与酒精有关的出生缺陷的物证。 妊娠期间暴露于中等水平酒精的大鼠的后代 在年轻时进行测试时，也会显示出学习上的显著障碍， 验证该动物模型在研究胎儿的影响方面的应用 酒精暴露(FAE)。我们的综合研究计划进行的初步研究 表明这些缺陷与特定的 突触可塑性机制与脑功能衰竭相关 长时程增强(LTP)的建立。的长期目标 这项综合研究计划补助金(IRPG)有两个方面：1)划定 更清楚地说，突触的分子和神经化学变化 胎儿期酒精暴露致可塑性机制及2)探讨 克服这些缺陷的新治疗策略。总体假设 对于IRPG来说，产前接触中等水平的乙醇 在谷氨酸水平的潜在机制上产生多种缺陷 乙醇在谷氨酸的作用机制中产生多种缺陷 海马区和内侧额叶皮质的受体依赖性长时程增强。这个 本IRPG中项目3的具体目标是定义FAE对 突触可塑性相关蛋白的水平和功能 机械装置。基于初步研究，我们的假设是蛋白质 蛋白激酶C(PKC)活性与GAP-43和GAP-43的水平及磷酸化 其他重要的可塑性相关蛋白在特定的大脑中发生变化 FAE大鼠的区域。为了检验这一想法，我们提出了以下具体建议 目的：1)研究PKC活性和GAP-43等蛋白的磷酸化 FAE大鼠海马区和内侧额叶皮质的PKC底物蛋白 基础状态和电刺激后的大鼠2)至 检测FAE对GAP-43活性依赖变化的影响 行为条件化过程中的磷酸化和基因表达，3) FAE大鼠PKC活性缺陷的原因分析及实验研究 评估其在突触可塑性机制中的意义和4) 探讨不同药物治疗对蛋白激酶C的影响 对照组和FAE大鼠脑组织中GAP-43的活性及相互关系 这些都与动物的行为和电生理特性有关。 脑血管病变的神经化学基础鉴定 FAE海马区和内侧额叶皮质的突触可塑性 老鼠将提高我们对产前酒精影响的理解 暴露在这些重要大脑结构的功能中。最终， 这些信息将有助于设计更好的治疗策略，以克服 与酒精相关的儿童的行为和认知障碍 神经发育障碍(ARND)。

DESCRIPTION: (Adapted from the Investigator's Abstract) Learning disabilities are among the most subtle yet most pervasive deficits related to prenatal alcohol exposure in children. These learning deficits, which may not become apparent until a child is school-aged, can occur in the absence of other physical evidence of alcohol-related birth defects. Offspring of rats exposed to moderate levels of alcohol during gestation also show a significant impairment in learning when tested as young adults, validating the use of this animal model in studies of the effect of fetal alcohol exposure (FAE). Initial studies by our integrative research program suggested that these deficits are related to specific alterations in synaptic plasticity mechanisms which correlated with a failure in the establishment of long-term potentiation (LTP). The long-term objectives of this Integrated Research Program Grant (IRPG) are two-fold: 1)to delineate more clearly the molecular and neurochemical alterations of synaptic plasticity mechanisms caused by prenatal alcohol exposure and 2) to explore new treatment strategies to overcome these deficits. The overall hypothesis for the IRPG is that prenatal exposure to moderate levels of ethanol produces multiple defects in the mechanisms underlying glutamate levels of ethanol produces multiple defects in the mechanisms underlying glutamate receptor-dependent LTP in the hippocampus and medial frontal cortex. The specific goal of Project 3 in this IRPG is to define the impact of FAE on the levels and function of proteins involved in synaptic plasticity mechanisms. Based upon preliminary studies, our hypothesis is that protein kinase C (PKC) activity and the levels and phosphorylation of GAP-43 and other important plasticity-associated proteins is altered in specific brain regions of FAE rats. To test this idea, we propose the following Specific Aims: 1)to study PKC activity and the phosphorylation of GAP-43 and other PKC substrate proteins in the hippocampus and medial frontal cortex of FAE rats, both under basal conditions and after electrical stimulation 2)to examine the impact of FAE on activity-dependent changes in GAP-43 phosphorylation and gene expression during behavioral conditioning, 3) to characterize the causes for the deficit in PKC activity in FAE rats and to evaluate its significance in synaptic plasticity mechanisms and 4) to investigate the effects of different pharmacological treatments on PKC activity and GAP-43 phosphorylation in control and FAE rats and 5) to relate these to the behavioral and electrophysicological properties of the animals. The identification of the neurochemical basis for the alterations in synaptic plasticity in the hippocampus and medial frontal cortices of FAE rats will improve our understanding of the effects of prenatal alcohol exposure in the function of these important brain structures. Ultimately, this information will help design better therapeutic strategies to overcome behavioral and cognitive deficits in children affected with Alcohol Related Neurodevelopmental Disorders (ARND).