ARND--IMPACT ON SYNAPTIC PLASTICITY MECHANISMS

描述：（改编自研究者摘要）学习 残疾是最微妙但最普遍的缺陷， 与产前酒精暴露有关 这些学习缺陷， 可能不会变得明显，直到一个孩子是学龄，可以发生在 没有其他与酒精有关的出生缺陷的身体证据。 妊娠期暴露于中等水平酒精的大鼠后代 在年轻时测试时也显示出明显的学习障碍， 验证了该动物模型在研究胎儿的影响中的用途， 酒精暴露（FAE）。 我们的综合研究项目的初步研究 这表明这些缺陷与特定的改变有关， 突触可塑性机制，这与失败的， 长时程增强（LTP）。 的长期目标 该综合研究计划补助金（IRPG）有两个方面：1）描述 更清楚地表明，突触的分子和神经化学变化， 产前酒精暴露引起的可塑性机制; 2）探索 新的治疗策略来克服这些缺陷。 总体假设 是产前暴露于中等水平的乙醇 在谷氨酸水平的基础机制中产生多种缺陷， 乙醇在谷氨酸的潜在机制中产生多种缺陷 海马和内侧额叶皮层的受体依赖性LTP。 的 在本IRPG中，项目3的具体目标是确定FAE对以下方面的影响 参与突触可塑性的蛋白质的水平和功能 机制等 根据初步研究，我们的假设是， 激酶C（PKC）活性和GAP-43和 其他重要的可塑性相关蛋白质在特定的大脑中被改变， FAE大鼠的区域。 为了验证这个想法，我们提出了以下具体的 目的：1）研究PKC活性和GAP-43磷酸化， FAE大鼠海马和内侧额叶皮层PKC底物蛋白的研究 大鼠，在基础条件下和电刺激后2）， 研究FAE对GAP-43活性依赖性变化的影响 磷酸化和基因表达，3） 描述FAE大鼠中PKC活性缺陷的原因， 评估其在突触可塑性机制中的意义; 4） 探讨不同药物治疗对PKC的影响 活性和GAP-43磷酸化，以及5）与 这些对动物的行为和电生理特性的影响。 确定神经化学基础的改变， FAE大鼠海马和内侧额叶皮层突触可塑性研究 老鼠将提高我们对产前酒精影响的理解 这些重要的大脑结构的功能。 最后， 这些信息将有助于设计更好的治疗策略， 受酒精影响的儿童的行为和认知缺陷 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).