HIPPOCAMPAL NEUROTRANSMITTER SYSTEM IN FETAL ALCOHOL RAT

长期学习障碍已在暴露的儿童中被描述。 在产前使用乙醇。海马体结构，大脑的一个区域 涉及到记忆巩固，对 孕期酒精暴露对人和宫内动物模型的影响 酒精暴露。形态、神经化学、电生理和 行为证据表明，大脑中存在功能缺陷。 胎儿期酒精暴露动物的海马区结构。在… 目前，对海马区的神经化学参数知之甚少。 或这些更改可能如何导致净减少 海马神经传递。这个项目的长期目标是 以确定孕期酒精引起的神经化学改变 以及它们之间可能存在什么关系 的改变和一些电生理和行为后果 产前酒精暴露。我们竞相更新的具体目标 资助金申请如下： 1)我们将研究产前酒精暴露对N-受体的影响 海马区的甲基-D-天冬氨酸(NMDA)和半定量(QUIS)亚型 谷氨酸受体，使用受体放射自显影技术。我们有 先前报道的谷氨酸总量和红藻氨酸敏感度降低 酒精胎鼠海马区谷氨酸结合的研究。NMDA 和Quis研究将完成我们的放射组织化学研究 酒精胎鼠海马区谷氨酸受体的结合。 2.)我们将研究NMDA受体和细胞因子之间的相互作用 苯环利定(PCP)受体及其变构调节 这些结合位点是由甘氨酸组成的。我们的初步结果表明 胎儿酒精海马区NMDA受体减少。这一削减 可能会影响NMDA/PCP系统如何激活阳离子选择性通道 被认为在海马神经元可塑性中起重要作用。 3.)我们将研究基础和quis受体介导的激活。 磷脂酰肌醇(Pl)在胎儿酒精海马结构中的水解。 放射性标记的磷酸肌醇在人体内的蓄积 将测量海马片。磷脂的水解是重要的一步 用于某些神经递质如谷氨酸的信号放大。 检查基础和准刺激的Pl水解将使我们能够 确定该受体-转导系统是否受胎儿的影响 酒精暴露。 4.)我们将研究胎儿酒精暴露对蛋白质的影响 蛋白激酶C(PKC)介导的海马区F1蛋白磷酸化。一个 F1蛋白的相对选择性的磷酸化与 随着长时程增强的产生，一种电生理 以现象思维为中介的记忆巩固功能 海马体结构。我们还将检查数量和分配情况 ~3H-佛波醇二丁酸酯与小鼠不同脑区PKC结合的研究 用放射组织化学技术测定对照组和胎鼠酒精含量。 5.)我们将研究胎儿酒精暴露对脑细胞数量的影响。 齿状颗粒和海马锥体神经元。一种解释是 谷氨酸受体结合位点数量的减少和 海马区苔藓状纤维锌的数量可能有所减少 含谷氨酸受体和锌的海马区神经元。我们 将测量齿状回颗粒层中的细胞密度 对照组和对照组大鼠海马区CA3、CA1和下丘脑锥体层 胎鼠酒精。

Long term learning disabilities have been described in children exposed to ethanol prenatally. The hippocampal formation, an area of the brain involved with memory consolidation, is quite sensitive to the effects of prenatal ethanol exposure both in humans and animal models of in utero ethanol exposure. Morphologic, neurochemical, electrophysiological and behavioral evidence indicate the presence of a functional deficit in the hippocampal formation of animals exposed to ethanol prenatally. At present, little is known about which hippocampal neurochemical parameters are altered or how these alterations might lead to a net decrease in hippocampal neurotransmission. The long-term objective of this project is to identify what prenatal ethanol-induced neurochemical alterations occur in hippocampal formation and what relationships may exist between these alterations and some electrophysiological and behavioral consequences of prenatal ethanol exposure. The specific aims of our competing renewal grant application are: 1.) We will examine the effect of prenatal ethanol exposure on the N- methyl-D-aspartate (NMDA) and quisqualate (QUIS) subtypes of hippocampal glutamate receptors, using receptor autoradiography techniques. We have previously reported reductions in total glutamate and kainate-sensitive glutamate binding in fetal alcohol rat hippocampal formation. The NMDA and QUIS studies will complete our radiohistochemical investigation of glutamate receptor binding in fetal alcohol rat hippocampal formation. 2.) We will examine the interaction between the NMDA receptor and the phencyclidine (PCP) receptor along with the allosteric regulation of these binding sites by glycine. Our preliminary results indicate a decrease in NMDA receptors in fetal alcohol hippocampus. This reduction could affect how the NMDA/PCP system activates a cation-selective channel thought to be play an important role in hippocampal neuronal plasticity. 3.) We will examine basal and QUIS receptor-mediated activation of phosphoinositide (Pl) hydrolysis in fetal alcohol hippocampal formation. The accumulation of radiolabelled inositol phosphate (3H-lP1) in hippocampal slices will be measured. Pl hydrolysis is an important step for signal amplification by some neurotransmitters such as glutamate. Examination of basal and QUIS-stimulated Pl hydrolysis will allow us to determine whether this receptor- transduction system is affected by fetal alcohol exposure. 4.) We will examine the effect of fetal ethanol exposure on protein kinase C (PKC) mediated phosphorylation of hippocampal F1 protein. A relatively selective phosphorylation of F1 protein has been associated with the generation of long term potentiation, an electrophysiological phenomenon thought to mediate the memory consolidation function of hippocampal formation. We will also examine the amount and distribution of 3H-phorbol dibutyrate binding to PKC in various brain regions of control and fetal alcohol rats using radiohistochemical techniques. 5.) We will examine the effect of fetal ethanol exposure on the number of dentate granule and hippocampal pyramidal neurons. One explanation for a reduction in the number of glutamate receptor binding sites and hippocampal mossy fiber zinc may be a decrease in the number of hippocampal formation neurons containing glutamate receptors and zinc. We will measure cell density in the stratum granulosum of dentate gyrus and stratum pyramidale of hippocampal CA3, CA1 and subiculum in control and fetal alcohol rats.