FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES

海马体在许多正常的 生理过程和病理情况，包括 阿尔茨海默氏症和癫痫。发展一种完整的理解 突触调控的分子和细胞机制 海马体的功能可能导致新的治疗策略 这些障碍中。直到最近，人们还认为大多数神经病- 对海马区功能的调制影响需要激活 外源性传入和谷氨酸的所有活动，主要是 海马区固有的神经递质，是由 配体门控阳离子通道的激活。然而，现在很明显， 谷氨酸也激活受体，称为代谢性谷氨酸。 受体(MGluR)，通过GTP与效应系统偶联 结合蛋白。到目前为止，已经克隆了5个mGluR亚型。然而， 不同mGluR亚型在神经元调节中的确切作用 海马区的兴奋性和突触传递尚不清楚。 对正常和病理性海马区的全面了解 功能将需要详细了解mGluRs在 调节海马区生理。有趣的是，IS、3R- ACPD(一种选择性mGluR激动剂)作用于海马片，增强 环磷酸腺苷对其他阳性受体激动剂的反应 与腺苷环化酶偶联。此外，3R-Acpd还具有许多重要的 海马体的生理效应。其中包括， 海马区CA1区突触抑制的减少和 在被唤起的群体中，齿状回出现尖峰。然而，准确的 MGluR激动剂调节的细胞和突触机制 海马区的抑制性和兴奋性突触反应不是 为人所知。此外，1S，3R-acpd诱导的生理相关性 环状AMP反应的增强作用尚不清楚。一系列 提出了微电极和膜片钳结合的实验方案 来自海马神经元的录音将被用来检验这一假设 1S，3R-acpd减轻CA1区突触抑制并诱发 通过减少兴奋性传递在齿状回中产生种群尖峰 抑制性中间神经元和齿状颗粒细胞。 此外，还将进行实验以确定生理作用 MGluR介导的环状AMP反应增强在调节中的作用 海马体中的突触传递。最后，特定的抗体 将针对每个克隆的mGluR亚型引发。这些将是 用于确定细胞和亚细胞的精确定位 不同亚型的mGluR在海马区的分布。这些 研究，加上电生理实验，将提供 有关特定mGluR亚型在 调节海马区功能。

The hippocampus plays an important role in a number of normal physiological processes and in pathological conditions, including Alzheimer's disease and epilepsy. Development of a complete understanding of the molecular and cellular mechanisms of regulation of synaptic function in the hippocampus could lead to new Strategies for treatment of these disorders. Until recently, it was thought that most neuro- modulatory influences on hippocampal function required activation of extrinsic afferents and that all of the actions of glutamate, the major neurotransmitter intrinsic to the hippocampus, were mediated by activation of ligandgated cation channels. However, it is now clear that glutamate also activates receptors, known as metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. To date, 5 mGluR subtypes have been cloned. However, the precise roles of the different mGluR subtypes in regulating neuronal excitability and synaptic transmission in the hippocampus are not known. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in regulating hippocampal physiology. Interestingly, application of IS,3R- ACPD (a selective mGluR agonist) to hippocampal slices, potentiates cyclic AMP responses to agonists of other receptors that are positively coupled to adenylate cyclase. Also, IS,3R-ACPD has a number of important physiological effects in the hippocampus. These include, among others, a decrease in synaptic -inhibition in hippocampal area CA1 and a decrease in evoked population spikes in the dentate gyrus. However, the precise cellular and synaptic mechanisms by which mGluR agonists modulate inhibitory and excitatory synaptic responses in the hippocampus are not known. Furthermore, the physiological relevance of 1S,3R-ACPD-induced potentiation of cyclic AMP responses is not known. A series of experiments is proposed in which microelectrode and patch clamp recordings from hippocampal neurons will be used to test the hypothesis that 1S,3R-ACPD decreases synaptic inhibition in area CA1 and evoked population spikes in dentate gyrus by reducing excitatory transmission onto inhibitory interneurons and dentate granule cells, respectively. Also, experiments will be performed to determine the physiological role of mGluR-mediated potentiation of cyclic AMP responses in regulating synaptic transmission in the hippocampus. Finally, specific antibodies will be raised against each of the cloned mGluR subtypes. These will be used to determine the precise cellular and subcellular localization of the different mGluR subtypes in the hippocampal formation. These studies, coupled with the electrophysiological experiments, will provide valuable information regarding the roles of specific mGluR subtypes in regulating hippocampal function.