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.
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