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Kainate receptor signaling at excitatory synapses

兴奋性突触的红藻氨酸受体信号传导

基本信息

批准号：
7466470
负责人：
Anis Contractor
金额：
$ 30.2万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7466470
关键词：
Address Affect Animal Model Biological Models Brain Calcium Chromosome Pairing Complex Condition Convulsants Coupling Demyelinating Diseases Development Epilepsy Excitatory Postsynaptic Potentials Excitatory Synapse Family Frequencies Gated Ion Channel Generations Genes Germ-Line Mutation GluR5 kainate receptor Glutamate Receptor Glutamates Goals Hippocampus (Brain)Human In Vitro Individual Kainic Acid Receptors Knockout Mice Link Mediating Memory Modeling Modification Molecular Mus Mutant Strains Mice Mutation Neuraxis Neurologic Neurons Neurotransmitter Receptor Nociception Numbers Pathway interactions Permeability Physiological Play Process Property Public Health Reagent Receptor Activation Receptor Signaling Recurrence Role Role playing therapy Signal Pathway Signal Transduction Site Slice Somatosensory Cortex Synapses Synaptic Transmission Synaptic plasticity Techniques Temporal Lobe Epilepsy Testing Validation chronic pain hippocampal pyramidal neuron insight kainate member mossy fiber neuronal excitability neurotransmitter release novel postsynaptic presynaptic receptor receptor function synaptic function therapeutic target tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Kainate receptors are a functionally unique sub-family of glutamate-gated ion channels that mediate synaptic transmission, modulate neurotransmitter release and regulate cellular excitability in the central nervous system (CNS). Because of the critical role these receptors play in brain function, they have been linked to several neurological conditions including chronic pain, neuroinflammatory demyelinating diseases and temporal lobe epilepsy (TLE). Despite significant progress in recent years, there remain a number of fundamental questions about the function of kainate receptors that have been elusive because comprehensive pharmacological tools targeting the kainate receptors have been lacking. In these studies we will make use of mice with targeted mutations in the genes that encode the kainate receptors in order to address some of these remaining questions. These animal models provide unique opportunities to describe the basic function of these receptors and clarify their contribution to normal and convulsant activity in the brain. Thus, using in vitro electrophysiological recording techniques in brain slices, we will: 1. Delineate the role of calcium permeable kainate receptors in regulating synaptic transmission and developmental plasticity in the hippocampus and cortex; 2. Determine the molecular pathways through which kainate receptors modulate intrinsic conductances, and thus regulate neuronal excitability in the hippocampus; 3. Test the contribution of postsynaptic kainate receptors to spike coupling, and thus determine their role in the recurrent CA3 network of the hippocampus; a major focus for the generation of synchronized epileptiform activity. These studies will provide important insight into the molecular mechanisms by which kainate receptors affect synapses and cellular excitability, and will validate them as potential therapeutic targets in human (TLE). PUBLIC HEALTH RELEVANCE: Kainate receptors are glutamate-gated neurotransmitter receptors that are critical to synaptic signaling and cellular excitability in the central nervous system. Pathophysiological activation of these receptors has been linked to several important neurological conditions including chronic pain, neuroinflammatory demyelinating diseases, and temporal lobe epilepsy. The goals of this study are to delineate the actions of kainate receptors at synapses and to comprehensively uncover their roles in modulating neuronal excitability, thus providing further validation of these receptors as potential therapeutic targets.

描述（由申请人提供）：红藻氨酸受体是谷氨酸门控离子通道的功能独特的亚家族，其介导突触传递、调节神经递质释放并调节中枢神经系统（CNS）中的细胞兴奋性。由于这些受体在脑功能中发挥的关键作用，它们与几种神经系统疾病有关，包括慢性疼痛，神经炎性脱髓鞘疾病和颞叶癫痫（TLE）。尽管近年来取得了重大进展，但仍然存在一些关于红藻氨酸受体功能的基本问题，这些问题一直难以捉摸，因为缺乏针对红藻氨酸受体的全面药理学工具。在这些研究中，我们将利用编码红藻氨酸受体的基因发生靶向突变的小鼠，以解决其中一些剩余的问题。这些动物模型提供了独特的机会来描述这些受体的基本功能，并阐明它们对大脑中正常和惊厥活动的贡献。因此，使用体外脑切片电生理记录技术，我们将：1。阐明红藻氨酸钙受体在海马和皮层突触传递和发育可塑性调节中的作用; 2.确定红藻氨酸受体调节内源性电导的分子途径，从而调节海马神经元的兴奋性; 3.测试突触后红藻氨酸受体对棘波耦合的贡献，从而确定它们在海马CA 3网络中的作用;这是同步癫痫样活动产生的主要焦点。这些研究将提供重要的深入了解红藻氨酸受体影响突触和细胞兴奋性的分子机制，并将验证它们作为潜在的治疗靶点在人类（TLE）。公共卫生关系：红藻氨酸受体是谷氨酸门控神经递质受体，其对中枢神经系统中的突触信号传导和细胞兴奋性至关重要。这些受体的病理生理激活与几种重要的神经系统疾病有关，包括慢性疼痛、神经炎性脱髓鞘疾病和颞叶癫痫。本研究的目的是描绘红藻氨酸受体在突触中的作用，并全面揭示它们在调节神经元兴奋性中的作用，从而进一步验证这些受体作为潜在的治疗靶点。