Kainate receptor signaling at excitatory synapses

描述(申请人提供)：海人藻酸受体是一个功能独特的谷氨酸门控离子通道亚家族，在中枢神经系统(CNS)中介导突触传递、调节神经递质释放和调节细胞兴奋性。由于这些受体在大脑功能中起着关键作用，它们被认为与多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，但由于缺乏针对红藻氨酸受体的全面药理学工具，关于红藻氨酸受体功能的一些基本问题仍然难以捉摸。在这些研究中，我们将利用编码红藻氨酸受体的基因发生定向突变的小鼠来解决这些剩余的问题。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，利用脑片的体外电生理记录技术，我们将：1.描述钙通透性海人藻酸受体在调节海马区和皮质的突触传递和发育可塑性中的作用；2.确定海人藻酸受体调节内在电导的分子途径，从而调节海马神经元的兴奋性；3.测试突触后海人藻酸受体对棘波耦合的贡献，从而确定它们在海马CA3网络中的作用；海藻酸受体是产生同步癫痫样活动的主要焦点。这些研究将对红藻氨酸受体影响突触和细胞兴奋性的分子机制提供重要的见解，并将证实它们是人类(TLE)的潜在治疗靶点。与公共健康相关：海人藻酸受体是谷氨酸门控的神经递质受体，对中枢神经系统中的突触信号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。本研究的目的是描述海人藻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，从而进一步证实这些受体是潜在的治疗靶点。

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.