Kainate receptor signaling at excitatory synapses

点击翻译按钮获取中文摘要

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.