Kainate Receptors in Signaling Between Hippocampal Mossy Cells and Granule Cells

海马苔藓细胞和颗粒细胞之间信号传导中的红藻氨酸受体

基本信息

批准号：
8914068
负责人：
GEOFFREY T SWANSON
金额：
$ 19.31万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914068
关键词：
AMPA Receptors Animal Model Anticonvulsants Appearance Architecture Axon Brain Brain Injuries C57BL/6N Mouse Cells Chronic Communication Contralateral Data Dendrites Dendritic Spines Disease model Epilepsy Equilibrium Excitatory Synapse Feedback Future Gene Targeting Health Hilar Hippocampus (Brain)Human Interneurons Ipsilateral Kainic Acid Kainic Acid Receptors Mediating Modeling Mus Mutant Strains Mice Neurons Pathway interactions Pattern Perforant Pathway Physiological Pilocarpine Play Population Presynaptic Terminals Process Property Proteins Pyramidal Cells Regulation Rodent Rodent Model Role Seizures Signal Transduction Signaling Protein Slice Structure of molecular layer of cerebellar cortex Synapses Synaptic plasticity Temporal Lobe Epilepsy Time dentate gyrus granule cell hippocampal pyramidal neuron information processing memory process mossy fiber mouse model neuronal excitability novel optogenetics postsynaptic presynaptic receptor receptor function selective expression synaptic function tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Mossy cells in the hilar region are important but relatively understudied contributors to integration of cortical input to the hippocampus. Signaling mechanisms that impact mossy cell excitability and synaptic function are relevant to physiological network function, such as encoding of patterns of input, and play a role in pathological adaptations, as occur in epilepsy. Kainate receptors play important modulatory roles in network excitability elsewhere in the hippocampus through diverse functional activities that are neuron- and synapse-specific. How kainate receptors might contribute to excitatory signaling in hilar mossy cells and between mossy cells and either hilar interneurons or dentate granule cells is entirely unknown and is the focus of this project. We will determine if kainate receptors contribute to either efferent or afferent signaling in mossy cells. This objective is relevant to models of temporal lobe epilepsy because (i) mossy cells are central to the two predominant models of circuit hyperexcitability in chronic forms of temporal lobe epilepsy, and (ii) aberrant kainate receptor function was recently shown to contribute to seizures in rodent seizure models. In Specific Aim 1, we will determine the role and composition of kainate receptors in mossy cells, focusing particularly on postsynaptic kainate receptor function at granule cell - mossy cell synapses. The subunit composition of mossy cell kainate receptors will be determined using a combination of pharmacological tools and gene-targeted mice. In Specific Aim 2, we will examine potential contributions by kainate receptors to signaling between mossy cells and dentate granule cells or hilar interneurons. The architecture of mossy cell projections has made studying these synapses challenging. We will develop a new mouse model in which channelrhodopsin is selectively expressed in mossy cells and subsequently photostimulate inputs to granule cells or hilar interneurons independent of either perforant path or CA3 collaterals. Pre- and postsynaptic function, mechanisms of short- and long-term synaptic plasticity, and the role of kainate receptors at these synapses will be determined for the first time. These studies will elucidate the physiological role played by kainate receptors in hilar circuits and lay the framework for understanding their pathological role in network hyperexcitability in seizure states.

描述（由申请人提供）：肺门区域中的苔藓细胞是重要但相对研究的促进者，这是对海马的整合。信号影响苔藓细胞兴奋性和突触功能的机制与生理网络功能有关，例如输入模式的编码，并在病理适应中起作用，如癫痫中发生。海藻受体通过神经元和突触特异性的各种功能活动在海马其他地方的网络兴奋性中起重要的调节作用。海藻酸盐受体如何有助于肺苔藓细胞，苔藓细胞和hilar膜中神经元或齿状颗粒细胞之间的兴奋性信号传导完全未知，并且是该项目的重点。我们将确定海谷酸酯受体是否有助于苔藓细胞中的传出或传播信号传导。该目标与颞叶癫痫的模型有关，因为（i）苔藓细胞以颞叶癫痫的慢性形式的两种主要电路模型的核心，并且（ii）最近显示出异常的海藻酸盐受体功能在啮齿动物癫痫模型中有助于癫痫发作。在特定的目标1中，我们将确定海藻酸盐受体在苔藓细胞中的作用和组成，尤其是颗粒细胞 - 苔藓细胞突触的突触后海藻酸盐受体功能。苔藓细胞水酸盐受体的亚基组成将使用药理学工具和靶向基因的小鼠的组合确定。在特定的目标2中，我们将研究海藻酸盐受体对苔藓细胞和齿状颗粒细胞或肺门神经元之间信号传导的潜在贡献。苔藓细胞预测的结构使研究这些突触具有挑战性。我们将开发一个新的小鼠模型，其中通道旋丁蛋白在苔藓细胞中有选择地表达，随后光刺激输入到颗粒细胞或hilar膜间神经元中，独立于穿孔路径或CA3侧支。首次确定突触前和突触后功能，短期和长期突触可塑性的机制以及海藻酸盐受体在这些突触中的作用。这些研究将阐明海藻酸盐受体在肺门电路中扮演的生理作用，并为了解其在癫痫发作状态的网络过度兴奋性中的病理作用奠定了框架。