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：
8807381
负责人：
GEOFFREY T SWANSON
金额：
$ 23.18万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8807381
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 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 public health relevance 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）：肺门区的苔藓细胞对于皮质输入到海马体的整合很重要，但研究相对较少。信令影响苔藓细胞兴奋性和突触功能的机制与生理网络功能相关，例如输入模式的编码，并在病理适应中发挥作用，如癫痫中发生的情况。红藻氨酸受体通过神经元和突触特异性的多种功能活动在海马其他部位的网络兴奋性中发挥重要的调节作用。红藻氨酸受体如何促进肺门苔藓细胞中以及苔藓细胞与肺门中间神经元或齿状颗粒细胞之间的兴奋性信号传导是完全未知的，也是本项目的重点。我们将确定红藻氨酸受体是否有助于苔藓细胞中的传出或传入信号传导。这一目标与颞叶癫痫模型相关，因为（i）苔藓细胞是慢性颞叶癫痫中回路过度兴奋的两种主要模型的核心，（ii）最近显示异常的红藻氨酸受体功能有助于癫痫发作啮齿动物癫痫发作模型。在具体目标 1 中，我们将确定苔藓细胞中红藻氨酸受体的作用和组成，特别关注颗粒细胞 - 苔藓细胞突触的突触后红藻氨酸受体功能。苔藓细胞红藻氨酸受体的亚基组成将通过药理学工具和基因靶向小鼠的组合来确定。在具体目标 2 中，我们将研究红藻氨酸受体对苔藓细胞和齿状颗粒细胞或肺门中间神经元之间信号传导的潜在贡献。苔藓细胞投射的结构使得研究这些突触变得具有挑战性。我们将开发一种新的小鼠模型，其中视紫红质通道蛋白在苔藓细胞中选择性表达，随后光刺激输入到颗粒细胞或肺门中间神经元，独立于穿通路径或 CA3 侧支。突触前和突触后功能、短期和长期突触可塑性的机制以及红藻氨酸受体在这些突触中的作用将首次得到确定。这些研究将阐明红藻氨酸受体在肺门回路中发挥的生理作用，并为理解其在癫痫状态网络过度兴奋中的病理作用奠定框架。