Kainate Receptors in Signaling Between Hippocampal Mossy Cells and Granule Cells

描述（由申请人提供）：门区的苔藓细胞是重要的，但相对研究不足的贡献者整合皮质输入海马。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（例如输入模式的编码）相关，并且在病理适应中起作用，如在癫痫中发生的。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。红藻氨酸受体如何可能有助于门苔藓细胞和苔藓细胞与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，是这个项目的重点。我们将确定红藻氨酸受体是否有助于苔藓细胞的传出或传入信号。这一目标与颞叶癫痫模型相关，因为（i）苔藓细胞是慢性形式的颞叶癫痫中回路过度兴奋的两种主要模型的中心，以及（ii）最近显示红藻氨酸受体功能异常有助于啮齿动物癫痫发作模型中的癫痫发作。在具体目标1中，我们将确定红藻氨酸受体在苔藓细胞中的作用和组成，特别关注颗粒细胞-苔藓细胞突触中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使用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门部中间神经元之间信号传导的潜在贡献。苔藓状细胞投射的结构使得研究这些突触具有挑战性。我们将开发一种新的小鼠模型，其中通道视紫红质在苔藓细胞中选择性表达，随后光刺激输入到颗粒细胞或独立于穿通路径或CA 3侧枝的门部中间神经元。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的作用将首次确定。这些研究将阐明红藻氨酸受体在门电路中所起的生理作用，并为理解其在癫痫发作状态下网络过度兴奋中的病理作用奠定框架。

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.