Kainate Receptors in Signaling Between Hippocampal Mossy Cells and Granule Cells

描述(由申请人提供)：肺门区域的苔藓细胞是重要的，但相对较少的研究有助于整合皮质输入到海马体。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有关，如输入模式的编码，并在病理适应中发挥作用，如癫痫。海人藻酸受体通过神经元和突触特有的不同功能活动，在海马区其他部位的网络兴奋性中发挥重要的调节作用。海人藻酸受体如何在肺门苔藓细胞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信号中发挥作用是完全未知的，这也是本项目的重点。我们将确定红藻氨酸受体是否参与苔藓细胞的传出或传入信号。这一目的与颞叶癫痫模型有关，因为(I)苔藓细胞是慢性形式颞叶癫痫两种主要的回路高兴奋性模型的中枢，以及(Ii)最近发现异常的海人藻酸受体功能与啮齿动物癫痫模型的癫痫发作有关。在特定的目标1中，我们将确定海人藻酸受体在苔藓细胞中的作用和组成，特别是在颗粒细胞-苔藓细胞突触中的突触后海人酸受体功能。苔藓细胞红藻氨酸受体的亚单位组成将使用药理学工具和基因靶标小鼠相结合的方法来确定。在特定的目标2中，我们将研究红藻氨酸受体在苔藓细胞和齿状颗粒细胞或肺门中间神经元之间的信号传递中的潜在作用。苔藓细胞投射的结构使研究这些突触具有挑战性。我们将开发一种新的小鼠模型，在该模型中，通道视紫红质在苔藓细胞中选择性表达，随后光刺激输入颗粒细胞或肺门间神经元，而不依赖于穿支路径或CA3侧支。将首次确定突触前和突触后的功能，突触的短期和长期可塑性的机制，以及海人藻酸受体在这些突触中的作用。这些研究将阐明海人酸受体在肺门回路中所起的生理作用，并为理解其在癫痫状态下网络过度兴奋中的病理作用奠定基础。

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.