Mossy fiber kainate receptors in gene-targeted mice

描述(申请人提供)：海人藻酸受体(KARs)是一个家族 谷氨酸受体，其激活导致海马区癫痫发作。卡尔斯 也调节突触传递和调节长期可塑性 大脑突触的数量。在海马区的CA3锥体细胞中，Kars是 定位于一种特殊的兴奋性突触--由苔藓纤维形成的突触 颗粒细胞的输入。在苔藓纤维突触的Kars是一个 突触后电流(KA-EPSC)在长时程和短时程增强诱导中的作用 突触强度的短期增强。这些活动的目标是 实验的目的是确定KAR激活导致 海马区突触强度和动作电位放电模式的改变 CA3区锥体神经元。这些问题将通过生理学检查 利用选择性药理化合物以及 缺乏一个或多个KAR亚基的基因靶标小鼠。 在特定目标1中，形成苔藓纤维KA-EPSCs的细胞机制将 通过在改变突触强度或改变突触强度的同时分析它们的属性进行检查 激活第二信使系统。这些实验将进一步 对苔藓纤维KARs不同生理作用的认识 SubServe，这将是阐明KAR5在 海马区的电路。在具体目标2中，我们将确定关键的 受体亚基和生理过程导致的激活 苔藓纤维与同步神经元放电模式有关。我们将测试是否 激发特性的变化可能是由非离子机制引起的 G蛋白介导的，或者说KARS和ION之间特别密切的联系 参与动作电位启动的通道。在具体目标3中，我们将 确定KARs在兴奋性突触可塑性中的作用 CA3锥体神经元上的突触。卡尔斯最近被牵连到 苔藓纤维突触长时程增强的诱导。我们会 通过检查突触前KARs和 利用基因靶向缺失LTP的小鼠确定LTP的亚基 或更多的KAR亚基。KARS在其他形式苔藓纤维可塑性中的作用 也将接受调查。

DESCRIPTION (provided by applicant): Kainate receptors (KARs) are a family of glutamate receptors whose activation leads to seizures in the hippocampus. KARs also modulate synaptic transmission and mediate long-term plasticity at a number of brain synapses. In CA3 pyramidal cells in the hippocampus, KARs are localized to one particular excitatory synapse-those formed by mossy fiber inputs from granule cells. KARs at mossy fiber synapses underlie an postsynaptic current (KA-EPSC) and play a role in the induction of long- and short-term potentiation of synaptic strength. The objective of these experiments is to determine the mechanisms by which KAR activation leads to altered synaptic strength and action potential firing patterns in hippocampal CA3 pyramidal neurons. These questions will be examined with a physiological approach that utilizes selective pharmacological compounds as well as gene-targeted mice lacking one or more KAR subunits. In Specific Aim 1, the cellular mechanisms that shape mossy fiber KA-EPSCs will be examined by analyzing their properties while altering synaptic strength or activating second messenger systems. These experiments will further understanding of the distinct physiological roles that mossy fiber KARs subserve, which will be integral for elucidating the role of KAR5 in hippocampal circuitry. In Specific Aim 2, we will determine the critical receptor subunits and physiological processes that lead from activation of mossy fiber KARs to synchronized neuronal firing patterns. We will test if changes in firing properties arise from non-ionic mechanisms, perhaps G-protein-mediated, or a particularly close association between KARs and ion channels involved in action potential initiation. In Specific Aim 3 we will establish the role of KARs involved in synaptic plasticity at excitatory synapses on CA3 pyramidal neurons. KARs were recently implicated in the induction of long-term potentiation (LTP) at mossy fiber synapses. We will extend our studies by examining the function of presynaptic KARs and determining the subunits underlying LTP using gene-targeted mice that lack one or more KAR subunits. The role of KARs in other forms of mossy fiber plasticity will also be investigated.