红藻氨酸受体（KAR）是中枢神经系统中介导兴奋性突触信息传递的谷氨酸受体家族成员之一，其活性和功能异常与多种神经系统疾病如癫痫症密切相关。KAR受体在大脑中的分布定位具有细胞和突触特异性，但是其中的分子机制不甚清楚。以大鼠海马培养脑片为研究系统，结合基因枪转染和膜片钳电生理记录分析技术，我们建立了异质性红藻氨酸受体GluK2/GluK4和GluK2/GluK5突触转运的研究方法，发现它们突触转运的分子基础是不同的，并且是由低亲和亚基GluK4和GluK5的细胞外氨基端结构域所决定的。本项目拟在上述研究基础之上，深入研究其中详细的分子机制，揭示其与C1q补体家族成员、Nrx跨膜蛋白形成的跨突触三元复合物在红藻氨酸受体突触特异定位中的功能和作用机制；以及所发现的作用机制在颞叶癫痫症小鼠动物模型中的潜在功能，为阐明兴奋性突触的生理功能机制及相关神经疾病发病机理提供理论基础。

Kainate receptors (KARs) are a subfamily member of glutamate receptors that mediate the excitatory synaptic transmission in the central nervous system, and their activity deregulation and malfunction are involved in several neurological diseases, such as epilepsy. In the brain, the distribution and localization of different KARs exhibit specificity for cellular and synaptic types. However, the underlying molecular mechanism(s) remains elusive. Using rat hippocampal cultured slice as study models and combining the techniques including the biolistic transfection and dual whole-cell and patch-clamp electrophysiological recording, we have established a research system to study synaptic trafficking of heteromeric KARs GluK2/GluK4 and GluK2/GluK5. And we found that the molecular machinery regulating their synaptic targeting is different and is depended on the extracellular N-terminal domains of the low-affinity subunits GluK4 and GluK5. Based on these current results, in this proposal we are planning to further study the underlying detailed molecular bases, especially the functional mechanism of potential transsynaptic trio-complex of KARs, C1q complementary family members and Nrx transmembrane proteins for specific synaptic localization of different KARs. Moreover, we will study the function of the revealed molecular mechanism in the mouse disease model of temporal lobe epilepsy. We believe that this study will provide important insights in to the physiological function of excitatory synapse as well as its pathological contribution to neurological disease.