谷氨酸受体亚基GluN2B在神经兴奋性中起着重要的作用，由于其分布、定位和转运受多种因素调控，其在癫痫发生发展中的机制仍不明确。NACHT和WD重复序列蛋白1（NWD1）是固有免疫蛋白亚家族成员，在大脑中高表达，目前尚未见报道其是否参与癫痫病理生理过程。我们前期在癫痫模型小鼠海马组织中发现NWD1蛋白增高，沉默NWD1减少GluN2B受体介导的海马锥体神经元及场电位癫痫样放电和兴奋性突触后电位。而NWD1与GluN2B膜蛋白水平及GluN2B-Tyr1472磷酸化程度正相关，且共表达于神经突触后膜。本项目拟通过体内和体外实验研究NWD1调控GluN2B-Tyr1472磷酸化介导GluN2B的胞吞再循环的动态转运规律，从而影响海马神经兴奋性平衡稳态及其机制，明确NWD1/GluN2B-Tyr1472在癫痫发生发展中的作用和机制。该项目将为癫痫的发病机制提供新线索，并为癫痫的诊治提供新策略。

Glutamic acid receptor subunit GluN2B plays an important role in neuroexcitability, but its distribution, location and transport are regulated by several factors; therefore, the specific mechanism of epileptogenesis in epilepsy is still unclear. NACHT and WD repeat domain-containing protein 1 (NWD1) is a member of the innate immune protein subfamily, and NWD1 is highly expressed in the brain. It has not been reported whether NWD1 is involved in the pathophysiological process of epilepsy. We found that the levels of NWD1 protein increased in hippocampal tissue obtained from a mouse model of epilepsy. The epileptiform discharges decreased in pyramidal neurons and in field potential after silencing NWD1, and there was a decrease in the GluN2B receptor-mediated excitatory postsynaptic currents. NWD1 was positively correlated with GluN2B membrane protein levels and with the phosphorylation of GluN2B-Tyr1472, and these protein were coexpressed in the postsynaptic membrane. This project aims to explore the regulation of the phosphorylation of GluN2B-Tyr1472 by NWD1, which mediates the dynamic transport of GluN2B endocytosis and recycling, both in vitro and in vivo. This study will identify and clarify the role and mechanism of NWD1/GluN2B-Tyr1472 in homeostasis and the mechanism of hippocampal neuroexcitability as well as in the occurrence and development of epilepsy. This study will also provide new clues about the pathogenesis of epilepsy and new strategies for the diagnosis and treatment of epilepsy.