Inhibition of Nwd1 activity attenuates neuronal hyperexcitability and GluN2B phosphorylation in the hippocampus
Inhibition of Nwd1 activity attenuates neuronal hyperexcitability and GluN2B phosphorylation in the hippocampus
复制标题
抑制 Nwd1 活性可减弱海马神经元过度兴奋和 GluN2B 磷酸化
DOI：
10.1016/j.ebiom.2019.08.050
复制
发表时间：
2019-09-01
期刊：
影响因子：
11.1
通讯作者：
Wang，Qing
中科院分区：
文献类型：
--
作者：
Yang，Qin;Huang，Zifeng;Wang，Qing
背景NACHT和WD重复结构域蛋白1（Nwd 1）是先天免疫蛋白亚家族的成员。nwd 1参与雄激素受体信号通路并参与轴突生长。然而，在癫痫发作的病理生理功能障碍的基础上的机制仍不清楚。MethodsBiochemical方法被用来评估Nwd 1的表达和本地化在红藻氨酸（KA）诱导的急性癫痫发作和颞叶癫痫（TLE）患者的小鼠模型。电生理记录被用来测量Nwd 1在调节突触传递和神经元超兴奋性的模型中的作用，无镁诱导的尿素酶体外。采用KA致痫动物模型，观察大鼠行为学改变和癫痫病理变化。GluN 2B的表达进行了测量，并与Tyr 1472-GluN 2B磷酸化的相关性进行了分析，在原代海马neurons.FindingsWe证明了高蛋白水平的Nwd 1从小鼠急性癫痫发作和TLE患者的脑组织。使用腺相关病毒（AAV）沉默Nwd 1在小鼠中深刻抑制神经元过度兴奋和急性癫痫发作的发生，这可能是由于减少含GluN 2B的NMDA受体依赖性突触传递引起的。此外，Nwd 1的活化减少减少了GluN 2B的表达和GluN 2B亚基在Tyr 1472处的磷酸化。在这里，我们报告了Nwd 1在体外和体内癫痫模型中以前未被认识但重要的作用，即，调节GluN 2B亚基在Tyr 1472处的磷酸化并调节神经元的过度兴奋性。同时，我们的发现可能为癫痫或其他过度兴奋相关的神经系统疾病的治疗提供一种治疗策略。基金资助者没有参与研究设计、数据收集、数据分析、解释或报告的撰写。
BackgroundNACHT and WD repeat domain-containing protein 1 (Nwd1) is a member of the innate immune protein subfamily. Nwd1 contributes to the androgen receptor signaling pathway and is involved in axonal growth. However, the mechanisms that underlie pathophysiological dysfunction in seizures remain unclear.MethodsBiochemical methods were used to assess Nwd1 expression and localization in a mouse model of kainic acid (KA)-induced acute seizures and temporal lobe epilepsy (TLE) patients. Electrophysiological recordings were used to measure the role of Nwd1 in regulating synaptic transmission and neuronal hyperexcitability in a model of magnesium-free-induced seizurein vitro. Behavioral experiments were performed, and seizure-induced pathological changes were evaluated in a KA-induced seizure modelin vivo. GluN2B expression was measured and its correlation with Tyr1472-GluN2B phosphorylation was analyzed in primary hippocampal neurons.FindingsWe demonstrated high protein levels of Nwd1 in brain tissues obtained from mice with acute seizures and TLE patients. Silencing Nwd1 in mice using an adeno-associated virus (AAV) profoundly suppressed neuronal hyperexcitability and the occurrence of acute seizures, which may have been caused by reducing GluN2B-containing NMDA receptor-dependent glutamatergic synaptic transmission. Moreover, the decreased activation of Nwd1 reduced GluN2B expression and the phosphorylation of the GluN2B subunit at Tyr1472.InterpretationHere, we report a previously unrecognized but important role of Nwd1 in seizure modelsin vitroandin vivo,i.e., modulating the phosphorylation of the GluN2B subunit at Tyr1472 and regulating neuronal hyperexcitability. Meanwhile, our findings may provide a therapeutic strategy for the treatment of epilepsy or other hyperexcitability-related neurological disorders.FundThe funders have not participated in the study design, data collection, data analysis, interpretation, or writing of the report.