POSH participates in epileptogenesis by increasing the surface expression of the NMDA receptor: a promising therapeutic target for epilepsy. (2nd December 2017)

• Record Type: Journal Article
• Authors: Wang, Xinshi; Tian, Xin; Yang, Yong; Lu, Xi; Li, Yun; Ma, Yuanlin; Zhang, Yanke; Zheng, Fangshuo; Lu, Shanshan; Xu, Demei; Xu, Xin; Wang, Wei; Wang, Xuefeng
• Is Part Of: Expert opinion on therapeutic targets. Volume 21:Number 12(2017:Dec.)
• Page Start: 1083
• Page End: 1094
• Publication Date: 2017-12-02
• Subjects: POSH -- epilepsy -- therapeutic target -- lentivirus -- electrophysiology -- patch clamp -- NMDA receptor; Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1080/14728222.2017.1394456
• Languages: English
• ISSNs: 1744-7631

Abstract

ABSTRACT: Objectives : Plenty of SH3 (POSH) was originally found to be a key regulator of neuronal apoptosis, axon outgrowth, and neuronal migration. However, the role of POSH in epilepsy has not been reported. Methods : We investigated the expression of POSH in patients with intractable temporal epilepsy (TLE) and in a kainic acid (KA)-induced mouse model, and then we performed behavioral, electrophysiological and biochemical analyses after the lentivirus (LV)-mediated knockdown or overexpression of POSH in the KA-induced model. Results : POSH overexpression shortened the latency of seizure onset, increased the frequency of spontaneous recurrent seizures, and increased the frequency of electrical epileptic discharges, while POSH knockdown had contrasting effects. Whole-cell patch-clamp recordings confirmed that POSH overexpression and knockdown were associated with increased and decreased miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents, respectively. Finally, co-immunoprecipitation showed that POSH and NMDA receptor subunit 1 (NMDAR1) precipitated with each other, and western blot analysis revealed that the surface expression of NMDAR1 was altered in the hippocampus of epileptic mice. Conclusion : These results show that POSH plays a critical role in the progression of epileptic seizures via NMDAR trafficking and suggest that the protein is a novel target for the treatment of human epilepsy.