SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities

作者全名："Zhang, Yanke; Wu, Junhong; Yan, Yin; Gu, Yixue; Ma, Yuanlin; Wang, Min; Zhang, Hui; Tao, Kaiyan; Lu, Yang; Yu, Weihua; Jing, Wei; Wang, Xuefeng; Tian, Xin"

作者地址："[Zhang, Yanke; Wu, Junhong; Yan, Yin; Gu, Yixue; Ma, Yuanlin; Zhang, Hui; Tao, Kaiyan; Jing, Wei; Wang, Xuefeng; Tian, Xin] Chongqing Med Univ, Dept Neurol, Chongqing Key Lab Neurol, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Zhang, Yanke; Wang, Min] Jining Med Univ, Dept Neurol, Affiliated Hosp, Jining, Shandong, Peoples R China; [Lu, Yang; Yu, Weihua] Chongqing Med Univ, Dept Geriatr, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Yu, Weihua] Chongqing Med Univ, Inst Neurosci, Chongqing 400016, Peoples R China"

通信作者："Jing, W; Wang, XF; Tian, X (通讯作者)，Chongqing Med Univ, Dept Neurol, Chongqing Key Lab Neurol, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：CELL DEATH & DISEASE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000791289400001

JCR分区：Q1

影响因子：9

年份：2022

卷号：13

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Aberrantly synchronized neuronal discharges in the brain lead to epilepsy, a devastating neurological disease whose pathogenesis and mechanism are unclear. SAPAP3, a cytoskeletal protein expressed at high levels in the postsynaptic density (PSD) of excitatory synapses, has been well studied in the striatum, but the role of SAPAP3 in epilepsy remains elusive. In this study, we sought to investigate the molecular, cellular, electrophysiological and behavioral consequences of SAPAP3 perturbations in the mouse hippocampus. We identified a significant increase in the SAPAP3 levels in patients with temporal lobe epilepsy (TLE) and in mouse models of epilepsy. In addition, behavioral studies showed that the downregulation of SAPAP3 by shRNA decreased the seizure severity and that the overexpression of SAPAP3 by recombinant SAPAP3 yielded the opposite effect. Moreover, SAPAP3 affected action potentials (APs), miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents in the CA1 region, which indicated that SAPAP3 plays an important role in excitatory synaptic transmission. Additionally, the levels of the GluN2A protein, which is involved in synaptic function, were perturbed in the hippocampal PSD, and this perturbation was accompanied by ultrastructural morphological changes. These results revealed a previously unknown function of SAPAP3 in epileptogenesis and showed that SAPAP3 may represent a novel target for the treatment of epilepsy."

基金机构："National Natural Science Foundation of China [81901324, 82001378, 81671286, 81871019]; National Clinical Key Specialty Construction Foundation of China"

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (Nos. 81901324, 82001378, 81671286, and 81871019) and the National Clinical Key Specialty Construction Foundation of China."