SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities.
SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities.
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SAPAP3 调节突触后密度中涉及 GluN2A 的癫痫发作
DOI：
10.1038/s41419-022-04876-9
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发表时间：
2022-05-05
影响因子：
9
通讯作者：
Tian, Xin
中科院分区：
文献类型：
--
作者：
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
大脑中异常同步的神经元放电导致癫痫，这是一种毁灭性的神经系统疾病，其发病机制和机制尚不清楚。SAPAP 3是一种在兴奋性突触的突触后密度（PSD）中高水平表达的细胞骨架蛋白，已在纹状体中得到充分研究，但SAPAP 3在癫痫中的作用仍然难以捉摸。在这项研究中，我们试图调查的分子，细胞，电生理和行为的后果SAPAP 3扰动在小鼠海马。我们确定了颞叶癫痫（TLE）患者和癫痫小鼠模型中SAPAP 3水平的显著增加。此外，行为学研究表明，通过shRNA下调SAPAP 3可降低癫痫发作的严重程度，而通过重组SAPAP 3过表达SAPAP 3则产生相反的效果。此外，SAPAP 3还影响CA 1区的动作电位（AP）、兴奋性突触后电流（mEPSC）和N-甲基-D-天冬氨酸受体（NMDAR）介导的电流，表明SAPAP 3在兴奋性突触传递中起重要作用。此外，参与突触功能的GluN 2A蛋白的水平在海马PSD中受到扰动，并且这种扰动伴随着超微结构形态学变化。这些结果揭示了SAPAP 3在癫痫发生中以前未知的功能，并表明SAPAP 3可能代表癫痫治疗的新靶点。
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.
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DOI：
10.1083/jcb.136.3.669
发表时间：
1997-02-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim E;Naisbitt S;Hsueh YP;Rao A;Rothschild A;Craig AM;Sheng M
通讯作者：
Sheng M
影响因子：
5.6
作者：
Holder JL Jr;Quach MM
通讯作者：
Quach MM
影响因子：
3
作者：
de Oliveira, Guilherme Nogueira M.;Kummer, Arthur;Teixeira, Antonio Lucio
通讯作者：
Teixeira, Antonio Lucio
影响因子：
2.5
作者：
Knopp, A;Kivi, A;Behr, J
通讯作者：
Behr, J
DOI：
10.1016/0013-4694(72)90177-0
发表时间：
1972-01-01
期刊：
ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY
影响因子：
--
作者：
RACINE, RJ
通讯作者：
RACINE, RJ