Zhang Yujiao, Li Zengyou, Gu Juan, Zhang Yanke, Wang Wei, Shen Hui, Chen Guojun, Wang Xuefeng
Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York, NY, U.S.A.
Clin Sci (Lond). 2015 Dec;129(12):1207-23. doi: 10.1042/CS20150202. Epub 2015 Sep 28.
Dysfunction of γ-aminobutyric acid A (GABAA) receptors (GABAARs) is a prominent factor affecting intractable epilepsy. Plic-1, an ubiquitin-like protein enriched in the inhibitory synapses connecting GABAARs and the ubiquitin protease system (UPS), plays a key role in the modification of GABAAR functions. However, the relationship between Plic-1 and epileptogenesis is not known. In the present study, we aimed to investigate Plic-1 levels in patients with temporal lobe epilepsy, as well as the role of Plic-1 in regulating onset and progression of epilepsy in animal models. We found that Plic-1 expression was significantly decreased in patients with epilepsy as well as pilocarpine- and pentylenetetrazol (PTZ)-induced rat epileptic models. Intrahippocampal injection of the PePα peptide, which disrupts Plic-1 binding to GABAARs, significantly shortened the latency of seizure onset, and increased the seizure severity and duration in these two epileptic models. Overexpressed Plic-1 through lentivirus transfection into a PTZ model resulted in a reduction in both seizure severity and generalized tonic-clonic seizure duration. Whole-cell clamp recordings revealed that the PePα peptide decreased miniature inhibitory postsynaptic currents (mIPSCs) whereas overexpressed Plic-1 increased mIPSCs in the pyramidal neurons of the hippocampus. These effects can be blocked by picrotoxin, a GABAAR inhibitor. Our results indicate that Plic-1 plays an important role in managing epileptic seizures by enhancing seizure inhibition through regulation of GABAARs at synaptic sites.
γ-氨基丁酸A（GABAA）受体（GABAARs）功能障碍是影响难治性癫痫的一个重要因素。Plic-1是一种富含于连接GABAARs和泛素蛋白酶系统（UPS）的抑制性突触中的泛素样蛋白，在GABAARs功能修饰中起关键作用。然而，Plic-1与癫痫发生之间的关系尚不清楚。在本研究中，我们旨在调查颞叶癫痫患者中Plic-1的水平，以及Plic-1在动物模型中调节癫痫发作起始和进展中的作用。我们发现，癫痫患者以及毛果芸香碱和戊四氮（PTZ）诱导的大鼠癫痫模型中Plic-1表达显著降低。海马内注射破坏Plic-1与GABAARs结合的PePα肽，显著缩短了癫痫发作起始的潜伏期，并增加了这两种癫痫模型中的癫痫发作严重程度和持续时间。通过慢病毒转染在PTZ模型中过表达Plic-1导致癫痫发作严重程度和全身强直阵挛性发作持续时间均降低。全细胞膜片钳记录显示，PePα肽降低了微小抑制性突触后电流（mIPSCs），而过表达Plic-1增加了海马锥体神经元中的mIPSCs。这些作用可被GABAAR抑制剂印防己毒素阻断。我们的结果表明，Plic-1通过在突触部位调节GABAARs来增强癫痫发作抑制，从而在控制癫痫发作中起重要作用。
