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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00287

M-calpain activation facilitates seizure induced KCC2 down regulation

 Li Wan1*, Liang Ren1,  Lulan Chen1, Guoxiang Wang1, Xu Liu2,  Benjamin Wang1 and  Yun Wang1*
  • 1Institutes of Brain Science, Fudan University, China
  • 2Neurology department, Zhongshan Hospital, Fudan University, China

Potassium chloride co-transporter 2 (KCC2), a major chloride transporter that maintains GABAA receptor inhibition in mature mammalian neurons, is down-regulated in the hippocampus during epileptogenesis. Impaired KCC2 function accelerates or facilitates seizure onset. Calpain, with two main subtypes of m- and μ-calpain, is a Ca2+-dependent cysteine protease that mediates the nonlysosomal degradation of KCC2. Although recent studies have demonstarted that calpain inhibitors exert antiepileptic and neuroprotective effects in animal models of acute and chronic epilepsy, whether calpain activation affects seizure induction through KCC2 degradation remains unknown. Our results showed that: 1) Blockade of calpain by non-selective calpain inhibitor MDL-28170 prevented convulsant stimulation induced KCC2 downregulation, and reduced the incidence and the severity of PTZ induced seizures. 2) m-calpain, but not μ-calpain, inhibitor mimicked MDL-28170 effect on preventing KCC2 downregulation. 3) Phosphorylation of m-calpain has been significantly enhanced during seizure onset, which was partly mediated by the calcium independent MAPK/ERK signaling pathway activation. 4) MAPK/ERK signaling blockade also had similar effect as total calpain blockade on both KCC2 downregulation and animal seizure induction. The results indicate that upregulated m-calpain activation by MAPK/ERK during convulsant stimulation down regulates both cytoplasm- and membrane KCC2, and in turn facilitates seizure induction. This finding may provide a foundation for the development of highly effective antiepileptic drugs targeting of m-calpain.

Keywords: Epilepsy, Calpain, KCC2, MAPK/ERK, PTZ

Received: 04 Mar 2018; Accepted: 30 Jul 2018.

Edited by:

Sabine Levi, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by:

Frantisek Jursky, Institute of Molecular Biology (SAS), Slovakia
Zheng Wu, Pennsylvania State University, United States
Claudio Rivera, Aix-Marseille Université, France  

Copyright: © 2018 Wan, Ren, Chen, Wang, Liu, Wang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mr. Li Wan, Institutes of Brain Science, Fudan University, Shanghai, China,
Prof. Yun Wang, Institutes of Brain Science, Fudan University, Shanghai, China,