title: KCC2 downregulation facilitates epileptic seizures.
abstract: GABAAreceptor-mediated inhibition depends on the maintenance of low level intracellular [Cl-] concentration, which in adult depends on neuron specific K+-Cl-cotransporter-2 (KCC2). Previous studies have shown that KCC2 was downregulated in both epileptic patients and various epileptic animal models. However, the temporal relationship between KCC2 downregulation and seizure induction is unclear yet. In this study, we explored the temporal relationship and the influence of KCC2 downregulation on seizure induction. Significant downregulation of plasma membrane KCC2 was directly associated with severe (Racine Score III and above) behavioral seizures in vivo, and occurred before epileptiform bursting activities in vitro induced by convulsant. Overexpression of KCC2 using KCC2 plasmid effectively enhanced resistance to convulsant-induced epileptiform bursting activities in vitro. Furthermore, suppression of membrane KCC2 expression, using shRNAKCC2plasmid in vitro and shRNAKCC2containing lentivirus in vivo, induced spontaneous epileptiform bursting activities in vitro and Racine III seizure behaviors accompanied by epileptic EEG in vivo. Our findings novelly demonstrated that altered expression of KCC2 is not the consequence of seizure occurrence but likely is the contributing factor.
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Lulan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Wanting
authors.initials: W
authors.lastname: Ren
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Yian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Qian
authors.affiliation: Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. yunwang@fudan.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003292:Convulsants / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000097:blood* / Q000235:genetics*; D000096922:K Cl- Cotransporters
chemical_list: D003292:Convulsants; D034741:RNA, Small Interfering; D027981:Symporters; D000096922:K Cl- Cotransporters