title: Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Chronic Epileptogenesis.
abstract: Unraveling mechanisms underlying epileptogenesis after brain injury is an unmet medical challenge. Although histopathological studies have revealed that reactive astrogliosis and tissue acidosis are prominent features in epileptogenic foci, their roles in epileptogenesis remain unclear. Here, we explored whether astrocytic acid-sensing ion channel-1a (ASIC1a) contributes to the development of chronic epilepsy. High levels of ASIC1a were measured in reactive astrocytes in the hippocampi of patients with temporal lobe epilepsy (TLE) and epileptic mice. Extracellular acidosis caused a significant Ca(2+) influx in cultured astrocytes, and this influx was sensitive to inhibition by the ASIC1a-specific blocker psalmotoxin 1 (PcTX1). In addition, recombinant adeno-associated virus (rAAV) vectors carrying a GFAP promoter in conjunction with ASIC1a shRNA or cDNA were generated to suppress or restore, respectively, ASIC1a expression in astrocytes. Injection of rAAV-ASIC1a-shRNA into the dentate gyrus of the wide type TLE mouse model resulted in the inhibition of astrocytic ASIC1a expression and a reduction in spontaneous seizures. By contrast, rAAV-ASIC1a-cDNA restored astrocytic ASIC1a expression in an ASIC1a knock-out TLE mouse model and increased the frequency of spontaneous seizures. Taken together, our results reveal that astrocytic ASIC1a may be an attractive new target for the treatment of epilepsy.
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.|The Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Yinxiu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Tangpeng Ou
authors.initials: TO
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Tianle
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
mesh_terms: D062565:Acid Sensing Ion Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D004827:Epilepsy / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels