title: Elevated Expression of Acid-Sensing Ion Channel 3 Inhibits Epilepsy via Activation of Interneurons.
abstract: Recent studies have indicated that acid-sensing ion channels may play a significant role in the termination of epilepsy. In particular, acid-sensing ion channel 3 (ASIC3) is expressed in the central nervous system and is most sensitive to extracellular pH. However, whether ASIC3 plays a role in epilepsy is unknown. In this study, qRT-PCR, Western blot, immunohistochemistry, double immunofluorescence labeling, and slice recordings were used. We first detected elevated ASIC3 expression patterns in the brains of temporal lobe epilepsy patients and epileptic rats. ASIC3 was expressed in neurons and glia in both humans and in an experimental model of epilepsy, and ASIC3 was colocalized with inhibitory GABAergic interneurons. By blocking ASIC3 with its antagonist APETx2, we observed that injected APETx2 shortened the latency to seizure and increased the incidence of generalized tonic clonic seizure compared to the control group in models of both pilocarpine- and pentylenetetrazole (PTZ)-induced seizures. Additionally, blocking ASIC3 significantly decreased the frequency of action potential (AP) firing in interneurons. Moreover, APETx2 significantly reduced the amplitudes and frequencies of miniature inhibitory postsynaptic currents (mIPSCs) while showed no differences with the APETx2 + bicuculline group and the bicuculline group. These findings suggest that elevated levels of ASIC3 may serve as an anti-epileptic mechanism via postsynaptic mechanisms in interneurons. It could represent a novel therapeutic strategy for epilepsy treatment.
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China.|Department of Neurology, The People's Hospital of Bishan District, 82 Xinsheng Road, Chongqing, 402760, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Neurology, Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, 637000, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Peking University, 5 Summer Palace road, Beijing, 100871, China.
authors.forename: Kewei
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China.
authors.forename: Zucai
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China. woodchen2015@163.com.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China. xfyp@163.com.|Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China. xfyp@163.com.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
mesh_terms: D062565:Acid Sensing Ion Channels / Q000096:biosynthesis*; D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D003064:Cnidarian Venoms / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C501880:APETx2 protein, Anthopleura elegantissima; C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D003064:Cnidarian Venoms
keywords: APETx2; Acid-sensing ion channel 3; GABA; Interneuron; Temporal lobe epilepsy