Altered Expression Pattern of Acid-Sensing Ion Channel Isoforms in Piriform Cortex After Seizures.
The piriform cortex (PC) is highly susceptible to chemical and electrical seizure induction. Epileptiform activity is associated with an acid shift in extracellular pH, suggesting that acid-sensing ion channels (ASICs) expressed by PC neurons may contribute to this enhanced epileptogenic potential. In epileptic rats and surgical samples from patients with medial temporal lobe epilepsy (TLE), PC layer II ASIC1a-immunopositive neurons appeared swollen with dendritic elongation, and there was loss of ASIC1a-positive neurons in layer III, consistent with enhanced vulnerability to TLE-induced plasticity and cell death. In rats, pilocarpine-induced seizures led to transient downregulation of ASIC1a and concomitant upregulation of ASIC2a in the first few days post-seizure. These changes in expression may be due to seizure-induced oxidative stress as a similar reciprocal change in ASIC1a, and ASIC2a expression was observed in PC12 cells following H2O2 application. The proportion of ASIC1a/ASIC2a heteromers was reduced in the acute phase following status epilepticus (SE) but increased during the latent phase when rats developed spontaneous seizures. Knockdown of ASIC2a by RNAi reduced dendritic length and spine density in primary neurons, suggesting that seizure-induced upregulation of ASIC2a contributes to dendritic lengthening in PC layer II in rats. Administration of the ASIC inhibitor amiloride before pilocarpine reduced the proportion of rats reaching Racine level IV seizures, protected layer II and III neurons, and prolonged survival in the acute phase following SE. Our findings suggest that ASICs may enhance susceptibility to epileptogenesis in the PC. Inhibition of ASICs, particularly ASIC2a, may suppress seizures originating in the PC.
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Hao
H
Wu
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Chao
C
Wang
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Bei
B
Liu
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Huanfa
H
Li
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Yu
Y
Zhang
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Shan
S
Dong
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China. gguodong@fmmu.edu.cn.
Guodong
G
Gao
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi'an, Shaanxi, 710038, People's Republic of China. zhanghua@fmmu.edu.cn.
Hua
H
Zhang
D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000584:Amiloride / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002452:Cell Count; D048430:Cell Shape / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D066195:Piriform Cortex / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
D062565:Acid Sensing Ion Channels; D020033:Protein Isoforms; D021122:Protein Subunits; D012333:RNA, Messenger; D000584:Amiloride
Acid-sensing ion channels; Epileptogenesis; Oxidative stress; Piriform cortex; Seizures