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Altered Expression Pattern of Acid-Sensing Ion Channel Isoforms in Piriform Cortex After Seizures

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Abstract

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.

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Acknowledgments

We sincerely thank the patients and their families for their participation and support in this study. This work was supported by the National Natural Science Foundation of China (grant numbers are 81271433 and 81471322).

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The authors declare that they have no conflict of interest.

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    1. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xin-si Road, Xi’an, Shaanxi, 710038, People’s Republic of China

      Hao Wu, Chao Wang, Bei Liu, Huanfa Li, Yu Zhang, Shan Dong, Guodong Gao & Hua Zhang

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    Hao Wu and Chao Wang contributed equally to this work.

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    Supplemental Fig. 1

    The mRNA and protein expression levels of ASIC1a and ASIC2a in rat piriform cortex from acute phase to latent phase. A The expression of ASIC1a mRNA was 64±7% of control on day 1 post-SE and 67±5% on day 3 (n=4 rats/group). B Expression of ASIC2a mRNA was 3.6±0.7-fold higher than control on day 1 and 2.8±0.5-fold higher on day 3 (n=4 rats/group). C Representative immunoblot and densitometric analysis of ASIC1a protein showing that expression was 50±7% of control on day 1 and 66±7% of control on day 3 (n=3 rats/group). D Representative immunoblot and densitometric analysis of ASIC2a showing that protein expression was 1.9±0.1-fold higher than control on day 1 and 1.9±0.2-fold higher on day 3 (n=3 rats/group). Data in A-D are presented as mean ± standard error of mean (SEM). *P<0.05 and **P<0.01 by one-way ANOVA compared to the control. (GIF 40 kb)

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    Wu, H., Wang, C., Liu, B. et al. Altered Expression Pattern of Acid-Sensing Ion Channel Isoforms in Piriform Cortex After Seizures. Mol Neurobiol 53, 1782–1793 (2016). https://doi.org/10.1007/s12035-015-9130-5

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