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Elevated Expression of Acid-Sensing Ion Channel 3 Inhibits Epilepsy via Activation of Interneurons

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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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (no. 81071039). The authors sincerely thank the patients and their families for their participation in this study. We also thank Tiantan Hospital and Xuanwu Hospital of the Capital University of Medical Sciences for the support of brain tissue procurement, as well as the National Institutes of Health of China and the Ethics Committee on Human Research of Chongqing Medical University.

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1Youyi Rd, Chongqing, 400016, China

    Qingqing Cao, Wei Wang, Juan Gu, Zucai Xu, Jie Li, Guojun Chen & Xuefeng Wang

  2. Department of Neurology, The People’s Hospital of Bishan District, 82 Xinsheng Road, Chongqing, 402760, China

    Qingqing Cao

  3. Department of Neurology, Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, 637000, China

    Guohui Jiang

  4. Department of Pharmacology, Peking University, 5 Summer Palace road, Beijing, 100871, China

    Kewei Wang

  5. Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China

    Xuefeng Wang

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  1. Qingqing Cao
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Correspondence to Guojun Chen or Xuefeng Wang.

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Cao, Q., Wang, W., Gu, J. et al. Elevated Expression of Acid-Sensing Ion Channel 3 Inhibits Epilepsy via Activation of Interneurons. Mol Neurobiol 53, 485–498 (2016). https://doi.org/10.1007/s12035-014-9014-0

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  • DOI: https://doi.org/10.1007/s12035-014-9014-0

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