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Inhibition of Acid Sensing Ion Channel 3 Aggravates Seizures by Regulating NMDAR Function

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Abstract

The existing data about whether acid sensing ion channels (ASICs) are proconvulsant or anticonvulsant are controversial. Particularly, acid sensing ion channel 3 (ASIC3) is the most sensitive to extracellular pH and has the characteristic ability to generate a biphasic current, but few studies have focused on the role of ASIC3 in seizure. Here we found ASIC3 expression was increased in the hippocampus of pilocarpine induced seizure rats, as well as in hippocampal neuronal cultures undergoing epileptiform discharge elicited by Mg2+-free media. Furthermore, ASIC3 blockade by the selective inhibitor APETx2 shortened seizure onset latency and increased seizure severity compared with the control in the pilocarpine induced seizure model. Incubation with APETx2 enhanced the excitability of primary cultured hippocampal neurons in Mg2+-free media. Notably, the aggravated seizure was associated with upregulation of the N-methyl-d-aspartate subtype of glutamate receptors (NMDARs), increased NMDAR mediated excitatory neurotransmission and subsequent activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cAMP-response element binding protein (CREB) signaling pathway. Moreover, co-immunoprecipitation confirmed the interaction between ASIC3 and NMDAR subunits, and NMDARs blockade prevented the aggravated seizure caused by ASIC3 inhibition. Taken together, our findings suggest that ASIC3 inhibition aggravates seizure and potentiates seizure induced hyperexcitability at least partly by the NMDAR/CaMKII/CREB signaling pathway, which implies that ASIC3 agonists may be a promising approach for seizure treatment.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (81471133), Natural Science Foundation of Hubei Province (2014CFB734), Health and Family Planning Commission of Hubei Province scientific research project (WJ2015MA007), and Wuhan Science and Technology Bureau scientific research project (2015060101010047).

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  1. Qian Cao and Zhe-Man Xiao have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Qian Cao, Zhe-Man Xiao, Xi Wang, Chao Weng, Man Ding & Zu-Neng Lu

  2. Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China

    Fan Zhu

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  1. Qian Cao
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Correspondence to Zu-Neng Lu.

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Cao, Q., Xiao, ZM., Wang, X. et al. Inhibition of Acid Sensing Ion Channel 3 Aggravates Seizures by Regulating NMDAR Function. Neurochem Res 43, 1227–1241 (2018). https://doi.org/10.1007/s11064-018-2540-9

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  • DOI: https://doi.org/10.1007/s11064-018-2540-9

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