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Compromised maturation of GABAergic inhibition underlies abnormal network activity in the hippocampus of epileptic Ca2+ channel mutant mice, tottering

  • Ion channels, receptors and transporters
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Abstract

Cholinergically induced network activity is a useful analogue of theta rhythms involved in memory processing or epileptiform activity in the hippocampus, providing a powerful tool to elucidate the mechanisms of synchrony in neuronal networks. In absence epilepsy, although its association with cognitive impairments has been reported, the mechanisms underlying hippocampal synchrony remain poorly investigated. Here we simultaneously recorded electrical activities from 64 sites in hippocampal slices of CaV2.1 Ca2+ channel mutant tottering (tg) mice, a well-established mouse model of spontaneous absence epilepsy, to analyze the spatiotemporal pattern of cholinergically induced hippocampal network activity. The cholinergic agonist carbachol induced oscillatory discharges originating from the CA3 region. In tg/tg mice, this hippocampal network activity was characterized by enhanced occupancy of discharges of relatively high frequency (6–10 Hz) compared to the wild type. Pharmacological analyses of slices, patch clamp electrophysiological characterization of isolated neurons, and altered patterns of hippocampal GABAA receptor subunit and Cl− transporter messenger RNA (mRNA) transcript levels revealed that this abnormality is attributable to a developmental retardation of GABAergic inhibition caused by immature intracellular Cl− regulation. These results suggest that the inherited CaV2.1 Ca2+ channel mutation leads to developmental abnormalities in Cl− transporter expression and GABAA receptor compositions in hippocampal neurons and that compromised maturation of GABAergic inhibition contributes to the abnormal synchrony in the hippocampus of tg absence epileptic mice.

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Acknowledgments

This work was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Japan Society for the Promotion of Science. A.N. is a research fellow of the Japan Society for the Promotion of Science. We thank Alpha MED Scientific, Inc. for supporting the MED system and Dr. T. Manabe (University of Tokyo) for helpful advice.

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The authors declare no competing financial interests.

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Author notes

  1. Takafumi Miki

    Present address: Department of Neurophysiology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, 610-0394, Japan

Authors and Affiliations

  1. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, 615-8510, Japan

    Akito Nakao, Takafumi Miki, Tomohiro Numata, Shigeki Kiyonaka & Yasuo Mori

  2. Department of Technology and Ecology, Hall of Global Environmental Research, Kyoto University, Kyoto, 606-8501, Japan

    Tomohiro Numata, Shigeki Kiyonaka & Yasuo Mori

  3. Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo, 102-0075, Japan

    Shigeki Kiyonaka & Yasuo Mori

  4. Bioscience Technology Development Office, Panasonic Corporation, Kyoto, 619-0237, Japan

    Ken Shimono & Hiroaki Oka

  5. Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, 444-8787, Japan

    Kaori Matsushita & Keiji Imoto

  6. Product Creation Headquarters, Eisai Co., Ltd., Tokyo, 112-8088, Japan

    Hiroo Ogura

  7. Neuroscience Product Creation Unit, Eisai Limited, Hatfield, Hertfordshire, AL10 9SN, UK

    Tetsuhiro Niidome

  8. Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA

    Jeffrey L. Noebels

  9. Department of Oral Biology, Graduate School of Dentistry, Tohoku University, Sendai, 980-8575, Japan

    Minoru Wakamori

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Correspondence to Yasuo Mori.

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Akito Nakao and Takafumi Miki contributed equally to this work.

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Nakao, A., Miki, T., Shimono, K. et al. Compromised maturation of GABAergic inhibition underlies abnormal network activity in the hippocampus of epileptic Ca2+ channel mutant mice, tottering . Pflugers Arch - Eur J Physiol 467, 737–752 (2015). https://doi.org/10.1007/s00424-014-1555-6

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