Ion channels, receptors and transporters

Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 4, pp 737-752

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

  • Akito NakaoAffiliated withDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
  • , Takafumi MikiAffiliated withDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
  • , Ken ShimonoAffiliated withBioscience Technology Development Office, Panasonic Corporation
  • , Hiroaki OkaAffiliated withBioscience Technology Development Office, Panasonic Corporation
  • , Tomohiro NumataAffiliated withDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniversityDepartment of Technology and Ecology, Hall of Global Environmental Research, Kyoto University
  • , Shigeki KiyonakaAffiliated withDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniversityDepartment of Technology and Ecology, Hall of Global Environmental Research, Kyoto UniversityCore Research for Evolution Science and Technology, Japan Science and Technology Agency
  • , Kaori MatsushitaAffiliated withDivision of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences
  • , Hiroo OguraAffiliated withProduct Creation Headquarters, Eisai Co., Ltd.
  • , Tetsuhiro NiidomeAffiliated withNeuroscience Product Creation Unit, Eisai Limited
    • , Jeffrey L. NoebelsAffiliated withDepartment of Neurology, Baylor College of Medicine
    • , Minoru WakamoriAffiliated withDepartment of Oral Biology, Graduate School of Dentistry, Tohoku University
    • , Keiji ImotoAffiliated withDivision of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences
    • , Yasuo MoriAffiliated withDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniversityDepartment of Technology and Ecology, Hall of Global Environmental Research, Kyoto UniversityCore Research for Evolution Science and Technology, Japan Science and Technology Agency Email author 

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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.

Keywords

CaV2.1 Ca2+ channel tottering mice Absence epilepsy Hippocampal network activity GABAergic maturation Cl homeostasis