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

Authors

  • Akito Nakao
    • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of EngineeringKyoto University
  • Takafumi Miki
    • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of EngineeringKyoto University
  • Ken Shimono
    • Bioscience Technology Development OfficePanasonic Corporation
  • Hiroaki Oka
    • Bioscience Technology Development OfficePanasonic Corporation
  • Tomohiro Numata
    • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of EngineeringKyoto University
    • Department of Technology and Ecology, Hall of Global Environmental ResearchKyoto University
  • Shigeki Kiyonaka
    • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of EngineeringKyoto University
    • Department of Technology and Ecology, Hall of Global Environmental ResearchKyoto University
    • Core Research for Evolution Science and TechnologyJapan Science and Technology Agency
  • Kaori Matsushita
    • Division of Neural Signaling, Department of Information PhysiologyNational Institute for Physiological Sciences
  • Hiroo Ogura
    • Product Creation HeadquartersEisai Co., Ltd.
  • Tetsuhiro Niidome
    • Neuroscience Product Creation UnitEisai Limited
  • Jeffrey L. Noebels
    • Department of NeurologyBaylor College of Medicine
  • Minoru Wakamori
    • Department of Oral Biology, Graduate School of DentistryTohoku University
  • Keiji Imoto
    • Division of Neural Signaling, Department of Information PhysiologyNational Institute for Physiological Sciences
    • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of EngineeringKyoto University
    • Department of Technology and Ecology, Hall of Global Environmental ResearchKyoto University
    • Core Research for Evolution Science and TechnologyJapan Science and Technology Agency
Ion channels, receptors and transporters

DOI: 10.1007/s00424-014-1555-6

Cite this article as:
Nakao, A., Miki, T., Shimono, K. et al. Pflugers Arch - Eur J Physiol (2015) 467: 737. doi:10.1007/s00424-014-1555-6
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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+ channeltottering miceAbsence epilepsyHippocampal network activityGABAergic maturationCl homeostasis

Supplementary material

424_2014_1555_MOESM1_ESM.pdf (735 kb)
ESM 1(PDF 734 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014