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

Akito Nakao, Takafumi Miki, Ken Shimono, Hiroaki Oka, Tomohiro Numata, Shigeki Kiyonaka, Kaori Matsushita, Hiroo Ogura, Tetsuhiro Niidome, Jeffrey L. Noebels, Minoru Wakamori, Keiji Imoto, Yasuo Mori

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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.

Original languageEnglish
Pages (from-to)737-752
Number of pages16
JournalPflugers Archiv European Journal of Physiology
Volume467
Issue number4
DOIs
Publication statusPublished - 01-01-2015

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

Nakao, A., Miki, T., Shimono, K., Oka, H., Numata, T., Kiyonaka, S., Matsushita, K., Ogura, H., Niidome, T., Noebels, J. L., Wakamori, M., Imoto, K., & Mori, Y. (2015). Compromised maturation of GABAergic inhibition underlies abnormal network activity in the hippocampus of epileptic Ca2+ channel mutant mice, tottering. Pflugers Archiv European Journal of Physiology, 467(4), 737-752. https://doi.org/10.1007/s00424-014-1555-6