Cellular Mechanisms of Pharmacoresistance in Slices from Epilepsy Surgery

  1. Gregory Bock and
  2. Jamie A. Goode
  1. R. A. Deisz

Published Online: 7 OCT 2008

DOI: 10.1002/0470846356.ch14

Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243

Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243

How to Cite

Deisz, R. A. (2002) Cellular Mechanisms of Pharmacoresistance in Slices from Epilepsy Surgery, in Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243 (eds G. Bock and J. A. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470846356.ch14

Author Information

  1. Department of Cell and Neurobiology, Institute of Anatomy, Charité, 10098 Berlin, Germany

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 25 MAR 2002

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470841464

Online ISBN: 9780470846353

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Summary

Slices of human cortical tissue from epilepsy surgery were investigated with intracellular recordings to elucidate the mechanisms contributing to augmented synaptic excitation and to repetitive activity. The analysis of single synaptic potentials revealed, amongst other differences to rodent cortex, a disturbance of GABAA inhibition, namely depolarizing responses. A tentative ionic mechanism, impaired KCl outward-transport (KCC2), was evaluated in a rat model (0-Mg hyperexcitability). The observed down-regulation of KCC2 mRNA after 0-Mg-ACSF exposure of slices may contribute to the depolarizations by GABA. The factors enabling repetitive activity were addressed with a paired-pulse paradigm. In slices from epilepsy surgery, synaptic responses were virtually constant with interstimulus intervals between 100 and 1000 ms. Tiagabine markedly prolonged the effects of released GABA at GABAA receptors, but paired-pulse behaviour was only slightly affected. We demonstrate that bicuculline-induced paroxysmal activity of rat cortex is frequency-limited (to about <1 Hz) by presynaptic GABAB receptors. The lack of frequency limitation of synaptic events suggests an impaired GABAB receptor function in the human epileptogenic cortex. The data are discussed regarding the pivotal role of KCl transport in epileptic disorders of various origins and the role of GABAB receptors in the frequency limitation of paroxysmal activity.