Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired absence epilepsy model

Jie Wu, Kevin Ellsworth, Marc Ellsworth, Katherine M. Schroeder, Kris Smith, Robert S. Fisher

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been shown to be a faithful model of acquired absence epilepsy, a devastating condition for which few therapies or models exist. We employed the CSI model to study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats. Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated from the nucleus reticularis of thalamus (nRt) treated and untreated with a cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs). Patchclamp results revealed that although there was no remarkable change in GABAA receptor affinity, both a loss of ability of benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+ inhibition of GABA A-receptor responses of nRt neurons occurred in Long-Evans Hooded rats previously administered U18666A. This change was specific, since no significant changes were found in neurons exposed to the GABA allosteric modulator, pentobarbital. Taken collectively, these findings provide evidence for abnormalities in benzodiazepine and Zn2+ modulation of GABA A receptors in the CSI model, and suggest that decreased γ2 subunit expression may underlie important aspects of generation of thalamocortical SWs in atypical absence seizures. The present results are also consistent with recent findings that mutation of the γ2 subunit of the GABAA receptor changes benzodiazepine modulation in families with generalized epilepsy syndromes.

Original languageEnglish (US)
Pages (from-to)230-240
Number of pages11
JournalBrain Research
Volume1013
Issue number2
DOIs
StatePublished - Jul 9 2004
Externally publishedYes

Keywords

  • Absence epilepsy
  • Cholesterol
  • Disorders of the nervous system
  • Epilepsy: basic mechanisms
  • GABA
  • Nucleus reticularis thalami (nRt)
  • Patch-clamp
  • Receptor

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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