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Enhanced tonic GABA(A) inhibition in typical absence epilepsy

Cope, David W., Di Giovanni, Giuseppe, Fyson, Sarah Jane, Orbán, Gergely, Errington, Adam Clarke ORCID: https://orcid.org/0000-0002-2171-389X, Lorincz, Magor, Gould, Timothy M., Carter, David Allan and Crunelli, Vincenzo ORCID: https://orcid.org/0000-0001-7154-9752 2009. Enhanced tonic GABA(A) inhibition in typical absence epilepsy. Nature Medicine 15 (12) , pp. 1392-1398. 10.1038/nm.2058

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Abstract

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired γ-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent 'tonic' inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT-1 in the genetic models tested, and GAT-1 is crucial in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioral correlates of seizures in normal rats. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
Publisher: Nature Publishing Group
ISSN: 1078-8956
Last Modified: 02 Dec 2022 11:49
URI: https://orca.cardiff.ac.uk/id/eprint/8813

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