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Title: Enhanced tonic GABAA inhibition in typical absence epilepsy
Authors: Cope, David W.
Di Giovanni, Giuseppe
Fyson, Sarah J.
Orban, Gergely
Errington, Adam C.
Lorincz, Magor L.
Gould, Timothy M.
Carter, David A.
Crunelli, Vincenzo
Keywords: Thalamus
Receptors, GABA-A
Issue Date: 2009
Publisher: Nature Publishing Group
Citation: Cope, D. W., Di Giovanni, G., Orban, G., Fyson, S. J., Errington, A. C., Lorinez, M. L..., Crunelli V. (2009). Enhanced tonic GABAA inhibition is required in typical absence epilepsy. Nature Medicine, 15(12), 1392-1398.
Abstract: The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic 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 critical 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 behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.
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