title: Enhanced tonic GABAA inhibition in typical absence epilepsy.
abstract: The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABA(A) 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 GABA(A) receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABA(A) 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.
authors: School of Biosciences, Cardiff University, Cardiff, UK.
authors: David W
authors: DW
authors: Cope
authors: Giuseppe
authors: G
authors: Di Giovanni
authors: Sarah J
authors: SJ
authors: Fyson
authors: Gergely
authors: G
authors: Orbán
authors: Adam C
authors: AC
authors: Errington
authors: Magor L
authors: ML
authors: Lorincz
authors: Timothy M
authors: TM
authors: Gould
authors: David A
authors: DA
authors: Carter
authors: Vincenzo
authors: V
authors: Crunelli
mesh_terms: D000818:Animals; D004832:Epilepsy, Absence / Q000378:metabolism* / Q000503:physiopathology; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology; D058787:GABA-A Receptor Antagonists; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; C493415:Slc6a1 protein, rat