Enhanced tonic GABAA inhibition in typical absence epilepsy

被引：330

作者：

Cope, David W. ^{[1
]}

Di Giovanni, Giuseppe ^{[1
]}

Fyson, Sarah J. ^{[1
]}

Orban, Gergely ^{[1
]}

Errington, Adam C. ^{[1
]}

Lorincz, Magor L. ^{[1
]}

Gould, Timothy M. ^{[1
]}

Carter, David A. ^{[1
]}

Crunelli, Vincenzo ^{[1
]}

机构：

[1] Cardiff Univ, Sch Biosci, Cardiff, S Glam, Wales

来源：

NATURE MEDICINE | 2009年 / 15卷 / 12期

基金：

英国惠康基金;

关键词：

GAMMA-HYDROXYBUTYRIC ACID; RAT-BRAIN; SYNAPTIC-TRANSMISSION; MOUSE MODEL; RECEPTORS; MECHANISMS; SPIKE; WAVE; THALAMUS; SEIZURES;

D O I：

10.1038/nm.2058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1392 / U6

页数：8

共 48 条

[1] Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice [J].