Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors

Errington, Adam Clarke ORCID: https://orcid.org/0000-0002-2171-389X, Cope, David William and Crunelli, Vincenzo ORCID: https://orcid.org/0000-0001-7154-9752 2011. Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors. Advances in Pharmacological Sciences 2011 , 790590. 10.1155/2011/790590

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Abstract

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABAA receptors (eGABAAR) and augmented “tonic” GABAA inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABAAR gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABAARs in absence epilepsy.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Neuroscience and Mental Health Research Institute (NMHRI) Medicine
Subjects:	Q Science > Q Science (General)
Publisher:	Hindawi
ISSN:	1687-6334
Date of First Compliant Deposit:	30 March 2016
Last Modified:	17 May 2023 21:11
URI:	https://orca.cardiff.ac.uk/id/eprint/32180

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