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RESEARCH PRODUCT

Enhanced tonic GABAA inhibition in typical absence epilepsy

Giuseppe Di GiovanniGiuseppe Di GiovanniTimothy M. GouldSarah Jane FysonGergely OrbanGergely OrbanVincenzo CrunelliMagor L. LorinczAdam C. ErringtonDavid W. CopeDavid Allan Carter

subject

GABA Plasma Membrane Transport ProteinsGABA Plasma Membrane Transport ProteinsCellular pathologystargazerBiologyPharmacologytonic currentSettore BIO/09 - FisiologiaArticleGeneral Biochemistry Genetics and Molecular BiologyTonic (physiology)spike–and–wave discharge03 medical and health sciencesEpilepsy0302 clinical medicineThalamusthalamusGenetic modelmedicineAnimalsGABA transporterGABA-A Receptor AntagonistsReceptorTHIP030304 developmental biology0303 health sciencesextrasynaptic tonic current GAT–1 thalamus spike–and–wave discharge GAERS stargazer lethargic GHB THIPGABAA receptorAminobutyratesPetit mal epilepsyGeneral Medicineextrasynapticmedicine.diseaseReceptors GABA-ARats3. Good healthEpilepsy Absenceabsence epilepsy GABA electrophysiology patch clampnervous systemGAT–1GAERSbiology.proteinlethargicGHB030217 neurology & neurosurgery

description

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.

10.1038/nm.2058