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Tonic GABAa current in absence epilepsy

Fyson, Sarah Jane 2010. Tonic GABAa current in absence epilepsy. PhD Thesis, Cardiff University.

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Typical absence seizures are characteristic of many idiopathic generalised epilepsies and the only seizure-type in childhood absence epilepsy. We know that absence seizures arise in thalamocortical networks and that GABAergic agents exacerbate or induce absences. Furthermore, raised levels of GABA have been identified in the ventrobasal thalamus in an established genetic animal model (genetic absence epilepsy rats from Strasbourg GAERS), which was later suggested as a result of aberrant GABA uptake. I have shown that enhanced tonic GABAa current in TC neurons of the VB is a common phenomenon across genetic and pharmacological models of absence seizures. Furthermore, my data show that increased extrasynaptic GABAaR (cGABAaR) function in the VB is both sufficient and necessary to induce SWDs. This is supported by the fact that focal intrathalamic application of a selective agonist for eGABAARs, THIP, was sufficient to elicit SWDs in normal animals and that mice lacking cGABAaRs were resistant to absence seizure induction by y-butyrolactone. Moreover, I have presented data that directly implicate aberrant type-1 GABA transporters (GAT-1) in SWD generation in vivo, with GAT-1 knockout mice exhibiting spontaneous SWDs and focal thalamic administration of the GAT-1 blocker, N0711, inducing SWDs in normal rats a potential new model of absence epilepsy. In addition, my data indicate that activation of postsynaptic GABAbRs enhances tonic GABAA current, presumably via the Gl o protein coupled adenyl cyclase pathway, which was present under control conditions and occurred in several brain areas. This postsynaptic GABAb-cGABAaR link is further supported by the fact that GBL failed to induce SWDs in 5-subunit knockout mice. Thus, one of the cellular thalamic pathologies that characterises absence seizures is an astrocyte-specific aberrant GAT-1 with the resulting elevated extracellular GABA level enhancing tonic GABAa current through two mechanisms: direct activation of high affinity eGABAARs and indirect increase in eGABAAR function due to activation of postsynaptic GABAbRs.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QR Microbiology
ISBN: 9781303218880
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:31

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