Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors
δ subunit containing eGABAARS in thalamocortical neurons are crucial for expression of SWDs. (a) Tonic GABAA currents are nearly completely ablated in VB TC neurons from δ −/− mice. In comparison, WT mice display robust tonic currents as revealed by focal application of GBZ to the recording chamber. (b) Bilateral EEG traces demonstrating that GBL (the GHB prodrug) induces SWDs in WT littermates but not in δ −/− mice. (c) Ethosuximide-sensitive SWDs that are observed in GBL-injected WT mice are significantly reduced in δ −/− mice. Graph summarises the total time spent in seizure. (d) Intrathalamic injection of δ subunit-specific antisense oligodeoxynucleotides (ODN) produced a significant reduction in time spent in seizure in GAERS for two days post injection. In contrast sham injection of a missense ODN had no significant effect on the occurrence of SWDs. (e) Graph summarising the effect of ODN injection into VB thalamus upon seizure number normalized to preinjection control values. (f) Graph summarising the effect of anti- and missense ODN injection into VB thalamus of GAERS animals upon tonic current amplitude measured in vitro. Acute brain slices were prepared 1 day after intrathalamic injections were administered. (a–f) reproduced from .
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