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GABAA receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1α6 mice with ectopic forebrain expression of GABAA receptorα6 subunits exhibit increased extrasynaptic GABAA receptor-mediated background conductance and reduced synaptic GABAA receptor currents in hippocampal CA1 neurons[W. Wisdenet al. (2002)Neuropharmacology43, 530–549]. Here we demonstrate that isolated CA1 neurons of these mice showed furosemide-sensitivity of GABA-evoked currents, confirming the functional expression ofα6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1α6 brain sections revealed pharmacological features that are unique forα6βγ2 andα6β receptors. The existence of atypicalα6β receptors was confirmed after completely eliminating GABAA receptors containingγ1,γ2,γ3 orδ subunits using serial immunoaffinity chromatography on subunit-specific GABAA receptor antibodies. Behaviourally, the Thy1α6 mice showed normal features with slightly enhanced startle reflex and struggle-escape behaviours. However, they were more sensitive to GABAA antagonists DMCM (shorter latency to writhing clonus) and picrotoxinin (shorter latency to generalized convulsions). Tiagabine, an antiepileptic GABA-uptake inhibitor that increases brain GABA levels, delayed picrotoxinin-induced convulsions at a low dose of 3.2 mg/kg in Thy1α6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1α6 mice. Altered balance between extrasynaptic and synaptic receptors thus affects seizure sensitivity to GABAergic convulsants. Importantly, the increased extrasynaptic inhibition, even when facilitated in the presence of tiagabine, was not able fully to counteract enhanced seizure induction by GABAA antagonists. [ABSTRACT FROM AUTHOR]

Abstract Benzodiazepine- and alcohol-induced ataxias in rodents have been proposed to be affected by the γ-aminobutyric acid type A (GABAA) receptor α6 subunit, which contributes to receptors specifically expressed in cerebellar granule cells. We have studied an α6 –/– mouse line for motor performance and drug sensitivity. These mice, as a result of a specific genetic lesion, carry a precise impairment at their Golgi-granule cell synapses. On motor performance tests (rotarod, horizontal wire, pole descending, staircase and swimming tests) there were no robust baseline differences in motor function or motor learning between α6 –/– and α6 +/+ mice. On the rotarod test, however, the mutant mice were significantly more impaired by diazepam (5–20 mg/kg, i.p.), when compared with α6 +/+ control and background C57BL/6J and 129/SvJ mouse lines. Ethanol (2.0–2.5 g/kg, i.p.) produced similar impairment in the α6 –/– and α6 +/+ mice. Diazepam-induced ataxia in α6 –/– mice could be reversed by the benzodiazepine site antagonist flumazenil, indicating the involvement of the remaining α1β2/3γ2 GABAA receptors of the granule cells. The level of activity in this synapse is crucial in regulating the execution of motor tasks. We conclude that GABAA receptor α6 subunit-dependent actions in the cerebellar cortex can be compensated by other receptor subtypes; but if not for the α6 subunit, patients on benzodiazepine medication would suffer considerably from ataxic side-effects. [ABSTRACT FROM AUTHOR]