[GABA.sub.A] receptor [alpha]4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol

The neurotransmitter GABA mediates the majority of rapid inhibition in the CNS. Inhibition can occur via the conventional mechanism, the transient activation of subsynaptic [GABA.sub.A] receptors ([GABA.sub.A]-RS), or via continuous activation of high-affinity receptors by low concentrations of ambient GABA, leading to 'tonic' inhibition that can control levels of excitability and network activity. The [GABA.sub.A]-R [alpha]4 subunit is expressed at high levels in the dentate gyrus and thalamus and is suspected to contribute to extrasynaptic [GABA.sub.A]-R-mediated tonic inhibition. Mice were engineered to lack the [alpha]4 subunit by targeted disruption of the Gabra4 gene. [alpha]4 Subunit knockout mice are viable, breed normally, and are superficially indistinguishable from WT mice. In electrophysiological recordings, these mice show a lack of tonic inhibition in dentate granule cells and thalamic relay neurons. Behaviorally, knockout mice are insensitive to the ataxic, sedative, and analgesic effects of the novel hypnotic drug, gaboxadol. These data demonstrate that tonic inhibition in dentate granule cells and thalamic relay neurons is mediated by extrasynaptic [GABA.sub.A]-RS containing the [alpha]4 subunit and that gaboxadol achieves its effects via the activation of this [GABA.sub.A]-R subtype. tonic inhibition | THIP | analgesia | sedative/hypnotic