Extrasynaptic GABA A Receptors of Thalamocortical Neurons: A Molecular Target for Hypnotics

Abstract

Among hypnotic agents that enhance GABA A receptor function, etomidate is unusual because it is selective for β 2 /β 3 compared with β 1 subunit-containing GABA A receptors. Mice incorporating an etomidate-insensitive β 2 subunit (β 2N265S ) revealed that β 2 subunit-containing receptors mediate the enhancement of slow-wave activity (SWA) by etomidate, are required for the sedative, and contribute to the hypnotic actions of this anesthetic. Although the anatomical location of the β 2 -containing receptors that mediate these actions is unknown, the thalamus is implicated. We have characterized GABA A receptor-mediated neurotransmission in thalamic nucleus reticularis (nRT) and ventrobasalis complex (VB) neurons of wild-type, β –/– 2 , and β 2N265S mice. VB but not nRT neurons exhibit a large GABA-mediated tonic conductance that contributes ∼80% of the total GABA A receptor-mediated transmission. Consequently, although etomidate enhances inhibition in both neuronal types, the effect of this anesthetic on the tonic conductance of VB neurons is dominant. The GABA-enhancing actions of etomidate in VB but not nRT neurons are greatly suppressed by the β 2N265S mutation. The hypnotic THIP (Gaboxadol) induces SWA and at low, clinically relevant concentrations (30 n m to 3 μ m ) increases the tonic conductance of VB neurons, with no effect on VB or nRT miniature IPSCs (mIPSCs) or on the holding current of nRT neurons. Zolpidem, which has no effect on SWA, prolongs VB mIPSCs but is ineffective on the phasic and tonic conductance of nRT and VB neurons, respectively. Collectively, these findings suggest that enhancement of extrasynaptic inhibition in the thalamus may contribute to the distinct sleep EEG profiles of etomidate and THIP compared with zolpidem.