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An Extrasynaptic GABA_A Receptor Mediates Tonic Inhibition in Thalamic VB Neurons

C. V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College, Cornell University, New York, New York

Submitted 25 April 2005; accepted in final form 4 September 2005

Whole cell patch-clamp recordings were obtained from thalamic ventrobasal (VB) and reticular (RTN) neurons in mouse brain slices. A bicuculline-sensitive tonic current was observed in VB, but not in RTN, neurons; this current was increased by the GABA_A receptor agonist 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridine-3-ol (THIP; 0.1 µM) and decreased by Zn²⁺ (50 µM) but was unaffected by zolpidem (0.3 µM) or midazolam (0.2 µM). The pharmacological profile of the tonic current is consistent with its generation by activation of GABA_A receptors that do not contain the ₁ or ₂ subunits. GABA_A receptors expressed in HEK 293 cells that contained ₄₂ subunits showed higher sensitivity to THIP (gaboxadol) and GABA than did receptors made up from ₁₂, _422s, or _122s subunits. Western blot analysis revealed that there is little, if any, ₃ or ₅ subunit protein in VB. In addition, co-immunoprecipitation studies showed that antibodies to the subunit could precipitate ₄, but not ₁ subunit protein. Confocal microscopy of thalamic neurons grown in culture confirmed that ₄ and subunits are extensively co-localized with one another and are found predominantly, but not exclusively, at extrasynaptic sites. We conclude that thalamic VB neurons express extrasynaptic GABA_A receptors that are highly sensitive to GABA and THIP and that these receptors are most likely made up of ₄₂ subunits. In view of the critical role of thalamic neurons in the generation of oscillatory activity associated with sleep, these receptors may represent a principal site of action for the novel hypnotic agent gaboxadol.

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