Extrasynaptic GABA_AReceptors 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 ␤ 2 /␤ 3 compared with ␤ 1 subunit-containing GABA A receptors. Mice incorporating an etomidate-insensitive ␤ 2 subunit (␤ 2N265S ) revealed that ␤ 2 subunitcontaining 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 ␤ 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, ␤ 2 Ϫ/Ϫ , and ␤ 2N265S mice. VB but not nRT neurons exhibit a large GABA-mediated tonic conductance that contributes ϳ80% 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 ␤ 2N265S mutation. The hypnotic THIP (Gaboxadol) induces SWA and at low, clinically relevant concentrations (30 nM to 3 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.

Excitability of cortical neurons depends upon a powerful tonic conductance in inhibitory networks

“…In this way, tonic inhibition on LTS cells would be an extrinsic, rather than intrinsic, regulator. This role of tonic inhibition in the cortex favoring slow wave activity associated with sleep fits with tonic inhibition in the thalamus promoting bursting and slow-wave activity (Belelli et al, 2005;Cope et al, 2005). With regard to this hypothesis, it is of interest whether FS cells have the same degree of tonic GABA A -mediated inhibition as LTS cells.…”

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABAA receptors

“…Although, in vitro studies conducted in mice suggest that the ventrobasal thalamus may be critical for THIP induced sleep promotion (Belelli et al, 2005;Jia et al, 2005), recent in vivo studies have shown that systemic THIP administration does not promote sleep in mice (Vyazovskiy et al, 2005; WinskySommerer et al, 2007).…”

Sleep and general anesthesia

“…64 A study that concluded that cortical changes in the EEG preceded changes in thalamic local field potentials at loss of consciousness supports this view but, interestingly, a recent study concluded the opposite during sleep onset. 65 Alternatively, anesthetics are known to hyperpolarize thalamocortical neurons, [66][67][68][69][70] and this could lead directly to the delta oscillations and spindle activity that are observed during anesthesia. Since the pattern of cortical deactivation that is seen during anesthesia resembles that of natural sleep, it seems more plausible to us that anesthetic effects at the level of the thalamus, or on the arousal pathways that modulate thalamic activity, are responsible for coordinating the overall network response.…”