Abstract
Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics. Inhibition of TC neurons is mediated predominantly by a combination of phasic and tonic inhibition, together with a recently described ‘spillover’ mode of inhibition, generated by the dynamic recruitment of extrasynaptic γ-aminobutyric acid (GABA)A receptors (GABAARs). Previous studies demonstrated that the intravenous anaesthetic etomidate enhances tonic and phasic inhibition in TC relay neurons, but it is not known how etomidate may influence spillover inhibition. Moreover, it is unclear how etomidate influences the excitability of TC neurons. Thus, to investigate the relative contribution of synaptic (α1β2γ2) and extrasynaptic (α4β2δ) GABAARs to the thalamic effects of etomidate, we performed whole-cell recordings from mouse TC neurons lacking synaptic (α10/0) or extrasynaptic (δ0/0) GABAARs. Etomidate (3 μm) significantly inhibited action-potential discharge in a manner that was dependent on facilitation of both synaptic and extrasynaptic GABAARs, although enhanced tonic inhibition was dominant in this respect. Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABAARs, which was significantly prolonged in the presence of etomidate. Thus, etomidate greatly enhanced the transient suppression of TC spike trains by evoked inhibitory postsynaptic potentials. Collectively, these results suggest that the deactivation of thalamus observed during etomidate-induced anaesthesia involves potentiation of tonic and phasic inhibition, and implicate amplification of spillover inhibition as a novel mechanism to regulate the gating of sensory information through the thalamus during anaesthetic states.
Highlights
The ability of general anaesthetics to impair consciousness, and induce analgesia, amnesia and immobility, has been exploited clinically for over a century (Rudolph & Antkowiak, 2004)
A substantial number of c-aminobutyric acid (GABAAR) with a typically ‘synaptic’ subunit composition exist extrasynaptically, the functional role of such receptors remains to be established (Kasugai et al, 2010). d-GABAARs have been proposed as important general anaesthetic targets, a suggestion supported by their abundant expression in brain regions implicated in some anaesthetic behaviours, including thalamocortical (TC) relay nuclei (Belelli et al, 2005; Jia et al, 2005)
Our recent demonstration that thalamic d-GABAARs may influence the kinetics of action potential-dependent phasic inhibition, in response to spike bursts (Herd et al, 2013), provides an additional route whereby etomidate may influence VB inhibition
Summary
The ability of general anaesthetics to impair consciousness, and induce analgesia, amnesia and immobility, has been exploited clinically for over a century (Rudolph & Antkowiak, 2004) Despite their routine clinical use, the neuroanatomical substrates of anaesthetic actions remain enigmatic, with several components of the circuitry regulating the sleep–wake cycle implicated to date (Franks, 2008). Electrophysiological, neuroimaging and modelling studies consistently pinpoint the thalamus as an important neural locus for anaesthetic-induced hypnosis (Angel, 1991; Fiset et al, 1999; Alkire et al, 2000; White & Alkire, 2003; Ching et al, 2010; Andrada et al, 2012) Such observations are consistent with the classical role of the thalamus in controlling transitions between conscious states (Steriade et al, 1993). While etomidate enhances both phasic and tonic currents recorded from TC neurons (Belelli et al, 2005), it is unknown how these respective actions influence the excitability of relay neurons
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