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The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABAA receptor-mediated inhibition.

Herd MB, Lambert JJ, Belelli D - Eur. J. Neurosci. (2014)

Bottom Line: Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics.Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABAA Rs, which was significantly prolonged in the presence of etomidate.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.

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Etomidate prolongs phasic suppression of VB tonic firing by potentiating synaptic and extrasynaptic GABAARs. (A–C) Whole-cell current-clamp recordings illustrating the suppression of VB tonic firing under control conditions (Ai–Ci), and in the presence of 3 μm etomidate (Aii–Cii), in WT (A), α10/0 (B) and δ0/0 (C) thalamic slices. The plots to the right of each trace depict the inter-spike interval (ISI) during the illustrated tonic spike train, and demonstrate blockade of action potentials during the eIPSP. Note that the ISI during the eIPSP is increased in the presence of etomidate across all mouse strains. (D) Bar graph comparing the effect of eIPSPs on the ISI of tonic spike trains, before and after etomidate, in WT (n = 8), α10/0 (n = 9) and δ0/0 (n = 6) VB neurons. The bar representations are depicted in the symbol key. ***P < 0.001 vs. baseline ISI, paired t-test. †††P < 0.001, ISI during eIPSP after etomidate application vs. control. The increased duration of the eIPSP-induced spike suppression observed in the presence of etomidate is not significantly influenced by mouse genotype (P = 0.58, mixed anova).
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fig03: Etomidate prolongs phasic suppression of VB tonic firing by potentiating synaptic and extrasynaptic GABAARs. (A–C) Whole-cell current-clamp recordings illustrating the suppression of VB tonic firing under control conditions (Ai–Ci), and in the presence of 3 μm etomidate (Aii–Cii), in WT (A), α10/0 (B) and δ0/0 (C) thalamic slices. The plots to the right of each trace depict the inter-spike interval (ISI) during the illustrated tonic spike train, and demonstrate blockade of action potentials during the eIPSP. Note that the ISI during the eIPSP is increased in the presence of etomidate across all mouse strains. (D) Bar graph comparing the effect of eIPSPs on the ISI of tonic spike trains, before and after etomidate, in WT (n = 8), α10/0 (n = 9) and δ0/0 (n = 6) VB neurons. The bar representations are depicted in the symbol key. ***P < 0.001 vs. baseline ISI, paired t-test. †††P < 0.001, ISI during eIPSP after etomidate application vs. control. The increased duration of the eIPSP-induced spike suppression observed in the presence of etomidate is not significantly influenced by mouse genotype (P = 0.58, mixed anova).

Mentions: For current-clamp experiments investigating the effect of etomidate on VB neuron excitability, input–output curves were constructed by plotting the number of action potentials generated as a function of stimulus amplitude. To quantify etomidate-induced shifts in input–output curves, data were fit with a Boltzman sigmoidal curve according to the equation y(x) = Nmax/1 + e(X – X50)/S + Nmax), where Nmax is the number of action potentials generated at the maximum stimulus amplitude (in this case 300 pA), X is the stimulus amplitude, X50 is the stimulus amplitude producing half-maximal spike output (hereafter ‘EA50’) and S is the slope factor. For experiments investigating the effect of eIPSPs on tonic spike trains, inter-spike intervals (ISIs) were measured throughout the spike train. For baseline measurements, ISIs were determined for a 5-s period preceding each eIPSP (minimum of three stimulations) to ensure spike rates recovered to stable frequencies following inhibition. The ISI during an IPSP was simply the interval between the final spike prior to delivery of an eIPSP and the first spike following recovery from inhibition. The transient suppression of tonic spike activity induced by an eIPSP was observed as an immediate and obvious increase in the ISI (see Figs2 and 3).


The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABAA receptor-mediated inhibition.

Herd MB, Lambert JJ, Belelli D - Eur. J. Neurosci. (2014)

Etomidate prolongs phasic suppression of VB tonic firing by potentiating synaptic and extrasynaptic GABAARs. (A–C) Whole-cell current-clamp recordings illustrating the suppression of VB tonic firing under control conditions (Ai–Ci), and in the presence of 3 μm etomidate (Aii–Cii), in WT (A), α10/0 (B) and δ0/0 (C) thalamic slices. The plots to the right of each trace depict the inter-spike interval (ISI) during the illustrated tonic spike train, and demonstrate blockade of action potentials during the eIPSP. Note that the ISI during the eIPSP is increased in the presence of etomidate across all mouse strains. (D) Bar graph comparing the effect of eIPSPs on the ISI of tonic spike trains, before and after etomidate, in WT (n = 8), α10/0 (n = 9) and δ0/0 (n = 6) VB neurons. The bar representations are depicted in the symbol key. ***P < 0.001 vs. baseline ISI, paired t-test. †††P < 0.001, ISI during eIPSP after etomidate application vs. control. The increased duration of the eIPSP-induced spike suppression observed in the presence of etomidate is not significantly influenced by mouse genotype (P = 0.58, mixed anova).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4215602&req=5

fig03: Etomidate prolongs phasic suppression of VB tonic firing by potentiating synaptic and extrasynaptic GABAARs. (A–C) Whole-cell current-clamp recordings illustrating the suppression of VB tonic firing under control conditions (Ai–Ci), and in the presence of 3 μm etomidate (Aii–Cii), in WT (A), α10/0 (B) and δ0/0 (C) thalamic slices. The plots to the right of each trace depict the inter-spike interval (ISI) during the illustrated tonic spike train, and demonstrate blockade of action potentials during the eIPSP. Note that the ISI during the eIPSP is increased in the presence of etomidate across all mouse strains. (D) Bar graph comparing the effect of eIPSPs on the ISI of tonic spike trains, before and after etomidate, in WT (n = 8), α10/0 (n = 9) and δ0/0 (n = 6) VB neurons. The bar representations are depicted in the symbol key. ***P < 0.001 vs. baseline ISI, paired t-test. †††P < 0.001, ISI during eIPSP after etomidate application vs. control. The increased duration of the eIPSP-induced spike suppression observed in the presence of etomidate is not significantly influenced by mouse genotype (P = 0.58, mixed anova).
Mentions: For current-clamp experiments investigating the effect of etomidate on VB neuron excitability, input–output curves were constructed by plotting the number of action potentials generated as a function of stimulus amplitude. To quantify etomidate-induced shifts in input–output curves, data were fit with a Boltzman sigmoidal curve according to the equation y(x) = Nmax/1 + e(X – X50)/S + Nmax), where Nmax is the number of action potentials generated at the maximum stimulus amplitude (in this case 300 pA), X is the stimulus amplitude, X50 is the stimulus amplitude producing half-maximal spike output (hereafter ‘EA50’) and S is the slope factor. For experiments investigating the effect of eIPSPs on tonic spike trains, inter-spike intervals (ISIs) were measured throughout the spike train. For baseline measurements, ISIs were determined for a 5-s period preceding each eIPSP (minimum of three stimulations) to ensure spike rates recovered to stable frequencies following inhibition. The ISI during an IPSP was simply the interval between the final spike prior to delivery of an eIPSP and the first spike following recovery from inhibition. The transient suppression of tonic spike activity induced by an eIPSP was observed as an immediate and obvious increase in the ISI (see Figs2 and 3).

Bottom Line: Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics.Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABAA Rs, which was significantly prolonged in the presence of etomidate.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.

Show MeSH
Related in: MedlinePlus