Dataset Information

The T-type calcium channel isoform Ca_v3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3?,5?,17?)-3-hydroxyandrostane-17-carbonitrile.

ABSTRACT:

Background

The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown.

Methods

We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Ca_v3.1 knock-out mice to investigate the molecular mechanisms of hypnosis induced by the neurosteroid analogue (3?,5?,17?)-3-hydroxyandrostane-17-carbonitrile (3?-OH).

Results

Patch-clamp recordings showed that 3?-OH inhibited isolated T-currents but had no effect on phasic or tonic ?-aminobutyric acid A currents. Also in acute brain slices, 3?-OH inhibited the spike firing mode more profoundly in WT than in Ca_v3.1 knockout mice. Furthermore, 3?-OH significantly hyperpolarised neurones, reduced the amplitudes of low threshold spikes, and diminished rebound burst firing only in WT mice. We found that 80 mg kg^-1 i.p. injections of 3?-OH induced hypnosis in >60% of WT mice but failed to induce hypnosis in the majority of mutant mice. A subhypnotic dose of 3?-OH (20 mg kg^-1 i.p.) accelerated induction of hypnosis by isoflurane only in WT mice, but had similar effects on the maintenance of isoflurane-induced hypnosis in both WT and Ca_v3.1 knockout mice. In vivo recordings of LFPs showed that a hypnotic dose of 3?-OH increased ?, ?, ?, and ? oscillations in WT mice in comparison with Ca_v3.1 knock-out mice.

Conclusions

The Ca_v3.1 T-channel isoform is critical for diminished thalamocortical excitability and oscillations that underlie neurosteroid-induced hypnosis.

SUBMITTER: Timic Stamenic T

PROVIDER: S-EPMC7844375 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

The T-type calcium channel isoform Ca<sub>v</sub>3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile.

Timic Stamenic Tamara T Feseha Simon S Manzella Francesca M FM Wallace Damon D Wilkey Davis D Corrigan Timothy T Fiedler Hanna H Doerr Patricia P Krishnan Kathiresan K Raol Yogendra H YH Covey Douglas F DF Jevtovic-Todorovic Vesna V Todorovic Slobodan M SM

British journal of anaesthesia 20200825 1

<h4>Background</h4>The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown.<h4>Methods</h4>We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Ca<sub>v</sub>3.1 knock-out mice to investigate the molecular mechanisms o ...[more]

PMID: 32859366

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Project description:We recently reported that a neurosteroid analogue with T-channel-blocking properties (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rat pups without triggering neuronal apoptosis. Furthermore, we found that the inhibition of the CaV3.1 isoform of T-channels contributes to the hypnotic properties of 3β-OH in adult mice. However, the specific mechanisms underlying the role of other subtypes of voltage-gated calcium channels in thalamocortical excitability and oscillations in vivo during 3β-OH-induced hypnosis are largely unknown. Here, we used patch-clamp recordings from acute brain slices, in vivo electroencephalogram (EEG) recordings, and mouse genetics with wild-type (WT) and CaV2.3 knock-out (KO) mice to further investigate the molecular mechanisms of neurosteroid-induced hypnosis. Our voltage-clamp recordings showed that 3β-OH inhibited recombinant CaV2.3 currents. In subsequent current-clamp recordings in thalamic slices ex vivo, we found that selective CaV2.3 channel blocker (SNX-482) inhibited stimulated tonic firing and increased the threshold for rebound burst firing in WT animals. Additionally, in thalamic slices we found that 3β-OH inhibited spike-firing more profoundly in WT than in mutant mice. Furthermore, 3β-OH reduced bursting frequencies in WT but not mutant animals. In ensuing in vivo experiments, we found that intra-peritoneal injections of 3β-OH were less effective in inducing LORR in the mutant mice than in the WT mice, with expected sex differences. Furthermore, the reduction in total α, β, and low γ EEG power was more profound in WT than in CaV2.3 KO females over time, while at 60 min after injections of 3β-OH, the increase in relative β power was higher in mutant females. In addition, 3β-OH depressed EEG power more strongly in the male WT than in the mutant mice and significantly increased the relative δ power oscillations in WT male mice in comparison to the mutant male animals. Our results demonstrate for the first time the importance of the CaV2.3 subtype of voltage-gated calcium channels in thalamocortical excitability and the oscillations that underlie neurosteroid-induced hypnosis.

Dataset Information

The T-type calcium channel isoform Ca_v3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3?,5?,17?)-3-hydroxyandrostane-17-carbonitrile.

Background

Methods

Results

Conclusions

Publications

The T-type calcium channel isoform Ca<sub>v</sub>3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The T-type calcium channel isoform Cav3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3?,5?,17?)-3-hydroxyandrostane-17-carbonitrile.

Background

Methods

Results

Conclusions

Publications

The T-type calcium channel isoform Ca<sub>v</sub>3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The T-type calcium channel isoform Ca_v3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3?,5?,17?)-3-hydroxyandrostane-17-carbonitrile.