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

Tamara Timic Stamenic, Simon Feseha, Francesca M. Manzella, Damon Wallace, Davis Wilkey, Timothy Corrigan, Hanna Fiedler, Patricia Doerr, Kathiresan Krishnan, Yogendra H. Raol, Douglas F. Covey, Vesna Jevtovic-Todorovic, Slobodan M. Todorovic

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 Cav3.1 knock-out mice to investigate the molecular mechanisms of hypnosis induced by the neurosteroid analogue (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH). Results: Patch-clamp recordings showed that 3β-OH inhibited isolated T-currents but had no effect on phasic or tonic γ-aminobutyric acid A currents. Also in acute brain slices, 3β-OH inhibited the spike firing mode more profoundly in WT than in Cav3.1 knockout mice. Furthermore, 3β-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 3β-OH induced hypnosis in >60% of WT mice but failed to induce hypnosis in the majority of mutant mice. A subhypnotic dose of 3β-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 Cav3.1 knockout mice. In vivo recordings of LFPs showed that a hypnotic dose of 3β-OH increased δ, θ, α, and β oscillations in WT mice in comparison with Cav3.1 knock-out mice. Conclusions: The Cav3.1 T-channel isoform is critical for diminished thalamocortical excitability and oscillations that underlie neurosteroid-induced hypnosis.

Original languageEnglish
Pages (from-to)245-255
Number of pages11
JournalBritish journal of anaesthesia
Volume126
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • calcium channel
  • electrophysiology
  • hypnosis
  • mechanisms of anaesthesia
  • neurosteroid
  • thalamus

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this