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 v 3.1 knockout mice to investigate the molecular mechanisms of hypnosis induced by the neurosteroid analogue (3b,5b,17b)-3hydroxyandrostane-17-carbonitrile (3b-OH). Results: Patch-clamp recordings showed that 3b-OH inhibited isolated T-currents but had no effect on phasic or tonic gaminobutyric acid A currents. Also in acute brain slices, 3b-OH inhibited the spike firing mode more profoundly in WT than in Ca v 3.1 knockout mice. Furthermore, 3b-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 À1 i.p. injections of 3b-OH induced hypnosis in >60% of WT mice but failed to induce hypnosis in the majority of mutant mice. A subhypnotic dose of 3b-OH (20 mg kg À1 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 v 3.1 knockout mice. In vivo recordings of LFPs showed that a hypnotic dose of 3b-OH increased d, q, a, and b oscillations in WT mice in comparison with Ca v 3.1 knockout mice. Conclusions: The Ca v 3.1 T-channel isoform is critical for diminished thalamocortical excitability and oscillations that underlie neurosteroid-induced hypnosis.
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