Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum

Srdjan M. Joksimovic, Yukitoshi Izumi, Sonja Lj Joksimovic, Vesna Tesic, Kathiresan Krishnan, Betelehem Asnake, Vesna Jevtovic-Todorovic, Douglas F. Covey, Charles F. Zorumski, Slobodan M. Todorovic

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Hypnotics and general anaesthetics impair memory by altering hippocampal synaptic plasticity. We recently reported on a neurosteroid analogue with potent hypnotic activity [(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile; 3β-OH], which does not cause developmental neurotoxicity in rat pups. Here, we investigated the effects of 3β-OH on neuronal excitability in the subiculum, the major output structure of the hippocampal formation, and synaptic plasticity at two key hippocampal synapses in juvenile rats. Methods: Biophysical properties of isolated T-type calcium currents (T-currents) in the rat subiculum were investigated using acute slice preparations. Subicular T-type calcium channel (T-channel) subtype mRNA expression was compared using qRT–PCR. Using electrophysiological recordings, we examined the effects of 3β-OH and an endogenous neuroactive steroid, allopregnanolone (Allo), on T-currents and burst firing properties of subicular neurones, and on the long-term potentiation (LTP) in CA3-CA1 and CA1-subiculum pathways. Results: Biophysical and molecular studies confirmed that Ca V 3.1 channels represent the dominant T-channel isoform in the subiculum of juvenile rats. 3β-OH and Allo inhibited rebound burst firing by decreasing the amplitude of T-currents in a voltage-dependent manner with similar potency, with 30–80% inhibition. Both neurosteroids suppressed LTP at the CA1-subiculum, but not at the CA3-CA1 Schaffer collateral synapse. Conclusions: Neurosteroid effects on T-channels modulate hippocampal output and provide possible molecular mechanisms for the amnestic action of the novel hypnotic 3β-OH. Effects on T-channels in the subiculum provide a novel target for amnestic effects of hypnotics.

Original languageEnglish
Pages (from-to)643-651
Number of pages9
JournalBritish journal of anaesthesia
Volume122
Issue number5
DOIs
StatePublished - May 2019

Keywords

  • T-type calcium channels
  • amnesia
  • general anaesthetic
  • hippocampus
  • neurosteroid
  • subiculum
  • synaptic plasticity

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