Srdjan M Joksimovic1, Yukitoshi Izumi2, Sonja Lj Joksimovic3, Vesna Tesic3, Kathiresan Krishnan4, Betelehem Asnake5, Vesna Jevtovic-Todorovic3, Douglas F Covey6, Charles F Zorumski2, Slobodan M Todorovic3. 1. Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO, USA. Electronic address: srdan.joksimovic@ucdenver.edu. 2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA. 3. Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO, USA. 4. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA. 5. Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA. 6. Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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 CaV3.1 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.
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 CaV3.1 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.
Authors: Slobodan M Todorovic; Sriyani Pathirathna; Barbara C Brimelow; Miljen M Jagodic; Seong-Hoon Ko; Xin Jiang; Kent R Nilsson; Charles F Zorumski; Douglas F Covey; Vesna Jevtovic-Todorovic Journal: Mol Pharmacol Date: 2004-07-27 Impact factor: 4.436
Authors: Francesca M Manzella; Douglas F Covey; Vesna Jevtovic-Todorovic; Slobodan M Todorovic Journal: J Neuroendocrinol Date: 2022-01-10 Impact factor: 3.627
Authors: Stefan Maksimovic; Nemanja Useinovic; Nidia Quillinan; Douglas F Covey; Slobodan M Todorovic; Vesna Jevtovic-Todorovic Journal: Int J Mol Sci Date: 2022-02-08 Impact factor: 5.923