Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum
| Autor: | Charles F. Zorumski, Yukitoshi Izumi, Sonja Lj. Joksimovic, Douglas F. Covey, Betelehem Asnake, Srdjan M. Joksimovic, Vesna Tesic, Slobodan M. Todorovic, Vesna Jevtovic-Todorovic, Kathiresan Krishnan |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
Neuroactive steroid Long-Term Potentiation Hippocampal formation Hippocampus Rats Sprague-Dawley 03 medical and health sciences Calcium Channels T-Type 0302 clinical medicine Neuroscience and Neuroanaesthesia 030202 anesthesiology Nitriles Medicine Animals Hypnotics and Sedatives Androstanols RNA Messenger Neuronal Plasticity business.industry Calcium channel Subiculum T-type calcium channel Long-term potentiation Calcium Channel Blockers Anesthesiology and Pain Medicine medicine.anatomical_structure nervous system Gene Expression Regulation Schaffer collateral Synaptic plasticity Female business Neuroscience |
| Zdroj: | Br J Anaesth |
| ISSN: | 1471-6771 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|