Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum.
Androstanols
/ pharmacology
Animals
Calcium Channel Blockers
/ pharmacology
Calcium Channels, T-Type
/ biosynthesis
Female
Gene Expression Regulation
/ drug effects
Hippocampus
/ drug effects
Hypnotics and Sedatives
/ pharmacology
Long-Term Potentiation
/ drug effects
Male
Neuronal Plasticity
/ drug effects
Nitriles
/ pharmacology
RNA, Messenger
/ genetics
Rats, Sprague-Dawley
T-type calcium channels
amnesia
general anaesthetic
hippocampus
neurosteroid
subiculum
synaptic plasticity
Journal
British journal of anaesthesia
ISSN: 1471-6771
Titre abrégé: Br J Anaesth
Pays: England
ID NLM: 0372541
Informations de publication
Date de publication:
May 2019
May 2019
Historique:
received:
30
05
2018
revised:
17
12
2018
accepted:
21
12
2018
pubmed:
28
3
2019
medline:
23
4
2019
entrez:
28
3
2019
Statut:
ppublish
Résumé
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. 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. Biophysical and molecular studies confirmed that Ca 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
Biophysical and molecular studies confirmed that Ca
CONCLUSIONS
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.
Identifiants
pubmed: 30916017
pii: S0007-0912(19)30072-8
doi: 10.1016/j.bja.2019.01.029
pmc: PMC6549045
pii:
doi:
Substances chimiques
3-hydroxyandrostane-17-carbonitrile
0
Androstanols
0
Calcium Channel Blockers
0
Calcium Channels, T-Type
0
Hypnotics and Sedatives
0
Nitriles
0
RNA, Messenger
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
643-651Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM102525
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH114866
Pays : United States
Informations de copyright
Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
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