Inhibition of T-type calcium current in the reticular thalamic nucleus by a novel neuroactive steroid.
Neurons of the nucleus reticularis of the thalamus (nRT) serve as an important inhibitory gate that controls trafficking of thalamocortical sensory signals and states of sleep, arousal, and epilepsy. T-type calcium channels in nRT play a crucial role in the subthreshold excitability of these neurons, but their modulation by neuroactive steroids has not been previously studied. Here we explored the effect of (3beta,5beta,17beta)-3-hydroxyandrostane-17-carbonitrile (3beta-OH), a novel neuroactive steroid on T-type currents recorded from nRT neurons in intact brain slices of young rats. We found in voltage-clamp experiments that 3beta-OH potently and reversibly decreased T-type Ca(2+) current amplitude and stabilized inactive states of the channels. In current-clamp experiments, 3beta-OH significantly decreased the frequency of action potential firing from negative membrane potentials and minimally changed passive membrane properties. Our results indicate that 5beta-reduced neuroactive steroids, through the mechanisms of inhibition of T-type Ca(2+) currents and diminished spike firing in nRT neurons, may be important agents in control of sensory information processing in physiological conditions and possibly pathological brain states associated with increased cellular excitability such as epilepsy and/or tissue ischemia/hypoxia.
Joksovic
Pavle M
PM
Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, VA 22908-0710, USA.
Covey
Douglas F
DF
Todorovic
Slobodan M
SM
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000732:Androstanols / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D020747:Calcium Channels, T-Type / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D020646:Intralaminar Thalamic Nuclei / Q000166:cytology*; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D013256:Steroids / Q000494:pharmacology*
C528101:3-hydroxyandrostane-17-carbonitrile; D000732:Androstanols; D020747:Calcium Channels, T-Type; D018696:Neuroprotective Agents; D009570:Nitriles; D013256:Steroids; D000255:Adenosine Triphosphate