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a Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, Virginia, USA b Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA c Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia, USA
Key Words: thalamus • T-type • neurosteroids • calcium • nucleus reticularis
Address for correspondence: Slobodan Todorovic, Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, VA 22908-0710. st9d{at}virginia.edu
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 (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-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 3β-OH potently and reversibly decreased T-type Ca2+ current amplitude and stabilized inactive states of the channels. In current-clamp experiments, 3β-OH significantly decreased the frequency of action potential firing from negative membrane potentials and minimally changed passive membrane properties. Our results indicate that 5β-reduced neuroactive steroids, through the mechanisms of inhibition of T-type Ca2+ 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.
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