Abstract
Nav1.6 is a major voltage-gated sodium channel in the central and peripheral nervous systems. Within neurons, the channel protein is concentrated at the axon initial segment and nodes of Ranvier, where it functions in initiation and propagation of action potentials. We examined the role of Nav1.6 in general anesthesia using two mouse mutants with reduced activity of Nav1.6, Scn8a medJ/medJ and Scn8a 9J/9J. The mice were exposed to the general anesthetics isoflurane and sevoflurane in step-wise increments; the concentration required to produce loss of righting reflex, a surrogate for anesthetic-induced unconsciousness in rodents, was determined. Mice homozygous for these mutations exhibited increased sensitivity to both isoflurane and sevoflurane. The increased sensitivity was observed during induction of unconsciousness but not during the recovery phase, suggesting that the effect is not attributable to compromised systemic physiology. Electroencephalographic theta power during baseline waking was lower in mutants, suggesting decreased arousal and reduced neuronal excitability. This is the first report linking reduced activity of a specific voltage-gated sodium channel to increased sensitivity to general anesthetics in vivo.
Highlights
Nav1.6 is encoded by the gene Scn8a and is one of the major voltage-gated sodium channels in the central nervous system [1,2]
There was a significant shift to the left in the best-fit curves and a decrease in EC50% value for isoflurane and sevoflurane for both Scn8amedJ/medJ [Isoflurane: EC50% = 0.74 (0.71–0.78) for Scn8amedJ/medJ vs 1.2(1.1–1.2) for littermate control group, p
In order to demonstrate quantitatively that the more potent anesthetic effects on the righting reflex in Scn8amedJ/medJ and Scn8a9J/9J mice were not due to the ataxic phenotype, we compared theta power, an independent measure of electroencephalographic and behavioral arousal, between the mutants and the littermate controls at the point of loss of righting reflex (LORR)
Summary
Nav1.6 is encoded by the gene Scn8a and is one of the major voltage-gated sodium channels in the central nervous system [1,2]. The Nav1.6 protein is concentrated within neurons at the axonal initial segment, where it regulates the initiation of action potentials [3,4]. The channel is concentrated at nodes of Ranvier and is present at lower abundance in soma and dendrites [5,6,7]. Nav1.6 is important for generation of persistent and resurgent currents and is expressed throughout the brain, including in the prefrontal cortex [8], basal ganglia [9], hippocampus [3,10], cerebellum [10,11,12], and brainstem [13].
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