title: Reduced Nav1.6 Sodium Channel Activity in Mice Increases In Vivo Sensitivity to Volatile Anesthetics.
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, Scn8amedJ/medJ and Scn8a9J/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.
authors.affiliation: Department of Anesthesiology, University of Michigan, 7433 Medical Science Building 1, 1150, West Medical Center Drive, Ann Arbor, Michigan, United States of America; Center for Consciousness Science, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Human Genetics, University of Michigan, 4808 Medical Science Building 2, 1241 East Catherine Street, Ann Arbor, Michigan, United States of America.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Jones
authors.affiliation: Department of Anesthesiology, University of Michigan, 7433 Medical Science Building 1, 1150, West Medical Center Drive, Ann Arbor, Michigan, United States of America.
authors.forename: Stella
authors.initials: S
authors.lastname: Wisidagamage
authors.affiliation: Department of Human Genetics, University of Michigan, 4808 Medical Science Building 2, 1241 East Catherine Street, Ann Arbor, Michigan, United States of America.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.affiliation: Department of Anesthesiology, University of Michigan, 7433 Medical Science Building 1, 1150, West Medical Center Drive, Ann Arbor, Michigan, United States of America; Center for Consciousness Science, University of Michigan, Ann Arbor, Michigan, United States of America; Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: George A
authors.initials: GA
authors.lastname: Mashour
mesh_terms: D000758:Anesthesia; D000762:Anesthesia Recovery Period; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004569:Electroencephalography; D007530:Isoflurane / Q000494:pharmacology; D008738:Methyl Ethers / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D000077149:Sevoflurane; D013826:Theta Rhythm / Q000187:drug effects; D014835:Volatilization; D014851:Wakefulness / Q000187:drug effects
chemical_list: D000777:Anesthetics; D008738:Methyl Ethers; D062557:NAV1.6 Voltage-Gated Sodium Channel; D000077149:Sevoflurane; D007530:Isoflurane