title: Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome.
abstract: Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our mouse genetic model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children Hospital Research Institute, Seattle, WA 98101, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Kalume
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Oakley
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Westenbroek
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Department of Biology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gile
authors.affiliation: Department of Biology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Horacio O
authors.initials: HO
authors.lastname: de la Iglesia
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. Electronic address: wcatt@u.washington.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004831:Epilepsies, Myoclonic / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D059330:GABAergic Neurons / Q000473:pathology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007395:Interneurons / Q000473:pathology*; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D018408:Patch-Clamp Techniques; D012892:Sleep Deprivation / Q000503:physiopathology; D012893:Sleep Wake Disorders / Q000209:etiology*; D013788:Thalamus / Q000473:pathology*; D014741:Video Recording; D014851:Wakefulness / Q000235:genetics
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1