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• W1976499564 abstract "Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel Na V 1.1. 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 Na V 1.1 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 Na V 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 Na V 1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of Na V currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice. • DS mice have abnormal sleep with increased brief wakes and reduced sleep spindles. • Delta wave power is reduced in Non-Rapid-Eye-Movement sleep. • Homeostatic sleep rebound after sleep deprivation is impaired. • Na V current and rebound action potentials are reduced in inhibitory RNT neurons. • Selective gene deletion in inhibitory neurons causes the same sleep impairment." @default.
• W1976499564 created "2016-06-24" @default.
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• W1976499564 date "2015-05-01" @default.
• W1976499564 modified "2023-10-16" @default.
• W1976499564 title "Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome" @default.
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• W1976499564 doi "https://doi.org/10.1016/j.nbd.2015.02.016" @default.
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