Altered sleep regulation in a mouse model ofSCN1A-derived genetic epilepsy with febrile seizures plus (GEFS+)

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Mutations in the voltage-gated sodium channel (VGSC) geneSCN1Aare responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients withSCN1Amutations often experience sleep abnormalities, suggesting thatSCN1Amay also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role forSCN1Ain the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis thatSCN1Acontributes to the regulation of sleep architecture, and by extension, thatSCN1Adysfunction contributes to the sleep abnormalities observed in patients withSCN1Amutations.


Using immunohistochemistry we first examined the expression of mouseScn1ain regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the humanSCN1AGEFS+ mutation R1648H (RH mutants). We also characterized the sleep–wake pattern following 6 h of sleep deprivation.

Key Findings

Immunohistochemistry revealed broad expression ofScn1ain the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization betweenScn1aimmunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced non–rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation.


These results establish a direct role forSCN1Ain the regulation of sleep and suggest that patients withSCN1Amutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression ofScn1ain specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with humanSCN1Amutations.

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