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Author Notes:

To whom correspondence should be addressed: Andrew Escayg, Emory University, Department of Human Genetics, 615 Michael Street, Whitehead Building, Suite 365-5, Atlanta, Georgia, 30322, USA. Telephone number (404) 712-8328; Fax number (404) 727-3949; aescayg@emory.edu

The first two authors contributed equally to the study.


Research Funding:

This study was funded by NIH grants to AE (NS072221) and KNP (NS060659) and CDM (F31NS074717). LP was supported by fellowships from AFIP and FAPESP (#07/50534-0). ST was supported by FAPESP (CEPID#98/14303-3). This research was also supported in part by the NINDS core facilities grant P30N5055077 to the Emory University Microscopy Core.


  • sleep
  • epilepsy
  • Scn1a
  • sodium channel
  • sleep deprivation

Altered Sleep Regulation in a Mouse Model of SCN1A-Derived Genetic Epilepsy with Febrile Seizures Plus (GEFS+)


Journal Title:



Volume 54, Number 4


, Pages 625-634

Type of Work:

Article | Post-print: After Peer Review


Purpose Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. Methods Using immunohistochemistry we first examined the expression of Scn1a in 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 electroencephalographic (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleep-wake pattern following 6 hours of sleep deprivation. Key Findings Immunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity 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 WT littermates during the recovery period following 6-hours of sleep deprivation. Significance These results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression of Scn1a in specific cells 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 human SCN1A mutations.

Copyright information:

© 2013 International League Against Epilepsy

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