Abstract
Dravet syndrome (DS) is associated with epilepsy, developmental delays, thermal dysregulation, and sleep disturbances. While seizures have been linked to hippocampal dysfunction, what drives sleep disturbances and thermal dysregulation is poorly understood. Using DS mice (Scn1aA1783V), we identified a link between sleep and thermoregulation. We found that DS mice exhibited lower core body temperature. Next, using electrocorticography, local field potential recordings, and core temperature monitoring, we showed that DS mice exhibited a lack of core temperature change during the transition from waking to non-rapid eye movement sleep. This is in contrast to wild-type (WT) mice, in which sleep onset coincided with a temperature drop. Additionally, warmth promoted sleep in WT, but not in DS mice. Vector-mediated expression of SCN1A or chemogenetic stimulation of the anterior hypothalamus restored the warmth-induced somnogenesis in DS mice. These findings highlight a connection between sleep and thermal dysregulation in DS, implicating altered neuronal activity of the hypothalamus.
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Acknowledgements
This work is dedicated to the memory of Dr. Saja Fadila, whose dedication, talent, and scientific insight were central to this study. We acknowledge the financial support of The Israel Science Foundation (#214/22, M.R.), Recanati Foundation, Gray Faculty of Medical & Health Sciences (M.R.); Marguerite Stolz Research Fellowship, The Gray Faculty of Medical & Health Sciences (M.R.); The American Dravet Syndrome Foundation (M.R., E.A.T., E.J.K.); The Dutch National Epilepsy Foundation 22-07 (G.K., E.A.T.); The Yoran Institute for Human Genome Research at Tel Aviv University (supported the Ph.D. scholarship of S.F.). The imaging facility MRI at Montpellier, a member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, Investments for the future). The Réseau d’Histologie Expérimentale de Montpellier - RHEM facility is supported by SIRIC Montpellier Cancer (Grant INCa_Inserm_DGOS_12553), the European Regional Development Fund, and the Occitanian region (FEDER-FSE 2014-2020 Languedoc Roussillon). We thank the members of the Rubinstein lab for constructive comments during the course of the study.
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Conceptualization: S.F. and M.R.; Methodology: S.F., G.K., H.M., A.M., S.R., M.B., B.B., I.G.D.R., E.J.K., E.A.T., and M.R.; Software: G.K. and S.R.; Validation: S.F., G.K., E.A.T., and M.R.; Formal Analysis: S.F., G.K., S.R., E.A.T., and M.R.; Investigation: S.F., G.K., H.M., A.M., S.R., M.B., and I.G.D.R.; Resources: B.B., I.G.D.R., and E.J.K.; Writing – original draft: S.F. and M.R.; Writing – Review & Editing: S.F., G.K., E.J.K., E.A.T., and M.R.; Supervision: E.A.T. and M.R. Funding Acquisition: E.A.T. and M.R.
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The authors declare no competing interests. S.F., B.B., I.G.D.R., E.J.K., and M.R. are co-inventors on a patent application covering the use of CAV2 vectors for the delivery of an SCN1A expression cassette to provide exogenous NaV1.1 activity for the treatment of Dravet syndrome and related disorders. The patent applicant is the French National Center for Scientific Research (CNRS), Université de Montpellier, together with Ramot at Tel Aviv University Ltd., and Fundacion Para Investigacion Medica Aplicada. The patent application was filed as GB2205299.7 and published as GB2621102A, with international extension PCT/IB2023/053703), and is currently pending. In the present manuscript, CAV2-SCN1A was used as an experimental tool to assess whether exogenous SCN1A expression can correct sleep and temperature deficits in DS mice.
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Fadila, S., Krivoshein, G., Majadly, H. et al. Disrupted temperature-sleep coupling mechanism in a Dravet syndrome mouse model. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69957-1
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DOI: https://doi.org/10.1038/s41467-026-69957-1
