Authors :
Presenting Author: Moran Rubinstein, PhD – Tel Aviv University
Saja Fadila, PhD – The Department of Human Molecular Genetics and Biochemistry – Tel Aviv University; Bertrand Beucher, PhD – IR-Search, PVM, BioCampus, CNRS, INSERM, University of Montpellier, Montpellier, France; Iria González Dopeso-Reyes, PhD – IR-Search, Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Eric Kremer, PhD – Researcher DR1, Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
Rationale:
Dravet syndrome (Dravet) is a devastating childhood epileptic encephalopathy caused by loss-of-function mutations in
SCN1A. Among the multifaceted phenotypes in Dravet, sleep disturbances are very common. Temperature dysregulation is also prevalent, with reduced sweating and intolerance to cold or heat. Sleep initiation is associated with reduced body core temperature, essential for sleep homeostasis, suggesting that sleep and temperature dysregulation might be linked in Dravet.
Methods:
To study the neuronal basis of sleep and thermoregulation, we used temperature, electrocorticography (EcoG), and depth recordings in Dravet mice (
Scn1aWT/A1783V) and their wild-type littermates. We focused on the effect of ambient temperature and sleep on body core temperature and the power at the delta frequency band (0.5 – 4 Hz).
Results:
Dravet mice had lower core temperature at baseline, with reduced ability to stabilize their temperature in changing ambient environments. Furthermore, ECoG recordings concomitant with temperature measurements revealed that Dravet mice fail to reduce their core temperature during the transition from wake to non-REM sleep.
The ventrolateral preoptic area (VLPO) is a sleep-promoting region that is also involved in regulating body temperature. Depth electrode recordings in the VLPO demonstrated that increased ambient temperature (from 25° C to 36° C) was associated with increased delta power in WT mice but not in Dravet mice. The delivery of an
SCN1A coding sequence, mediated by canine adenovirus type 2 vector (CAV2-SCN1A), in neurons in the VLPO and VLPO projecting regions, corrected the temperature-dependent increase in delta power. Moreover, chemogenetic enhancement of the excitability of VLPO neurons that project to the lateral hypothalamic area (LHA) was sufficient to correct the temperature-dependent delta power increase in Dravet mice.
Conclusions:
Together, our data indicate a link between sleep and thermal dysregulation in Dravet and demonstrate that reduced activity of the VLPO is involved in these deficits.
Funding: The Israel Science Foundation (#1454/17, #214/22), The Yoran Institute for Human Genome Research at Tel Aviv University