Lost in Sleep Transition: Tangled Sleep and Thermoregulation in Dravet Syndrome

Abstract

Original Article Citation

Fadila S, Krivoshein G, Majadly H, Mavashov A, Ranen S, Brusel M, Dopeso-Reyes IG, Beucher B, Kremer EJ, Tolner EA, Rubinstein M. Disrupted temperature-sleep coupling mechanism in a Dravet syndrome mouse model. Nature Communications. 2026;17:3232.

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.

Commentary

Dravet syndrome (DS) is an early-life epileptic encephalopathy caused primarily by loss-of-function mutations in SCN1A, which encodes the voltage-gated sodium channel Na_v1.1. ¹ Patients with DS experience complex febrile seizures and multiple seizure types and are often refractory to treatment. ² In addition to severe epilepsy, DS is associated with numerous comorbidities, including developmental delay, autism, dysautonomia, and sleep impairment. ³ Dysautonomia in DS manifests as a range of symptoms affecting cardiac and respiratory function, diaphoresis, sleep, and temperature regulation. ³ Sleep disturbances include difficulty initiating and maintaining sleep, abnormalities in sleep-wake transition and sleep-related breathing, and nocturnal seizures. ⁴

Mouse models of DS recapitulate many key clinical features, including spontaneous seizures, behavioral challenges, and temperature-induced seizures. These mouse models also exhibit autonomic nervous system dysregulation, longer circadian period, and sleep abnormalities, which include reduced delta wave power, increased wake, and fewer sleep spindles.^5–7 In the current study, Fadila and colleagues identified alterations in sleep transition and thermoregulation in the Scn1a^A1783V mouse model of DS and demonstrated that increasing SCN1A expression or activating neurons in the anterior hypothalamus restored more normal sleep patterns and temperature regulation in the mutant mice. ⁸

First, Fadila and colleagues investigated body temperature regulation in DS and wild-type (WT) mice at postnatal days 21–25. ⁸ Mice were placed in a beaker on a heated pad set to 30°C for 30 min followed by a 15-min recovery period at room temperature (RT). DS mice exhibited a lower core body temperature at baseline compared to WT littermates, but body temperatures were comparable between DS and WT mice at the end of the 30-min period. Interestingly, following the 15 min of recovery at RT, DS mice had a significantly lower body temperature compared to WT mice. These observations differ from a previous study that noted comparable baseline temperatures in heterozygous Scn1a knockout mice, while body temperature remained elevated in the mutant mice when exposed to warmer temperatures. ⁶ It is possible that the disparities between these studies were due to the different DS mouse models used or the duration of body temperature elevation. Nevertheless, both studies demonstrate that DS mice exhibit altered thermoregulation when exposed to different ambient temperatures.

To investigate whether wake-sleep transitions were altered in DS mice, the authors performed 2–4 h of ECoG/EMG (electrocorticography/electromyography) recordings while continuously monitoring body temperature during sleep transitions. ⁸ Power spectral density analysis revealed an increase in ECoG delta power and delta ratio (total power between 0.9 and 3.9 Hz divided by total power between 0.9 and 99 Hz) in WT mice in the wake to non-rapid eye movement (NREM) transition, which was also accompanied by a reduction in core body temperature. This reduction in body temperature occurred in 65% of the transitions. In contrast, the delta ratio was comparable during wake and NREM in DS mice, and less than 21% of the wake to NREM transitions were associated with a reduction in body temperature. Given the sleep transition impairments observed in DS mice, the authors next investigated whether a warmer environment (36°C for 1 h) would promote sleep in 5- to 6-week-old DS mice. Warm ambient environments (32–36°C) have been shown to shorten sleep latency and facilitate NREM sleep by activating neurons in the hypothalamus. WT mice exhibited an increase in delta power during wake to NREM transition at room and elevated temperatures. In contrast, the warmer temperature did not promote sleep in the DS mice, and the delta ratio was unaltered, demonstrating that DS mice exhibit impairments in warmth-induced somnogenesis and wake-sleep transition.

To determine whether the observed sleep impairments in DS mice were due to reduced Na_v1.1 levels in the hypothalamus, Fadila and colleagues bilaterally injected their previously generated canine adenovirus type 2 harboring an SCN1A expression cassette (CAV2-SCN1A) ⁹ into the anterior hypothalamus of DS and WT mice. Injection of CAV2-SCN1A was able to increase the percentage of NREM sleep and the delta ratio at RT and a warmer environment (29°C) in DS mice, demonstrating that increasing Na_v1.1 levels in the anterior hypothalamus was able to restore warmth-induced somnogenesis and sleep transition in the mutant mice. Interestingly, the authors found that CAV2-SCN1A treatment was not able to ameliorate deficits in nest-building behavior, which is a sleep preparatory behavior. Furthermore, interictal spiking was comparable between DS mice treated with CAV2-SCN1A and untreated DS mice, suggesting that the hypothalamus does not contribute to epileptiform activity or spontaneous seizures in DS. These observations differ from the authors’ previous study, where administration of CAV2-SCN1A in the hippocampus or thalamus were able to significantly reduce epileptiform activity and spontaneous seizures in DS mice ⁹ ; however, sleep transition and thermoregulation were not examined in their previous study.

The hypothalamus is comprised of a heterogeneous population of excitatory and inhibitory neurons. Given that SCN1A is broadly expressed in excitatory and inhibitory neurons, and CAV2-SCN1A promotes the activity of transduced cells, the authors speculated that increasing the excitability of the hypothalamus via chemogenetic activation might yield similar results as CAV2-SCN1A administration. Thus, the authors injected CAV2-hM3D-IRES-mCitrine in the anterior hypothalamus, and mice were administered saline or clozapine N-oxide (CNO, 10 mg/kg). As expected, DS mice that received saline exhibited impaired warmth-induced somnogenesis; however, CNO administration restored warmth-induced somnogenesis and increased the delta power during NREM, demonstrating that acute activation of hypothalamic neurons was also able to restore more normal sleep-temperature function in DS mice.

Fadila and colleagues demonstrated that DS mice exhibit impairments in sleep transition and thermoregulation, expanding the constellation of autonomic nervous system-related comorbidities observed in DS mouse models.^5–7 Furthermore, the authors showed that increasing SCN1A expression and acute activation of anterior hypothalamic neurons were sufficient to restore sleep transition and thermoregulation in DS mice, ⁹ suggesting that neuronal dysfunction within the anterior hypothalamus might contribute to these phenotypes in DS. The preoptic area of the hypothalamus plays a central role in regulating delta power, sleep-wake cycles, temperature, and energy homeostasis. ¹⁰ Given the cellular heterogeneity of the hypothalamus, future studies could investigate which specific cell populations underlie the sleep transition and thermoregulation abnormalities observed in DS mice. Of note, CAV2-SCN1A contains the neuronal-specific enolase (NSE) promoter, which results in increased SCN1A expression in both excitatory and inhibitory neurons. Furthermore, CAV2 also has efficient retrograde transport properties. Therefore, it is plausible that multiple cell types in the hypothalamus, as well as projections to the hypothalamus, collectively contribute to the observed improvements in sleep and thermoregulation in DS mice. Additionally, because multiple aspects of sleep architecture deteriorate with age, it would be informative to determine whether disruptions in sleep and temperature regulation persist or worsen in older DS mice. Such findings would have important clinical relevance, as age-related reductions in delta power during NREM sleep are associated with an increased risk of cognitive impairment. Future work should also examine whether restoration of sleep in DS mice can improve cognitive outcomes. Together, the findings by Fadila and colleagues highlight the anterior hypothalamus as an important regulator of sleep transition and thermoregulation in DS, which opens promising avenues for understanding and uncovering therapeutic strategies not only for DS, but also for a broader range of neurological disorders characterized by sleep and thermoregulation dysfunction.

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.