Altered sleep regulation in a mouse model of SCN1A‐derived genetic epilepsy with febrile seizures plus (GEFS+)

Abstract

Summary 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.

Regulation of Thalamic and Cortical Network Synchrony by Scn8a

“…While Scn1a and Scn8a are both expressed in cortical inhibitory neurons (Dutton et al, 2013; Lorincz and Nusser, 2008; Ogiwara et al, 2007; Papale et al, 2013; Yu et al, 2006), in sharp contrast to the severe epilepsy that occurs following deletion of Scn1a in interneurons (Cheah et al, 2012; Dutton et al, 2013), Scn8a deletion in inhibitory neurons (via Ppp1r2 or Dlx5 / 6) produced neither convulsive seizures nor increased susceptibility to fluorothyl-induced generalized tonic-clonic seizures (Figure 1A). It follows that co-segregation of Scn1a and Scn8a mutant alleles can exert opposing influences on excitatory and inhibitory components of the cortical network to approximate normal levels of excitability.…”

Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome

“…In a recent study, Papale and colleagues (2013) characterized sleep abnormality in a mouse model of GEFS+ expressing the R1649H mutation in one allele of Scn1a . The GEFS+ mice exhibited increased wakefulness and reduced NREM and REM sleep duration during periods of darkness, when mice are primarily awake, but not during the light phase, when mice are primarily sleeping.…”

Model systems for studying cellular mechanisms ofSCN1A-related epilepsy

“…However, little is known regarding the underlying mechanisms (Papale et al 2013;Petruccelli et al 2015). Additional studies addressing comorbidities caused by SCN1A mutations will be important in helping us understand the full spectrum of disorders caused by SCN1A mutations.…”