Bidirectional sleep-seizure interactions and orexin in a mouse model of tuberous sclerosis complex-related epilepsy

A strong bidirectional relationship exists between epilepsy and sleep, with seizures often occurring more frequently in sleep and, in turn, sleep being disrupted by seizures. However, the mechanistic basis of seizure-sleep interactions is poorly understood. In this study, we characterized the relationship between seizures and sleep in a mouse model of the genetic disorder tuberous sclerosis complex (TSC) and investigated potential mechanisms underlying seizure-sleep interactions related to hypothalamic orexin.

Tsc1^GFAPCKO mice were used to investigate the relationship between seizures and sleep with video, electroencephalographic (EEG), and electromyographic analysis, including the dependence of seizure frequency on vigilance state (awake, rapid eye movement [REM], non-REM) and the effect of seizures on the wake-sleep cycle. Orexin expression in hypothalamus was assessed by immunohistochemistry in relation to seizure frequency. The effect of orexin antagonists on sleep and seizures was tested by video-EEG.

Overall seizures occurred most commonly in non-REM sleep in Tsc1^GFAPCKO mice but had the highest seizure frequency in REM sleep after normalizing for amount of time spent in each vigilance state. Conversely, seizures were associated with disruptions in the sleep-wake cycle, particularly a decrease in REM sleep. Tsc1^GFAPCKO mice with seizures had increased orexin expression compared with control mice or Tsc1^GFAPCKO mice without seizures. The orexin antagonist suvorexant reversed the decrease in REM sleep but had no significant effect on seizures in Tsc1^GFAPCKO mice.

A bidirectional relationship between seizures and sleep was demonstrated in a mouse model of TSC, with relative seizure frequency surprisingly being highest in REM sleep and seizures causing a disruption of REM sleep. Hypothalamic orexin may partly mediate these seizure-sleep interactions, and orexin antagonists may represent rational therapies for sleep disorders in TSC.