Abstracts

Rationale: Sleep disorders are a prevalent comorbid condition in epilepsy. Symptoms include inappropriate sleep-wake transitions and reduced sleep efficiency. These symptoms, are shared by sleep disorders in the non-epileptic population, which are associated with a dysregulation of orexin neurotransmission from the lateral hypothalamus. Orexin neurons spontaneously fire and activate the ascending reticular activating system to stimulate wakefulness and arousal. Local adenosine inhibits orexinergic activity. We hypothesized that the orexin system is hyperactive in Kcna1-null mice, a clinically relevant model of temporal lobe epilepsy with comorbid sleep disorders. Methods: Seizure propagation was monitored using 72 hr video-subdural and depth EEG recordings. We investigated the pathology of the orexinergic system in the lateral hypothalamus (LH) of Kcna1-null mice, which have approximately seven seizures a day, using immunohistochemistry and mitochondrial analyses. Functional changes of spontaneous activity in LH were determined using multi-electrode array recordings and adenosine type 1 receptor pharmacology. Kcna1-null mice were administered almorexant, an orexin receptor antagonist, and sleep architecture (duration of NREM, wake, REM and incidence of arousals) was determined. Results: EEG analyses indicated that the more severe seizures propagate to the LH. Immunohistochemical assessment indicates that injury is apparent in the LH, as determined by increased blood-brain-barrier permeability, astrogliosis and impaired mitochondrial bioenergetics. Astrogliosis and impaired mitochondria are both upstream of reduced adenosine tone. Adenosine is responsible for inhibiting orexin and promoting sleep. Multielectrode extracellular recordings of the spontaneously firing orexin neurons indicate a reduced response to adenosine receptor agonists and antagonists, which suggests reduced adenosine inhibition of orexin in Kcna1-null LH. Administration of almorexant increased NREM in Kcna1-null mice. Conclusions: Collectively, these data suggest Kcna1-null mice have a hyperactive orexin system that may contribute to their sleep disorder comorbidity.