Face validation and pharmacologic analysis of Sik3^Sleepy mutant mouse as a possible model of idiopathic hypersomnia

Idiopathic hypersomnia (IH) is a chronic neurologic disorder with unknown mechanisms that result in long night-time sleep, daytime sleepiness, long non-refreshing naps, and difficult awakening presenting as sleep drunkenness. IH patients are typically diagnosed by shorter sleep latency on multiple sleep latency test (MSLT) along with long sleep time. Only symptomatic drug treatments are currently available for IH and no animal model to study it. Sleepy mice carry a splicing mutation in the Sik3 gene, leading to increased sleep time and sleep need. Here we used a mouse version of MSLT and a decay analysis of wake EEG delta power to validate the Sleepy mutant mouse as an animal model for IH. Sleepy mice had shorter sleep latency in the dark (active) phase than wild-type mice. They also showed lower decay of EEG delta density during wakefulness, possibly reflecting increased sleep inertia. These data indicate that the Sleepy mouse may have partial face validity as a mouse model for idiopathic hypersomnia. We then investigated the effect of orexin-A and the orexin receptor 2-selective agonist YNT-185 on the sleepiness symptoms of the Sleepy mouse. Intracerebroventricular orexin-A promoted wakefulness for 3 h and decreased wake EEG delta density after injection in Sleepy mice and wild-type mice. Moreover, Sleepy mice but not wild-type mice showed a sleep rebound after the orexin-A-induced wakefulness. Intraperitoneal YNT-185 promoted wakefulness for 3 h after injection in Sleepy mice, indicating the potential of using orexin agonists to treat not only orexin deficiency but hypersomnolence of various etiologies.