Attenuated orexinergic signaling underlies sleep-wake problems in a Mecp2-null mouse model of Rett syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disorder mainly caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies reported sleep problems characterized by changes in architecture and sleep-wake patterns in both RTT patients and animal models of RTT. However, little is known about the neural mechanisms underlying the sleep-wake problems in humans or animals. In this study, Mecp2-null mice showed decreased locomotor activity during the dark period of light-dark conditions, but behaviorally showed no significant deficits in the photic regulation of circadian rhythms. Piezoelectric monitoring demonstrated that Mecp2-null mice slept mainly in short bouts and spent less time in long sleep bouts than their wild-type littermates. Electroencephalographic analysis revealed that Mecp2-null mice had very short, frequent periods of sleep during the dark period, indicating frequent state transitions between wakefulness and non-REM sleep during the dark period. Greater numbers of short sleep bouts during the dark period than during the light period could indicate that Mecp2-null mice spent more time napping during their typically active period. MeCP2 deficiency affected the expression of several neuromodulator genes in hypothalamic regions. Specifically, the expression of hypocretin/orexin receptor (Hcrtr) 1 and 2 genes were significantly lower in several brain regions of Mecp2-null mice, and these mice exhibited attenuated hypocretin/orexin receptor signaling in in vivo microdialysis studies of hypocretin/orexin receptor agonist YNT-185. These results indicate disturbance of the hypocretin/orexin system in Mecp2-null mice, which might cause sleep-wake problems such as increased somnolence in the active phase.