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

Abstract

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.