Reduced orexin signaling may cause Rett syndrome sleep problems
Study: Mice with disorder spent less time awake during normally active period
Reduced production of orexin and its receptors is associated with problems in sleep-wake cycles in a mouse model of Rett syndrome (RTT), a study suggests. Orexin is a signaling molecule that regulates sleep and wakefulness in the brain.
While circadian rhythms that regulate the sleep-wake cycle were generally unaffected in Rett mice, they had more fragmented sleep, characterized by frequent interruptions, and spent less time awake during their normally active period, the data showed.
“These results indicate disturbance of the [orexin] system in [Rett] mice, which might cause sleep-wake problems such as increased [drowsiness] in the active phase,” researchers wrote. “Regulation of [orexin] signaling may be a potential strategy for addressing sleep-wake symptoms in RTT.”
The study, “Attenuated orexinergic signaling underlies sleep–wake problems in a Mecp2-null mouse model of Rett syndrome,” was published in Neurobiology of Disease.
MeCP2 mutations linked to sleep problems in Rett syndrome patients
Rett syndrome is a neurodevelopmental disorder mainly caused by mutations in the gene that carries instructions for MeCP2, a protein with a critical role in brain development and function.
MeCP2 is produced at high levels in the brain’s hypothalamus, which is responsible for regulating sleep cycles, also referred to as circadian rhythms.
It’s thought that MeCP2 defects may underlie the sleep problems seen in Rett patients, including excessive daytime sleepiness and difficulty in falling and staying asleep. In fact, certain MeCP2 mutations have been linked with sleep problems in people with Rett.
Still, “the neural mechanisms underlying the sleep-wake problems of RTT patients and animal models have not yet been fully investigated,” wrote the researchers, who examined the effects of an MeCP2 deficiency on circadian rhythms and sleep in a Rett mouse model.
The team first examined the circadian rhythms in Rett and healthy mice between 6 and 8 weeks of age. Results showed Rett mice had less spontaneous activity under dark conditions, when mice are more active, than healthy mice, but their circadian rhythms remained generally intact over light and dark cycles.
The quality of [Rett] sleep may be compromised due to the highly fragmented nature of their sleep pattern.
While mice are primarily nocturnal, they sleep about 12 hours per day, with multiple short naps, called sleep bouts, throughout the day and night. Overall, Rett mice slept for the same amount of time as healthy mice, but the time they spent in shorter sleep bouts was longer than that of healthy mice, which spent more time in more prolonged sleep bouts.
“The quality of [Rett] sleep may be compromised due to the highly fragmented nature of their sleep pattern,” the team wrote.
During periods of light, Rett mice spent significantly less time awake and significantly more time in non-rapid eye movement (NREM) sleep, the phase of sleep that’s considered the quiet or restful phase, than healthy mice. Rett mice also had more transitions from NREM sleep to being awake, and fewer transitions from rapid eye movement (REM) sleep, the stage of sleep when most dreams happen, to wakefulness.
During dark periods, Rett mice had much higher numbers of transitions from wakefulness to NREM and from NREM to awake.
Expression of orexin-encoding gene much lower in brains of Rett mice
The researchers then investigated the expression, or activity, of clock genes, which work together to regulate circadian rhythms, in the hypothalamus. The expression of certain genes (Tac1, Oxt, Pomc, and Hcrtr1) in the hypothalamus that are involved in the sleep-wake cycle was significantly lower in Rett mice than in healthy mice.
This indicated that the “loss of MeCP2 leads directly or indirectly to [expression] dysregulation of these genes in the hypothalamus,” the researchers noted.
Looking more closely, the team focused on orexin, also known as hypocretin, a signaling molecule that regulates sleep and wakefulness. Tests showed the expression of the gene that encodes orexin, as well as that of orexin’s receptors (Hcrtr1 and Hcrtr2), were significantly lower in the brains of Rett mice than in healthy mice.
The prefrontal cortex, a brain region whose activity correlates with wakefulness, contains nerves that release the signaling molecules noradrenaline and dopamine. Studies show differences in the levels of noradrenaline and dopamine in the prefrontal cortex during wakefulness and sleep.
When the researchers treated mice with YNT-185, a molecule that binds to orexin receptors, the levels of noradrenaline and dopamine outside cells rose in healthy mice, but not Rett mice, suggesting that “altered expression of hypocretin/orexin receptors in the [prefrontal cortex] influence [noradrenaline] and [dopamine] dynamics involved in arousal-related behavior,” the researchers noted.
“Our results demonstrate that MeCP2 deficiency affects the sleep-wake system and circadian [characteristics] through changes in hypothalamic gene expressions,” and were the “first to implicate the hypocretin/orexin system in RTT-associated sleep-wake disturbances,” the researchers wrote.
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