Angelman syndrome and melatonin: What can they teach us about sleep regulation

Abstract

In 1965, Dr Harry Angelman reported a neurodevelopmental disorder affecting three unrelated children who had similar symptoms: brachycephaly, mental retardation, ataxia, seizures, protruding tongues, and remarkable paroxysms of laughter. Over the past 50 years, the disorder became Angelman's namesake and symptomology was expanded to include hyper-activity, stereotypies, and severe sleep disturbances. The sleep disorders in many Angelman syndrome (AS) patients are broadly characterized by difficulty falling and staying asleep at night. Some of these patients sleep less than 4 hours a night and, in most cases, do not make up this lost sleep during the day-leading to the speculation that AS patients may "need" less sleep. Most AS patients also have severely reduced levels of melatonin, a hormone produced by the pineal gland exclusively at night. This nightly pattern of melatonin production is thought to help synchronize internal circadian rhythms and promote nighttime sleep in humans and other diurnal species. It has been proposed that reduced melatonin levels contribute to the sleep problems in AS patients. Indeed, emerging evidence suggests melatonin replacement therapy can improve sleep in many AS patients. However, AS mice show sleep problems that are arguably similar to those in humans despite being on genetic backgrounds that do not make melatonin. This suggests the hypothesis that the change in nighttime melatonin may be a secondary factor rather than the root cause of the sleeping disorder. The goals of this review article are to revisit the sleep and melatonin findings in both AS patients and animal models of AS and discuss what AS may tell us about the underlying mechanisms of, and interplay between, melatonin and sleep.

Keywords: Ube3a; Angelman syndrome; melatonin; sleep.

Figure 1:. Two-process model depictions of how sleep might be altered in Angelman syndrome.

In these simplified models, Process C (C; circadian clock) provides drive for wakefulness and Process S (S; sleep homoeostasis) builds pressure to sleep. At any time of day, whichever drive is higher dictates sleep-state (light blue shading = wake, yellow shading = sleep). Under normal conditions (A) Wake drive (blue curve), driven by Process C, dominates during the day keeping the subject awake; sleep-drive (yellow curve) is building simultaneously, just at a slower rate. At night, melatonin (M) is produced, the circadian clock stops providing wake drive, and the accumulation of sleep drive causes the subject to fall asleep; sleep causes sleep drive to dissipate. In Angelman syndrome, sleep disorders could be caused by changes to circadian control (B), sleep homeostatic control (C), or both (not shown). Data suggest that AS patients may have a long circadian period and/or a delayed and suppressed nighttime melatonin rhythm, as depicted by Process C and melatonin curves (B). If Process S is normal, then Process C may compete against it during the night, delaying and suppressing both sleep and melatonin production. Alternatively, data also suggest the sleep homeostatic process is blunted (C) and may accumulate less efficiently. In this scenario, overall sleep drive is reduced, leading to decreases in sleep. In either B or C, not sleeping may also lead to an increase of light exposure at night (i.e. turning on lights or TV) that may further contribute to circadian-like deficits in sleep regulation (indicated by the arrows in C).

Figure 2:. Sleep patterns are disrupted in AS model mice.

A. Total sleep or wake in wild type (Ube3a^m+/p+) or AS (Ube3a^m-/p+) mice recorded over an uninterrupted 24 h period in 12 h light/dark cycle. Data are shown as percentage of each 2 h block spent asleep or awake within each mouse, averaged within genotypes (mean+/−SEM; n=6 wild type or 8 AS mice). Note the difference in sleep/wake amounts between genotypes across the night (indicated by the gray shading). B. AS model mice exhibit reduced nighttime sleep-pressure accumulation. Left - NREM sleep intensity, as measured by delta power, is significantly reduced in Ube3a^m-/p+ mice during the latter portion of the night. * = p<0.05 between genotypes, n= 6–8 mice. Right - The increase in the wave-incidence (I2– 6) across the night (wake period) is abolished in Ube3a^m-/p+ mice. Representative EEG recordings (black and red) are shown above bandpass-filtered versions (gray and dark red) of the same EEG recording. The incidence of peaks in the upper 30% by amplitude (blue line) in the filtered signal were counted in epochs scored as waking are indicated by arrowheads. I2– 6 has been previously validated as a measure of sleep-pressure accumulation in awake mice. I2– 6 significantly increased across the active period in wild type (* = p<0.05) but not Ube3a^m-/p+mice. All data are replotted from Ehlen et al, 2015.