Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome

Abstract

Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder with electroencephalographic (EEG) abnormalities and sleep disturbances. It results from lack of the functional maternal allele of UBE3A, which encodes a ubiquitin-protein ligase. Different mechanisms of UBE3A inactivation correlate with clinical phenotypes of varying severity; the majority of cases of AS are due to a de novo maternal deletion of the 15q11-q13 region.

Methods: Ube3a maternal-deficient mice (Ube3a m-/p+) were generated in a C57Bl/6J background. This study compares cortical EEG and architecture of the sleep-waking cycle in adult Ube3a m-/p+ mice compared with those of age-matched WT (m+/p+) mice, under baseline conditions or after 4-h sleep deprivation (SD).

Results: Ube3a m-/p+ mice exhibited: reduced slow-wave sleep (SWS) amount with increase waking (W) at the dark/light transitions; increased SWS and W episode numbers; and deterioration of paradoxical sleep (PS) over 24 h [amount: -44%; episode duration: -46%; episode number: -40%; theta peak frequency (TPF) acceleration: 7.6 Hz vs. 7.0 Hz in WT mice]. Characteristic paroxysmal EEG discharges are observed during W and SWS associated with synchronous muscle bursting activity during hypoactive W. During the recovery period following SD, Ube3a m-/p+ mice exhibited no rebound either in slow-wave activity (+89% in WT) or in delta-power spectra but a slight rebound in PS amount (+20%).

Conclusions: These data validate the mouse model produced by null mutation of the maternal Ube3a gene and provide useful results to investigate and better understand the molecular basis of sleep disturbances in AS patients.