AUTHOR=Shi Shu-qun , Mahoney Carrie E. , Houdek Pavel , Zhao Wenling , Anderson Matthew P. , Zhuo Xinming , Beaudet Arthur , Sumova Alena , Scammell Thomas E. , Johnson Carl Hirschie 

TITLE=Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2022.837523

DOI=10.3389/fnbeh.2022.837523

ISSN=1662-5153

ABSTRACT=<p>Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene <italic>Ube3a</italic>. Comparing newly generated mouse models for <italic>Ube3a</italic> downregulation (models of Angelman syndrome) vs. <italic>Ube3a</italic> upregulation (models for autism), we find reciprocal effects of <italic>Ube3a</italic> gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that <italic>Ube3a</italic> is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, <italic>Ube3a</italic>-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in <italic>Ube3a</italic>-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by <italic>Ube3a</italic> deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced <italic>Ube3a</italic> gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.</p>