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

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a . Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associa...

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Published in:Frontiers in Behavioral Neuroscience Vol. 16; p. 837523
Main Authors: 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
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media SA 23.03.2022
Frontiers Research Foundation
Frontiers Media S.A
Subjects:
Angelman syndrome
Angelman's syndrome
Animal models
Autism
Brain research
circadian
Circadian rhythm
Circadian rhythms
Dosage
Gene dosage
Gene expression
Genotype & phenotype
Imprinting
Locomotor activity
Neurodevelopment
neurodevelopmental disorders
Neurons
Neuroscience
Neurosciences. Biological psychiatry. Neuropsychiatry
Phenotypes
Physical activity
Proteins
RC321-571
sleep
Sleep deprivation
Sleep disorders
UBE3A (E6AP)
Ubiquitin
ubiquitin ligase
Ubiquitin-protein ligase
UBE3A (E6AP)
sleep
ubiquitin ligase
Angelman syndrome
circadian
imprinting
neurodevelopmental disorders
autism
ISSN:1662-5153, 1662-5153
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Summary:Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a . Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a 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, Ube3a -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 Ube3a -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 Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.
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These authors share first authorship
This article was submitted to Individual and Social Behaviors, a section of the journal Frontiers in Behavioral Neuroscience
Edited by: Emi Hasegawa, University of Tsukuba, Japan
Reviewed by: Li Wang, Children’s National Hospital, United States; Ling Shan, Netherlands Institute for Neuroscience (KNAW), Netherlands
ISSN:1662-5153
1662-5153
DOI:10.3389/fnbeh.2022.837523