title: Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact.
abstract: Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3a(m-/p+) mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3a(m-/p+) mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus--the site of the mammalian circadian clock--indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3a(m-/p+) mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3a(m+/p+)) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3a(m-/p+) mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS.
  
  
  CONCLUSIONS
  Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering the Ube3a gene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.
authors.affiliation: Department of Neurobiology and.
authors.forename: J Christopher
authors.identifier: http://orcid.org/0000-0003-3223-9262
authors.initials: JC
authors.lastname: Ehlen
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Kelly A
authors.identifier: http://orcid.org/0000-0001-5282-0666
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Department of Neurobiology and.
authors.forename: Lennisha
authors.initials: L
authors.lastname: Pinckney
authors.affiliation: Department of Neurobiology and.
authors.forename: Cloe L
authors.initials: CL
authors.lastname: Gray
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, and.
authors.forename: Susan
authors.initials: S
authors.lastname: Burette
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.affiliation: Department of Neurobiology and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Evans
authors.affiliation: Department of Neurobiology and.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Brager
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zylka
authors.affiliation: Department of Neurobiology and kpaul@msm.edu bphilpot@med.unc.edu jdebruyne@msm.edu.
authors.forename: Ketema N
authors.identifier: http://orcid.org/0000-0002-7024-8664
authors.initials: KN
authors.lastname: Paul
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 kpaul@msm.edu bphilpot@med.unc.edu jdebruyne@msm.edu.
authors.forename: Benjamin D
authors.identifier: http://orcid.org/0000-0003-2746-9143
authors.initials: BD
authors.lastname: Philpot
authors.affiliation: Department of Pharmacology and Toxicology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, kpaul@msm.edu bphilpot@med.unc.edu jdebruyne@msm.edu.
authors.forename: Jason P
authors.identifier: http://orcid.org/0000-0001-9803-9568
authors.initials: JP
authors.lastname: DeBruyne
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D058256:Brain Waves / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D005260:Female; D006706:Homeostasis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000235:genetics*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Angelman syndrome; EEG; Ube3a; imprinting; sleep; suprachiasmatic nucleus