Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT

Quan Li; Dawn H Loh; Takashi Kudo; Danny Truong; Matthew Derakhshesh; Zoë MacDowell Kaswan; Cristina A Ghiani; Rosemarie Tsoa; Yin Cheng; Yi E Sun; Christopher S Colwell

doi:10.1016/j.nbd.2015.03.009

Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT

Neurobiol Dis. 2015 May:77:155-64. doi: 10.1016/j.nbd.2015.03.009. Epub 2015 Mar 14.

Authors

Affiliations

¹ Laboratory of Circadian and Sleep Medicine, Department of Psychiatry, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles 90095-1759, USA; Department of Psychiatry, University of California, Los Angeles, Box 957332, 635 S. Charles E. Young Dr, Los Angeles, CA 90095-7332, USA; Molecular, Cellular and Integrative Physiology Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Laboratory of Circadian and Sleep Medicine, Department of Psychiatry, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles 90095-1759, USA.
³ Department of Psychiatry, University of California, Los Angeles, Box 957332, 635 S. Charles E. Young Dr, Los Angeles, CA 90095-7332, USA.
⁴ Department of Psychiatry, University of California, Los Angeles, Box 957332, 635 S. Charles E. Young Dr, Los Angeles, CA 90095-7332, USA. Electronic address: ysun@mednet.ucla.edu.
⁵ Laboratory of Circadian and Sleep Medicine, Department of Psychiatry, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles 90095-1759, USA. Electronic address: ccolwell@mednet.ucla.edu.

PMID: 25779967
DOI: 10.1016/j.nbd.2015.03.009

Abstract

Disturbances in the sleep/wake cycle are prevalent in patients with Rett syndrome (RTT). We sought to determine whether the circadian system is disrupted in a RTT model, Mecp2(-/y) mice. We found that MeCP2 mutants showed decreased strength and precision of daily rhythms of activity coupled with extremely fragmented sleep. The central circadian clock (suprachiasmatic nucleus) exhibited significant reduction in the number of neurons expressing vasoactive intestinal peptide (VIP) as well as compromised spontaneous neural activity. The molecular clockwork was disrupted both centrally in the SCN and in peripheral organs, indicating a general disorganization of the circadian system. Disruption of the molecular clockwork was observed in fibroblasts of RTT patients. Finally, MeCP2 mutant mice were vulnerable to circadian disruption as chronic jet lag accelerated mortality. Our finds suggest an integral role of MeCP2 in the circadian timing system and provides a possible mechanistic explanation for the sleep/wake distrubances observed in RTT patients. The work raises the possibility that RTT patients may benefit from a temporally structured environment.

Keywords: Circadian rhythms; MeCP2; Rett syndrome (RTT); Sleep; Suprachiasmatic nucleus (SCN); VIP.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / genetics
Animals
Cells, Cultured
Chronobiology Disorders / etiology*
Chronobiology Disorders / genetics
Disease Models, Animal*
Embryo, Mammalian
Gene Expression Regulation / genetics
In Vitro Techniques
Male
Methyl-CpG-Binding Protein 2 / genetics
Methyl-CpG-Binding Protein 2 / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity / genetics
Mutation / genetics
Patch-Clamp Techniques
Period Circadian Proteins / genetics
Period Circadian Proteins / metabolism
Rett Syndrome / complications*
Rett Syndrome / genetics
Sleep Wake Disorders / etiology

Substances

Mecp2 protein, mouse
Methyl-CpG-Binding Protein 2
Per2 protein, mouse
Period Circadian Proteins