title: Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity.
abstract: Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behavior of the Mecp2(+/-) mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating hypothalamic-pituitary-adrenal axis dysregulation. EE of Mecp2(+/-) mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, 3010, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Mari A
authors.initials: MA
authors.lastname: Kondo
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gray
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales, 2145, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pelka
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Sook-Kwan
authors.initials: SK
authors.lastname: Leang
authors.affiliation: Western Sydney Genetics Program, Children's Hospital at Westmead, Westmead, New South Wales, 2145, Australia.|Disciplines of Paediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales, 2145, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, 3010, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003345:Corticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology*; D010641:Phenotype; D010805:Physical Conditioning, Animal; D010913:Pituitary-Adrenal System / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000628:therapy
chemical_list: D003345:Corticosterone
keywords: brain-derived neurotrophic factor; environmental enrichment; exercise; methyl-CpG-binding protein 2; neurodevelopmental disorder