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Affective dysfunction in a mouse model of Rett syndrome: therapeutic effects of environmental stimulation and physical activity

Kondo, Mari A., Gray, Laura J., Pelka, Gregory J., Leang, Sook-Kwan, Christodoulou, John, Tam, Patrick P. L. and Hannan, Anthony J. 2016, Affective dysfunction in a mouse model of Rett syndrome: therapeutic effects of environmental stimulation and physical activity, Developmental neurobiology, vol. 76, no. 2, pp. 209-224, doi: 10.1002/dneu.22308.

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Title Affective dysfunction in a mouse model of Rett syndrome: therapeutic effects of environmental stimulation and physical activity
Author(s) Kondo, Mari A.
Gray, Laura J.
Pelka, Gregory J.
Leang, Sook-Kwan
Christodoulou, John
Tam, Patrick P. L.
Hannan, Anthony J.
Journal name Developmental neurobiology
Volume number 76
Issue number 2
Start page 209
End page 224
Total pages 16
Publisher Wiley
Place of publication London, Eng.
Publication date 2016-02
ISSN 1932-8451
1932-846X
Summary 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 Mecp2tm1Tam 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.
Language eng
DOI 10.1002/dneu.22308
Field of Research 1109 Neurosciences
1116 Medical Physiology
1702 Cognitive Science
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, Wiley
Persistent URL http://hdl.handle.net/10536/DRO/DU:30082055

Document type: Journal Article
Collection: School of Medicine
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Created: Wed, 09 Mar 2016, 14:44:08 EST

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