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Affective dysfunction in a mouse model of R ett syndrome: Therapeutic effects of environmental stimulation and physical activity
Author(s) -
Kondo Mari A.,
Gray Laura J.,
Pelka Gregory J.,
Leang SookKwan,
Christodoulou John,
Tam Patrick P. L.,
Hannan Anthony J.
Publication year - 2016
Publication title -
developmental neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.716
H-Index - 129
eISSN - 1932-846X
pISSN - 1932-8451
DOI - 10.1002/dneu.22308
Subject(s) - mecp2 , rett syndrome , neurodevelopmental disorder , neuroscience , corticosterone , environmental enrichment , stimulation , hippocampal formation , psychology , biology , medicine , endocrinology , phenotype , autism , psychiatry , gene , genetics , hormone
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 . © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 209–224, 2016