Research reportEnvironmental enrichment alters locomotor behaviour and ventricular volume in Mecp21lox mice
Introduction
Rett syndrome (RTT) is an autism spectrum developmental disorder associated with mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). These mutations lead to severe behavioural and neuropathological deficits [8], [10]. We have shown previously that deficits in the Mecp21lox mouse model of RTT [4] are parallel to those observed in human RTT [20]. Some of the behavioural and neuroanatomical deficits can be attenuated by manipulating the epigenetic environment; for example, by supplementing the diet with choline [16], [24]. In this study, we examined whether exposing post-weaning (juvenile) mice to environmental enrichment (EE) provides similar beneficial effects in Mecp21lox mice.
In normal rodents EE can lead to positive, long-term effects on neuroanatomy and behaviour, including increases in neurogenesis, dendritic branching, synaptogenesis and spine creation, neurotrophin expression, and improved performance on tests of spatial, motor and associative memory [11], [15], [22], [23]. These positive effects are evident even when exposure to EE is brief and begins late in adulthood (10–20 months in mice) [13], [18], suggesting that intervention and brain plasticity can occur well in adulthood, long after most neuronal development has occurred. EE also can alter the onset and prevalence of neurodegenerative diseases. For example, in mouse models, EE slows the onset of motor decline in Huntington's disease [11], improves spatial learning performance [2], [12] and reduces amyloid depositions [5] in Alzheimer's disease, reduces dopaminergic cell loss in Parkinson's disease [6], and very recently, has been shown to ameliorate motor coordination deficits in a heterozygous mouse model of RTT [14]. Human Alzheimer's patients also show increased cognitive function following cognitive stimulation [19], suggesting EE can be an effective therapy in humans.
Given these examples, we postulated that EE could be a potential treatment for RTT. We report here that EE attenuates specific behavioural deficits in Mecp21lox mice, and reduces ventricle volume in both C57/BL6 and Mecp21lox mice.
Section snippets
Animals and environmental enrichment
All experiments were conducted on male null (−/0) Mecp21lox mice, back-crossed for over 10 generations, and their C57/BL6 (+/0) littermates, with procedures approved by the Wellesley College Institutional Animal Care and Use Committee. Mecp21lox mice were generated as described previously [4]. Female heterozygous founder mice (a gift from Dr. R. Jaenisch) were bred with +/0 males to establish and maintain a colony of Mecp21lox mutants. At weaning (postnatal day [PD] 21), −/0 and +/0 mice were
Environmental enrichment attenuates locomotor activity deficits in −/0 mice
Consistent with our previous data, −/0 mice displayed reduced locomotor activity. NE +/0 mice had greater locomotor activity than NE −/0 mice [F(1, 74) = 21.98, p ≪ 0.001; Fig. 1A]. A treatment effect of EE was also revealed [F(1, 74) = 4.12, p = 0.05], with post hoc analysis on the genotype × EE interaction showing that EE improved locomotor activity of −/0 mice (p < 0.05), but not of +/0 mice.
Environmental enrichment does not affect motor coordination performance
The accelerating rotor-rod tests the mouse's balance and coordination. Compared to +/0 mice, −/0 mice had lower
Discussion
Over 90% of cases of RTT are associated with mutations of the X-chromosome linked gene coding for the transcriptional repressor molecule MeCP2 [1], [3]. Behavioural and anatomical deficits have been characterized and included motor and cognitive deficits and reduced whole brain and striatal volumes [9], [21]. These deficits are also seen in −/0 mice [4], [16], [20], [24], that have a deletion of exon 3 of the Mecp2 gene, resulting in a loss of functional MeCP2 protein [4]. We included only −/0
Acknowledgements
This research was funded by the following sources: National Science Foundation, International Rett Syndrome Association (IRSA), Merck-AAAS, Howard Hughes Medical Institute, and Wellesley College Faculty Award. We would also like to thank L. Baldwin for assistance with statistical analyses, U. Berger for genotyping and P. Carey and G. Quinan for animal care.
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