Research report
Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp21lox mice

https://doi.org/10.1016/j.bbr.2008.07.008Get rights and content

Abstract

Rett syndrome (RTT) is an autistic spectrum developmental disorder associated with mutations in the X-linked Mecp2 gene, and severe behavioural and neuropathological deficits. In a mouse model of RTT (Mecp21lox), we examined whether environmental enrichment (EE) alters behavioural performance and regional brain volume. At weaning, Mecp21lox and control mice were assigned to enriched or standard housing. From postnatal day 29 to 43, mice were subjected to behavioural tasks measuring motor and cognitive performance. At postnatal day 44, volumes of whole brain, cerebellum, ventricles, and motor cortex were measured using magnetic resonance imaging. EE provided subtle improvements to locomotor activity and contextual fear conditioning in Mecp21lox mice. Additionally, EE reduced ventricular volumes, which correlated with improved locomotor activity, suggesting that neuroanatomical changes contribute to improved behaviour. Our results suggest that post-weaning EE may provide a non-invasive palliative treatment for RTT.

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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