Elsevier

Neuroscience

Volume 146, Issue 3, 25 May 2007, Pages 907-921
Neuroscience

Behavioural neuroscience
Behavioral and anatomical abnormalities in Mecp2 mutant mice: A model for Rett syndrome

https://doi.org/10.1016/j.neuroscience.2007.02.009Get rights and content

Abstract

Over 90% of Rett syndrome (RTT) cases have a mutation in the X-linked gene encoding methyl CpG binding-protein 2 (MeCP2). A mouse model that reprises clinical manifestations of the disease would be valuable for examining disease mechanisms. Here, we characterize physical and behavioral measures, as well as brain region volumes in young adult mice that have mutations in mouse methyl CpG binding-protein 2 gene (Mecp2) to serve as a baseline for other studies. Hemizygous males, which produce no functional protein, exhibit hypoactivity and abnormalities in locomotion, stereotypies, and anxiety reminiscent of the clinical condition. The mutant males also exhibit cognitive deficits in fear conditioning and object recognition relative to wildtypes. Volumetric analyses of male brains revealed a 25% reduction in whole brain volume in mutants relative to wildtypes; regional differences were also apparent. Mutants had decreased volumes in three specific brain regions: the amygdala (39%), hippocampus (21%), and striatum (29%). Heterozygous females, which produce varying amounts of functional protein, displayed a less severe behavioral phenotype. The mutant females exhibit abnormalities in locomotion, anxiety measures, and cognitive deficits in object recognition in an open field. This study provides the first evidence that the abnormal motor and cognitive behavioral phenotype in Mecp2 mice is consistent with specific volume reductions in brain regions associated with these behaviors, and shows how these data parallel the human condition. The Mecp2 mutant mice provide a very good model in which to examine molecular and behavioral mechanisms, as well as potential therapeutic interventions in RTT.

Section snippets

Subjects

Mecp21lox mice were generated as described previously (Chen et al., 2001). Two female founder mice heterozygous for the Mecp21lox null allele were obtained from Dr. R. Jaenisch (Massachusetts Institute of Technology, Cambridge, MA, USA) and used to establish a colony of Mecp21lox animals in the Department of Biological Sciences, Wellesley College. These heterozygous females of mixed genetic background (primarily BALB/C with some 129 and C57BL/6) were mated to wildtype C57BL/6J males; the

Males

Mnull mice appeared normal at birth and relatively normal when very young but could be identified occasionally by an altered gait as early as 4 weeks of age and by a significantly reduced body weight by 5 weeks of age. The body weight of Mnulls (n=21) was about half that of Mwts (n=19) (13.4±0.82 and 21.0±1.00 g respectively) [t(38)=46.9, P<0.001]. In all males, body tremors and shaking paws were noted by 5 weeks of age, and piloerection and periods of labored breathing as early as 6 weeks.

Motor deficits are associated with reductions in striatal volume

We have characterized mice with a deletion of Mecp2. Mnulls, with a mutated copy of the Mecp2 gene on their single X chromosome and no functional Mecp2 protein (Chen et al., 2001), exhibit severe motor deficits compared with wildtype males based on observations of stereotypies, abnormalities in gait and grip strength, reduced motor coordination, reduced dark cycle locomotor activity, and severely impaired swim performance. Many of these motoric abnormalities are observable by 5 weeks of age.

Conclusions

The Mecp2 mutant mice described, both here and in other studies, exhibit a phenotype that is less severe than RTT. For example, Mnull mice survive to early adulthood, and Fheteros survive to middle-age, in contrast to human RTT reports in which males only survive a year or two past birth and females survive to early adulthood (Schneider and Glaze, 2002). These differences in the effects of Mecp2 deletions in mice versus humans could result from differences in MeCP2 function in the two species,

Acknowledgments

We thank Dr. Rudolf Jaenisch for providing the founder mice for our colony, Dr. Mark Baxter for discussing these data and reading the manuscript, and Kristen Washington for setting up the automated contextual fear conditioning equipment. We also thank Olive Mwerziwa, Shoshana Maxwell, Mimi Gay-Antaki and Kathryn Swann for support with some of the experiments, and Pat Carey and Ginny Quinan for excellent animal care. Financial support for this project was provided from the following sources:

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