Human Molecular Genetics Advance Access published online on January 25, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn026
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Targeted Delivery of an Mecp2 Transgene to Forebrain Neurons Improves the Behavior of Female Mecp2-Deficient Mice
1 Division of Genetics and Development, Toronto Western Research Institute, Toronto, Ontario, M5T 2S8, Canada 2 Division of Brain Imaging and Behavior, Toronto Western Research Institute, Toronto, Ontario, M5T 2S8, Canada 3 University of Toronto Epilepsy Research Program, Toronto, Ontario, M5S 1A8, Canada 4 Department of Surgery (Neurosurgery), University of Toronto, Toronto, Ontario, M5S 1A8, Canada
* To whom correspondence should be addressed: Tel: (416) 603-5800 ext. 2933; Fax: (416) 603-5745; E-mail: jeubanks{at}uhnres.utoronto.ca
Received October 29, 2007; Revised January 18, 2008; Accepted January 18, 2008
Rett syndrome is an X-linked neurological condition affecting almost exclusively girls that is caused by mutations of the MECP2 gene. Recent studies have shown that transgenic delivery of MeCP2 function to Mecp2-deficient male mice can improve their Rett-like behavior. However, as the brain of a Rett girl contains a mosaic of MeCP2 expressing and non-expressing neurons, and the over-expression of MeCP2 in neurons can induce a severe progressive neurological phenotype, testing whether functional rescue can be achieved by gene reintroduction strategies in a female model of Rett syndrome is warranted. To address this, we generated transgenic mice expressing an epitope-tagged Mecp2 transgene in forebrain neurons. These mice over-express MeCP2 protein at about 1.6X normal levels in cortex, and develop impaired motor behavior by 9-12 months of age. To test whether forebrain targeted MeCP2 restoration would improve behavior in female Mecp2–/+ mice, we crossed these transgenics with Mecp2–/+ mice, and examined the behavioral properties of the female rescue mice for one year. These assessments revealed that the diminished rearing activity, impaired mobility, and the diminished locomotive activity of female Mecp2–/+ mice were restored to wild-type levels in the rescue mice. These results show that improvement of Rett-like behavior can be achieved in Mecp2–/+ females by targeted gene reintroduction without inducing deficits relating to MeCP2 over-expression.