Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice

• Published in: Human molecular genetics 2008-05, Vol.17 (10), p.1386-1396
• Main Authors: Jugloff, Denis G.M., Vandamme, Katrina, Logan, Richard, Visanji, Naomi P., Brotchie, Jonathan M., Eubanks, James H.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain - physiopathology; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Maternal Behavior; Methyl-CpG-Binding Protein 2 - analysis; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Molecular and cellular biology; Motor Activity; Neurons - metabolism; Prosencephalon - metabolism; Rett Syndrome - genetics; Rett Syndrome - psychology; Rett Syndrome - therapy; Transgenes
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn026

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 re-introduction 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 1.6 times 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 1 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 re-introduction without inducing deficits relating to MeCP2 over-expression.