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Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linked  MECP2  gene. Although the loss of MeCP2 function affects many neural systems, impairments of catecholaminergic function have been hypothesized to underlie several of the cardinal behavioral deficits of RTT patients and Mecp2-deficient mice. Although recent  Mecp2  reactivation studies indicate that RTT may be a reversible condition, it remains unclear whether specifically preserving Mecp2 function within a specific system will be sufficient to convey beneficial effects. Here, we test whether the selective preservation of Mecp2 within catecholaminergic cells will improve the phenotype of Mecp2-deficient mice. Our results show that this targeted preservation of Mecp2 significantly improves the lifespan, phenotypic severity and cortical epileptiform discharge activity of both male and female Mecp2-deficient mice. Further, we found that the catecholaminergic preservation of Mecp2 also improves the ambulatory rate, rearing activity, motor coordination, anxiety and nest-building performances of Mecp2-deficient mice of each gender. Interestingly, our results also revealed a gender-specific improvement, as specific cortical and hippocampal electroencephalographic abnormalities were significantly improved in male, but not female, rescue mice. Collectively, these results support the role of the catecholaminergic system in the pathogenesis of RTT and provide proof-of-principle that restoring MeCP2 function within this specific system could represent a treatment strategy for RTT.

Selective preservation of MeCP2 in catecholaminergic cells is sufficient to improve the behavioral phenotype of male and female Mecp2-deficient mice