Early Motor Phenotype Detection In A Female Mouse Model Of Rett Syndrome Is Improved By Cross-Fostering

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. Mecp2 mutant mice recapitulate many of the clinical features of RTT, but the majority of behavioral assessments have been conducted in male Mecp2 hemizygous null mice as offspring of heterozygous dams. Given that RTT patients are predominantly female, we conducted a systematic analysis of developmental milestones, sensory abilities, and motor deficits, following the longitudinal decline of function from early postnatal to adult ages in female Mecp2 heterozygotes of the conventional Bird line (Mecp2(tm1.1bird-/+)), as compared to their female wildtype littermate controls. Further, we assessed the impact of postnatalmaternal environment on developmental milestones and behavioral phenotypes. Cross-fostering to CD1 dams accelerated several developmentalmilestones independent of genotype, and induced earlier onset of weight gain in adult female Mecp2(tm1.1bird-/+) mice. Cross-fostering improved the sensitivity of a number of motor behaviors that resulted in observable deficits in Mecp2(tm1.1bird-/+) mice at much earlier (6-7 weeks) ages than were previously reported (6-9 months). Our findings indicate that female Mecp2(tm1.1bird-/+) mice recapitulate many of the motor aspects of RTT syndrome earlier than previously appreciated. In addition, rearing conditions may impact the phenotypic severity and improve the ability to detect genotype differences in female Mecp2 mutant mice.