Persistent Disruptions in Prefrontal Connectivity Despite Behavioral Rescue by Environmental Enrichment in a Mouse Model of Rett Syndrome

Rett syndrome, a neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene, is characterized by severe motor, cognitive, and emotional impairments. Some of the deficits may result from changes in cortical connections, especially downstream projections of the prefrontal cortex (PFC), which may also be targets of restoration following rearing conditions such as environmental enrichment that alleviate specific symptoms. Here, using a heterozygous Mecp2^+/− female mouse model closely analogous to human Rett syndrome, we investigated the impact of early environmental enrichment on behavioral deficits and PFC connectivity. Behavioral analyses revealed that enriched housing rescued fine motor deficits and reduced anxiety, with enrichment-housed Mecp2^+/− mice performing comparably to wild-type (WT) controls in rotarod and open field assays. Anatomical mapping of top-down anterior cingulate cortex (ACA) projections demonstrated altered PFC connectivity in Mecp2^+/− mice, with increased axonal density in the somatosensory cortex and decreased density in the motor cortex compared to WT controls. ACA axons revealed shifts in hemispheric distribution, particularly in the medial network regions, with Mecp2^+/− mice exhibiting reduced ipsilateral dominance. These changes were unaffected by enriched housing, suggesting that structural abnormalities in PFC connectivity persist despite behavioral improvements. Enriched housing rescued brain-derived neurotrophic factor (BDNF) levels in the hippocampus but failed to restore BDNF levels in the PFC, consistent with the persistent deficits observed in prefrontal axonal projections. These findings highlight the focal nature of changes induced by reduction of MeCP2 and by exposure to environmental enrichment and suggest that environmental enrichment starting in adolescence can alleviate behavioral deficits in Mecp2^+/− mice without reversing abnormalities in large-scale cortical connectivity.