Visual Recovery Reflects Cortical MeCP2 Sensitivity in Rett Syndrome.

Abstract

OBJECTIVE: Rett syndrome (RTT) is a devastating neurodevelopmental disorder with developmental regression affecting motor, sensory, and cognitive functions. Sensory disruptions contribute to the complex behavioral and cognitive difficulties and represent an important target for therapeutic interventions. Although genetic medicine-based therapies targeting MeCP2 have successfully restored motor and respiratory functions in animal models, their ability to reverse sensory deficits across levels of the visual pathway remains largely unexplored. METHODS: Using genetically reversible mouse models of MeCP2 deficiency (Mecp2and Mecp2), we applied advanced electrophysiological, anatomical, and behavioral techniques to evaluate visual function, a critical sensory domain impaired in both animal models and RTT patients. RESULTS: In Mecp2mice, initiating MeCP2 expression after postnatal day 35 (P35) reversed progressive cortical dysfunction, prevented thalamic circuit disorganization, and restored visual function, despite some remaining cortical anatomical abnormalities. Even in fully regressed adult Mecp2heterozygous female mice, MeCP2 reactivation was sufficient to reduce the symptoms. INTERPRETATION: These findings highlight the remarkable sensitivity of cortical circuits to MeCP2 expression in both developing and mature brain. Importantly, restoring just 60%-70% of MeCP2 protein levels was sufficient to rescue sensory functions, even after the onset of regression. This underscores the transformative potential of genetic medicine-based therapies in RTT, suggesting that even partial restoration of MeCP2 can meaningfully improve sensory processing and quality of life for patients.