Visual Circuit Regression and its Rescue in RTT Mouse Models

Recent groundbreaking studies in mouse models of neurodevelopmental disorder Rett Syndrome (RTT) have demonstrated that some symptoms, such as general health conditions, defects in mobility, coordination and breathing are reversible. These results raise the question of whether other RTT symptoms, such as impairments in sensory modalities, cognition, social interaction and communication can also be rescued. These features of human behavioral repertoire are all acquired in an experience-dependent manner during well-defined critical periods of plasticity in early postnatal life. As adulthood is reached, neuronal circuits consolidate and plasticity diminishes. Using the visual system model for regression, the Fagiolini laboratory will address these important questions and test the hypothesis that reversal of sensory circuit defects in Mecp2 KO mice requires the correction of such E/I circuit imbalance. In the present R01, Fagiolini will test whether recovery can occur in sensory systems by either globally re-expressing Mecp2 or by manipulating E/I balance selectively in cortex. . In particular, during the next five years we will test for reversal of sensory system circuitopathies with Mecp2 re-expression We will test whether and when disruption of the visual thalamic and cortical circuitry is reversible by desilencing Mecp2 using Mecp2lox-stop/y Cre-ER (Stop/y,CreER) mice. Visual circuit function will be assessed by behavioral assays, in vivo and in vitro recordings and anatomical analysis of LGN and V1. To test the effects of PV circuits in regression and recovery, we will also examine whether re-expression of Mecp2 in PV circuits or acute reduction of cortical PV-cell activity can reverse or prevent sensory system regression in Mecp2 deficient mice.