Rett syndrome (RTT), a devastating pediatric disorder, is caused by de-novo mutations in the MECP2 gene. The key feature and basic requirement for Rett syndrome diagnoses is the loss of acquired skills or regression, occurring between the ages of 1.5 and 4-5 years after an apparent initial normal development. Once regression is complete, it was thought that the symptoms were irreversible in adults. Mice deficient in Mecp2 recapitulate many of the symptomatic features of RTT. Recent groundbreaking studies in these mouse models have demonstrated that some symptoms of the disorder, 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. To begin to delineate the possibilities and limitations of RTT reversibility, it is necessary to have a better understanding of the underlying mechanism of regression. Neuronal circuits in Mecp2 deficient mice are disrupted and exhibit aberrant excitatory-inhibitory (E/I) balance well before the onset of symptomatic regression. Whether these abnormalities lead to regression is still not clear. Using a sensory circuit model for regression established by the Chen and Fagiolini laboratories, we 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. The Chen and Fagiolini Laboratories have independently demonstrated that after initial normal development in Mecp2 KO mice a progressive disruption of thalamic and cortical visual circuits occurs both at the anatomical and functional level. The time course of this regression tracks very closely with onset of RTT phenotypic symptoms. Notably a specific inhibitory circuit, involving the fast-spiking parvalbumin-positive cells (PV), is abnormally connected very early in development prior to the onset of visual function abnormalities and may contribute to silencing of cortical circuits. These results suggest that early abnormalities in the PV inhibitory circuit could drive gradual regression of visual function. PV cells not only regulate critical developmental periods in multiple cortical systems, but also constantly and dynamically adjust brain activity. Here, we will test whether recovery can occur in sensory systems by either globally re-expressing Mecp2 or by manipulating E/I balance selectively in cortex. Taken together, the results of our proposal will provide insight into underlying neuronal circuit dysfunction and regression and, importantly, into novel approaches for treatment.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
