Circuit-based therapy for rett syndrome

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DESCRIPTION (provided by applicant): The first symptoms of neurodevelopmental disorder such as Rett Syndrome appear during early childhood when sensory experience is sculpting neuronal circuits in what it will become the mature brain6. Mutations in MeCP2 gene account for 80% of RTT cases. MeCP2 regulates the expression of a wide range of genes and can coordinate either transcriptional repression or activation depending on the molecular and/or cellular context. This directly implicates an epigenetic pathway in neurodevelopmental disorders. Interestingly, perturbation of MeCP2 expression shifts the dynamic cortical excitatory/inhibitory balance in favor of inhibition in visual cortex18. Moreover, sensory experience can selectively induce MeCP2 phosphorylation, regulating dendritic patterning, spine morphogenesis, and BDNF transcription101. Surprisingly, RTT-like neurological defects can be rescued by delayed restoration of MeCP2 gene31,32,54 as well as overexpression of BDNF9. By establishing the principle of reversibility in mice, these studies suggest that RTT and related disorders are also reversible, even in the late stages of the disease. Our research has revealed that excitatory/inhibitory balance dictates the timing of critical periods of visual cortical maturation23. Direct manipulation of this balance can accelerate or delayed activity-dependent processes and can be used successfully to rescue plasticity defects23-25,46,47 . Perturbing neuronal activity causes aberrant gene-expression patterns, many of which are linked to misregulated epigenetic systems. Our central hypothesis is that the excitatory/inhibitory balance drives MeCP2 regulation of gene translation and repression in an activity-dependent manner during critical periods of heightened cortical plasticity in infancy. Their disruption leads to the complex behavioral phenotype of neurodevelopmental disorders such as Rett Syndrome. Hence, manipulation of Excitatory/Inhibitory balance will be used to rescue cortical impairments in animal models of Rett syndrome. By applying in vivo electrophysiological techniques, we aim to reveal role of MeCP2 function in excitatory/inhibitory circuit balance during cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: In the present grant, we propose to test the hypothesis that an excitatory/inhibitory balance drives a complex epigenetic state of gene translation and repression in an activity-dependent manner during critical periods of heightened cortical plasticity in infancy. Their disruption leads to the complex behavioral phenotype of neurodevelopmental disorders such as Rett Syndrome and ASDs. By applying in vivo electrophysiological techniques, we aim to reveal MeCP2 function in relation to excitatory/inhibitory circuit balance in cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in animal models of Rett Syndrome.