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 brain. Mutations in MeCP2 gene account for 80% of RTT cases. MeCP2 is a member of transcriptional repressor family and a linker between DNA methylation, chromatin remodeling and subsequent gene silencing. 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 cortex. Moreover, sensory experience can selectively induce MeCP2 phosphorylation, regulating dendritic patterning, spine morphogenesis, and BDNF transcription. Surprisingly, RTT-like neurological defects can be rescued by delayed restoration of MeCP2 gene as well as overexpression of BDNF. 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 maturation. Direct manipulation of this balance can accelerate or delayed activity-dependent processes and can be used successfully to rescue plasticity defects. Perturbing neuronal activity causes aberrant gene-expression patterns, many of which are linked to misregulated epigenetic systems. We hypothesized that the CP plasticity reflects a particular epigenetic state of translation and repression of specific genes in an activity-dependent manner. Preliminary results showed a dynamic balance between two global epigenetic states, histone acetylation and DNA demethylation, during the critical period for visual cortex. Direct manipulation of them in adulthood was sufficient to re-express cortical plasticity.
Our central hypothesis is that the excitatory/inhibitory balance drives a complex epigenetic state of translation and repression of specific genes 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 molecular techniques to probe systems physiology, we aim to reveal the reciprocal relationship of chromatin status and MeCP2 function to excitatory/inhibitory circuit balance in cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in neurodevelopmental disorders.
