This is a Clinical Investigator Award, providing an opportunity for a medical investigator to develop into an independent researcher. Dysfunction of MeCP2 (methyl CpG binding protein 2) can lead to Rett syndrome and a subset of autism spectrum disorders and other neuropsychiatric disorders, yet mechanisms by which MeCP2 functions in the brain remain unclear. This project will investigate how MeCP2 is phosphorylated with neuronal activity and how these phosphorylation events modify MeCP2's regulation of gene expression and synaptic development in the brain. Serine 421 was previously identified as a site of activity-dependent phosphorylation that regulates activity-induced brain-derived neurotrophic factor (Bdnf) expression, spine maturation, and dendritic arborization. This research will identify and characterize additional sites of activity-dependent phosphorylation of MeCP2 and determine the role of activity-dependent phosphorylation of MeCP2 in Bdnf expression and development of functional inhibitory and excitatory synapses. The proposed experiments will provide a better understanding of mechanisms by which MeCP2 regulates gene expression and synaptic development and how dysfunction of MeCP2 leads to autism spectrum disorders and other neuropsychiatric phenotypes. Improved understanding of the mechanism of MeCP2 function may guide the development of new treatments for these disorders in the future.