It is well known that Rett Syndrome, a severe postnatal childhood neurological disorder, is mostly caused by mutations in the MECP2 gene. However, how deficiencies in MeCP2 contribute to the neurological dysfunction of Rett Syndrome is not clear. We aimed to resolve the role of MeCP2 epigenetic regulation in postnatal brain development in an Mecp2-deficient mouse model. We found that, while Mecp2 was not critical for the production of immature neurons in the dentate gyrus (DG) of the hippocampus, the newly generated neurons exhibited pronounced deficits in neuronal maturation, including delayed transition into a more mature stage, altered expression of presynaptic proteins and reduced dendritic spine density. Furthermore, analysis of gene expression profiles of isolated DG granule neurons revealed abnormal expression levels of a number of genes previously shown to be important for synaptogenesis. Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis.