Rett syndrome is a neurological disease of early childhood. It is associated with deleterious mutations of the gene encoding methyI-CpG-binding protein 2 (MECP2) but it remains unclear how MECP2-deficiency results in neuronal disease. The function of MECP2 may be to regulate modifications to histones, the main protein component of chromatin. This, in turn, affects gene expression. Two such modifications, histone acetylation and methylation, will be investigated in this study using three model systems. First, a mouse model will be used to compare the developing cerebral cortex in wildtype mice and mice with certain histone modifications. Primary cortical cells will also be examined to determine if drug-induced changes in histone acetylation affect neuronal growth and survival. Finally, histone methylation will be studied in human postmortem cerebral cortex tissue of subjects diagnosed with Rett syndrome. It is expected that these approaches will provide a clear and comprehensive picture of the developmental regulation of histone modifications in cortical neurons, including potential changes in the MECP2-deficient brain.