Overexpression of the transcriptional regulator MECP2 causes autistic features and abnormal neuronal structure and function in humans and mice. We hypothesize that the severity of cortical dysfunction mediated by MECP2 overexpression depends on the overall maturity of the brain, such that overexpression in an embryonic or early postnatal brain will have harsher consequences than overexpression in a fully matured mouse brain. We also hypothesize that the damage to cortical circuits mediated by MECP2 overexpression are cumulative and become more entrenched with time, so reversal of MECP2 overexpression in the early postnatal period will more fully ameliorate disease phenotypes than reversal in the mature mouse. To test these hypotheses, we will study autistic behaviors and motor cortical circuits in mice that overexpress MECP2 at different stages of development. We will then assess the entrenchedness of disease phenotypes by reversing gene overexpression in 1) a developing postnatal brain and 2) a fully matured mouse brain. The results will help elucidate mechanisms of cortical circuit dysfunction in autism. Moreover, the data have that potential to provide proof of principle of the degree to which MECP2 duplication syndrome and autism are reversible, as well as information essential to the design of therapies and therapeutic regimens for such autistic spectrum disorders.