PROJECT SUMMARY Over the past ~15 years, we have examined the role of MeCP2 in neurotransmission as a transcriptional factor impacting gene expression. Our data has revealed that MeCP2 is a bona fide regulator of synaptic function with bidirectional changes in MeCP2 resulting in reciprocal alterations in neurotransmission. We have also shown alterations in MeCP2 expression in mice result in several behavioral phenotypes as well as deficits in specific measures of synaptic plasticity further implicating MeCP2 as a key mediator of synaptic processes. A rather surprising finding in the field of depression has been the demonstration that ketamine, an NMDA receptor antagonist, has rapid and long-lasting antidepressant responses in depressed individuals. We are investigating the mechanism of the antidepressant action of ketamine, and found that the sustained antidepressant effects are dependent on MeCP2 Ser421 phosphorylation. In contrast, the rapid antidepressant action of ketamine is not dependent on MeCP2 Ser421 phosphorylation, revealing a distinct mechanism between rapid and sustained effects. The objective of this grant is to explore the novel hypothesis that MeCP2- dependent transcriptional mechanisms underlie the sustained antidepressant effects of ketamine. We will use state of the art behavioral as well as cellular and biochemical approaches to examine our hypothesis. Collectively, these studies will contribute to a better understanding of mechanisms underlying the maintenance of antidepressant effects as well as provide novel insight into MeCP2 regulation as a therapeutic target.