PROJECT SUMMARY The objective of this application is to investigate the role of MeCP2 in the sustained antidepressant action of ketamine. Studies from our laboratory, as well as others, demonstrate that MeCP2 is a strong regulator of synaptic function with bidirectional changes in MeCP2 expression producing reciprocal alterations in neurotransmission. Studies have been examining how intracellular signaling mechanisms produce the acute antidepressant action of ketamine and transition to a sustained effect that may last over a week. This sustained ketamine effects requires the function of Methyl-CpG binding protein 2 (MeCP2), specifically MeCP2 Ser421 phosphorylation. We propose experiments to identify the mechanisms by which acute ketamine administration elicits MeCP2 phosphorylation at Ser421 and how this event is required for the sustained, but not the rapid effects of ketamine. A mechanistic understanding of the sustained effects of ketamine, and the underlying neurobiology, provide possible avenues to prolong antidepressant action and thus reduce the frequency of ketamine administration and potential adverse effects.