Building on recent research confirming how ketamine induces rapid antidepressant action, Professor of Pharmacology Lisa Monteggia, PhD, at Vanderbilt University, and her collaborators, have now shown how the molecular mechanism of the gene MeCP2 (coding for methyl CpG binding protein 2) and associated synaptic adaptability are critical to the long-term antidepressant effects of ketamine. While MeCP2 has been shown to be important for typical antidepressants, this new research indicates that, in cooperation with ketamine’s initial target, the gene is important for long-term antidepressant action, Dr. Monteggia said. The researchers discovered that MeCP2 influences ketamine’s behavioral effect as well as potentiation—the strengthening of synapses—improving its antidepressant effects over time. The new work also shows that the long-term effects of ketamine involve synaptic adaptability, or plasticity—not simply structural changes. Dr. Monteggia and her team went on to show that repeated exposure to ketamine further strengthened synaptic plasticity—eliciting more plasticity of plasticity—which the team termed “metaplasticity.” This may explain why repeated doses of ketamine produce a cumulative and prolonged effect.