“Metaplasticity” Discovery Points to Ketamine’s Long-Term Antidepressant Effects

Relaxed Happy Psychedelic

A new discovery enables researchers to target the neural pathway responsible for extending ketamine’s antidepressant effects without the need for the drug itself.

Building on recent research confirming how ketamine induces rapid antidepressant action, Professor of Pharmacology Lisa Monteggia and her collaborators show how the molecular mechanism of the gene MeCP2 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 research indicates that, in cooperation with ketamine’s initial target, the gene is important for long-term antidepressant action, 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. This work also shows that the long-term effects of ketamine involve synaptic adaptability, or plasticity—not simply structural changes. 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.

Why It Matters

“We think we have the pathway in the brain to engage these long-term effects,” said Monteggia, also director of the Vanderbilt Brain Institute. “To have an impact on treatment or clinical drug development, you must know the processes in the brain that are involved. This is the first research that gives us an explanation for how ketamine produces long-term effects involving synaptic plasticity in the brain and why ketamine has cumulative antidepressant effects—a huge step forward.”

This discovery will allow researchers to target the neural pathway that prolongs ketamine’s antidepressant effects without the drug itself. While ketamine has significant promise, it also carries abuse liabilities, as the drug can trigger psychomedical effects. At low doses the drug is not harmful, but no one knows the outcome of sustained use of ketamine to date. This discovery may be a way to circumvent the unintended and still unknown negative effects of ketamine exposure.

What’s Next

With the knowledge that MeCP2 can regulate gene expression, researchers are now looking to understand the neural pathway of the gene more fully, and to find commonalities with common antidepressants to extend their effects.

 Reference: “Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation” by Ji-Woon Kim, Anita E. Autry, Elisa S. Na, Megumi Adachi, Carl Björkholm, Ege T. Kavalali and Lisa M. Monteggia, 28 Junr 2021, Nature Neuroscience.
DOI: 10.1038/s41593-021-00868-8

Collaborators on this research include Ege Kavalali, professor of pharmacology and William Stokes Chair in Experimental Therapeutics, and Vanderbilt postdoctoral researcher Ji-Woon Kim, as well as Anita Autry of Albert Einstein College of Medicine, Elisa Na of Texas Woman’s University, Megumi Adachi of Astellas Pharma, and Carl Bjorkholm of University of Texas Southwestern Medical Center.

Funding: This work was supported by National Institutes of Health grants MH070727, MH081060 and MH066198, the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education grant 2016R1A6A3A03008533, and the Swedish Pharmaceutical Society and the Swedish Society for Medical Research.

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