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Targeting metaplasticity mechanisms to promote sustained antidepressant actions

Molecular Psychiatry (2024)Cite this article

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Abstract

The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.

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Fig. 1: Translatable metaplasticity concepts.
Fig. 2: Molecular mechanisms of NMDAR activation-dependent LTP.
Fig. 3: Strategies for targeting metaplastic mechanisms.

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Acknowledgements

We thank Drs. Gustavo Medeiros, John Donello, John Wagner, Fernando Goes, Carlos Zarate, and all members of the Gould laboratory for critical reviews of the manuscript.

Funding

This work was supported by NIH/NIMH R01MH107615 and U.S. Department of Veterans Affairs Merit Awards 1I01BX004062 and 1I01BX006018 to TDG. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Kyle A. Brown & Todd D. Gould

  2. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Todd D. Gould

  3. Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Todd D. Gould

  4. Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA

    Todd D. Gould

Authors
  1. Kyle A. Brown
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  2. Todd D. Gould
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Contributions

KAB and TDG contributed to the conception of the work; KAB wrote the manuscript and TDG critically revised the work.

Corresponding author

Correspondence to Todd D. Gould.

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Competing interests

TDG is listed as an inventor in patents and patent applications related to the pharmacology and use of a ketamine metabolite, (2 R,6 R)-hydroxynorketamine, in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. TDG has assigned his patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. KAB declares no competing interests.

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Brown, K.A., Gould, T.D. Targeting metaplasticity mechanisms to promote sustained antidepressant actions. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02397-1

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  • DOI: https://doi.org/10.1038/s41380-023-02397-1

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