Ketamine's rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors

Abstract

Ketamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine's therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, when a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within one hour after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine's effects on animals' behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.

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Article and author information

Author details

  1. Anastasiya Zaytseva

    Molecular, Cellular and Integrative Neurosciences Program, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Evelina Bouckova

    Molecular, Cellular and Integrative Neurosciences Program, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. McKennon J Wiles

    Molecular, Cellular and Integrative Neurosciences Program, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Madison H Wustrau

    Department of Biomedical Sciences, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Isabella G Schmidt

    Molecular, Cellular and Integrative Neurosciences Program, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hadassah Mendez-Vazquez

    Department of Biomedical Sciences, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Latika Khatri

    Department of Cell Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Seonil Kim

    Molecular, Cellular and Integrative Neurosciences Program, Colorado State University, Fort Collins, United States
    For correspondence
    seonil.kim@colostate.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0451-2180

Funding

Colorado State University

  • Anastasiya Zaytseva
  • Evelina Bouckova
  • McKennon J Wiles
  • Madison H Wustrau
  • Isabella G Schmidt
  • Seonil Kim

Boettcher Foundation

  • Seonil Kim

NIH/NCATS Colorado CTSA Grant (UL1 TR002535)

  • Seonil Kim

NIA (R03AG072102)

  • Seonil Kim

BrightFocus Foundation

  • Seonil Kim

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Helen E Scharfman, Nathan Kline Institute and New York University Langone Medical Center, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#3408) of Colorado State University. The protocol was approved by the Committee on the Ethics of Animal Experiments of Colorado State University. All surgery was performed under urethane anesthesia, and every effort was made to minimize suffering.

Version history

  1. Preprint posted: December 5, 2022 (view preprint)
  2. Received: January 7, 2023
  3. Accepted: June 23, 2023
  4. Accepted Manuscript published: June 26, 2023 (version 1)
  5. Version of Record published: July 4, 2023 (version 2)

Copyright

© 2023, Zaytseva et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Anastasiya Zaytseva
  2. Evelina Bouckova
  3. McKennon J Wiles
  4. Madison H Wustrau
  5. Isabella G Schmidt
  6. Hadassah Mendez-Vazquez
  7. Latika Khatri
  8. Seonil Kim
(2023)
Ketamine's rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors
eLife 12:e86022.
https://doi.org/10.7554/eLife.86022

Share this article

https://doi.org/10.7554/eLife.86022

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