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Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus

Anastasiya Zaytseva, Evelina Bouckova, McKennon J. Wiles, Madison H. Wustrau, Isabella G. Schmidt, Hadassah Mendez-Vazquez, Latika Khatri, View ORCID ProfileSeonil Kim
doi: https://doi.org/10.1101/2022.12.05.519102
Anastasiya Zaytseva
1Molecular, Cellular and Integrative Neurosciences Program,
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Evelina Bouckova
1Molecular, Cellular and Integrative Neurosciences Program,
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McKennon J. Wiles
1Molecular, Cellular and Integrative Neurosciences Program,
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Madison H. Wustrau
2Department of Biomedical Sciences, Colorado State University, Fort Collin, CO 80523.
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Isabella G. Schmidt
1Molecular, Cellular and Integrative Neurosciences Program,
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Hadassah Mendez-Vazquez
2Department of Biomedical Sciences, Colorado State University, Fort Collin, CO 80523.
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Latika Khatri
3Department of Cell Biology, New York University Grossman School of Medicine, New York, New York 10016.
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Seonil Kim
1Molecular, Cellular and Integrative Neurosciences Program,
2Department of Biomedical Sciences, Colorado State University, Fort Collin, CO 80523.
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  • ORCID record for Seonil Kim
  • For correspondence: seonil.kim@colostate.edu
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Abstract

Ketamine is shown to enhance excitatory synaptic drive in the hippocampus, 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 inhibits 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 for one hour in cultured mouse hippocampal neurons significantly reduces calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately induces the expression of Ca2+- Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). Such ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and synaptic plasticity in cultured hippocampal neurons. 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’ behavior. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity in the hippocampus, which in turn enhances synaptic strength to induce rapid antidepressant actions.

Competing Interest Statement

The authors have declared no competing interest.

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Posted December 05, 2022.
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Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus
Anastasiya Zaytseva, Evelina Bouckova, McKennon J. Wiles, Madison H. Wustrau, Isabella G. Schmidt, Hadassah Mendez-Vazquez, Latika Khatri, Seonil Kim
bioRxiv 2022.12.05.519102; doi: https://doi.org/10.1101/2022.12.05.519102
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Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus
Anastasiya Zaytseva, Evelina Bouckova, McKennon J. Wiles, Madison H. Wustrau, Isabella G. Schmidt, Hadassah Mendez-Vazquez, Latika Khatri, Seonil Kim
bioRxiv 2022.12.05.519102; doi: https://doi.org/10.1101/2022.12.05.519102

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