Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors
Anastasiya Zaytseva, Evelina Bouckova, McKennon J. Wiles, Madison H. Wustrau, Isabella G. Schmidt, Hadassah Mendez-Vazquez, L. Khatri, Seonil Kim
bioRxiv January 16, 2023 preprint DOI: 10.7554/elife.86022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study combining cultured neurons and in vivo mouse experiments |
|---|---|
| Population | Cultured mouse hippocampal neurons and mice of both sexes |
| Interventions | Ketamine CP-AMPAR antagonist |
| Dose | sub-anesthetic dose; low dose |
| Duration | One hour of ketamine treatment in cultured neurons; within one hour after treatment in mice |
| Measures | open field test, tail suspension test |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine at a low dose appears to reduce calcineurin activity in the hippocampus, which increases GluA1 phosphorylation and expression of calcium-permeable, GluA2-lacking AMPA receptors, enhancing synaptic strength. This mechanism is proposed to underlie ketamine's rapid reduction of anxiety- and depression-like behavior in mice, since blocking CP-AMPARs abolished the behavioral effects. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 26
- Brain region-specific action of ketamine as a rapid antidepressant. Science August 9, 2024
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- Ketamine Reverses Chronic Stress‐Induced Behavioral Changes via the Expression of Ca 2+ ‐Permeable AMPA Receptors in Mice The FASEB Journal August 26, 2025
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
- Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker International Journal of Molecular Sciences August 7, 2025
and 21 more in the library
Cites 40
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
and 35 more in the library