Ketamine Reverses Chronic Stress‐Induced Behavioral Changes via the Expression of Ca 2+ ‐Permeable AMPA Receptors in Mice
Joshua C. Flowers, Paige E. Vetter, McKennon J. Wiles, Seung Hyun Roh, Ellison R. Black, Evelina Bouckova, Madison H. Wustrau, Rahmi Lee, Sang-Hun Lee, Seonil Kim
The FASEB Journal August 26, 2025 DOI: 10.1096/fj.202501763r (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Female and male mice |
| Intervention | Ketamine |
| Dose | low-dose |
| Topics | Ketamine Esketamine |
| Keywords | Ampa receptor Hippocampus Glutamatergic Hippocampal formation Nmda receptor Glutamate receptor Antidepressant Behavioural despair test Chronic stress Social defeat Pharmacology |
| Citations | 7 |
| Key findings | Low-dose ketamine reverses chronic stress-induced social, cognitive, and depression-like behaviors through CP-AMPAR expression in the hippocampus. |
Abstract
ABSTRACT Chronic stress affects brain functions, leading to the development of mental disorders like anxiety and depression, as well as cognitive decline and social dysfunction. Among many biological changes in chronically stressed brains, disruptions in AMPA Receptor (AMPAR)‐mediated synaptic transmission in the hippocampus are associated with stress responses. We have revealed that low‐dose ketamine rapidly induces the expression of GluA1‐containing, GluA2‐lacking Ca 2+ ‐Permeable AMPARs (CP‐AMPARs), which enhances glutamatergic synaptic strength in hippocampal neurons. Additionally, subanesthetic low‐dose ketamine decreases anxiety‐ and depression‐like behaviors in naïve animals. In addition to reducing depression, some research indicates that ketamine may have protective effects against chronic stress in both humans and animals. However, the role of CP‐AMPARs in the actions of ketamine's antistress effects is largely unknown. We use whole‐cell patch‐clamp recordings from CA1 pyramidal neurons in female and male hippocampal slices and multiple behavioral assays, including reciprocal social interaction, contextual fear conditioning, and tail suspension test. We demonstrate that low‐dose ketamine treatment reverses chronic restraint stress (CRS)‐induced social dysfunction, a loss of hippocampus‐dependent fear learning and memory, and depression‐like behavior in both female and male mice. Furthermore, we show that the ketamine‐induced antistress effects on these behaviors are dependent on CP‐AMPAR expression. Our findings suggest that subanesthetic low‐dose ketamine rapidly triggers the expression of CP‐AMPARs in the hippocampus, which induces antidepressant and antistress effects.
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 4
- Structural Neurotoxic and Neuroprotective Effects of Ketamine and Esketamine in Preclinical and Human Studies: A Systematic Review Research Square May 27, 2026
- Age-related moderation of adjunctive psychotherapy and early life stress effects on depression symptom reductions following ketamine treatment: Initial insights from a large, naturalistic sample. Journal of Affective Disorders February 4, 2026
- Investigation of Potential Therapeutic Effects of New Rapid-Acting Antidepressant Drugs (RAADs) Using Stress-Based Models of Depression Biomolecules August 24, 2026
- The epigenetic mechanisms of ketamine in the treatment of depression: a systematic review. Epigenomics November 7, 2025
Cites 34
- 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
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
- Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. American Journal of Psychiatry March 29, 2019
and 29 more in the library