Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats
Yun-Qiang Wan, Jian-Guo Feng, Mao Li, Maohua Wang, Li Liu, Xueru Liu, Xiao-Xia Duan, Chun-Xiang Zhang, Xiao-Bin Wang
Experimental and Molecular Medicine October 1, 2018 DOI: 10.1038/s12276-018-0164-4 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Rats, including normal rats and rats subjected to chronic unpredictable mild stress (CUMS), plus primary neuron cultures |
| Intervention | Ketamine |
| Measures | Sucrose preference test, forced swimming test |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine increased miR-29b-3p expression in the rat prefrontal cortex, and miR-29b-3p negatively regulates GRM4. Depressive-like CUMS rats showed lower miR-29b-3p and higher GRM4, which ketamine reversed. Overexpressing miR-29b-3p via rAAV relieved depressive behaviors in CUMS rats and lowered GRM4, leading the authors to propose the miR-29b-3p/GRM4 pathway as a critical mediator of ketamine's antidepressant effect and a potential therapeutic target for major depression. |
Abstract
Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine’s antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats’ depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine’s antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder. Changes in the levels of a microRNA molecule that regulates the activity of a specific gene may be responsible for some of the antidepressant effects of the drug ketamine. Ketamine is used as a tranquilizer and anesthetic, especially in veterinary practice, but there is increasing interest in its antidepressant action in humans. Researchers in China and USA led by Xiao-Bin Wang at the Affiliated Hospital of Southwest Medical University in Luzhou, China, found that ketamine dramatically raised the levels of a specific microRNA in the prefrontal cortex region of rats’ brains. This effect was linked to the ability of the microRNA to inhibit a gene and thus decrease the production of a receptor protein in brain cell membranes. The molecular signaling pathway this research has identified could be a target for new antidepressant therapies.
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
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- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- miR-98-5p plays a critical role in depression and antidepressant effect of ketamine Translational Psychiatry September 3, 2021
- Epigenetic mechanisms of rapid-acting antidepressants Translational Psychiatry September 4, 2024
- Novel mechanisms underlying rapid-acting antidepressants: ketamine-like compounds, neurosteroid GABAkines, and psychedelics. Drug Discovery Today June 1, 2025
- Epigenetic landscapes of classical psychedelics and ketamine: molecular mechanisms of long-lasting neuromodulation Molecular Psychiatry July 10, 2026
and 7 more in the library
Cites 7
- Ketamine for chronic pain: risks and benefits British Journal of Clinical Pharmacology February 21, 2013
- Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model Translational Psychiatry February 23, 2016
- Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discovery Today February 6, 2016
- microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus The International Journal of Neuropsychopharmacology September 1, 2013
- Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behavioural Brain Research March 21, 2011
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