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Cited by 60Treatment of Major DepressionMicroRNA in disease regulationNeuroscience and Neuropharmacology Research

Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats

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Wan, Yun-Qiang, Feng, Jian-Guo, Li, Mao, Wang, Mao-Zhou, Liu, Li, Liu, Xueru, Duan, Xiao-Xia, Zhang, Chun-Xiang +1 more·2018·Experimental & Molecular Medicine
DOI 10.1038/s12276-018-0164-4PMC PMC6204429
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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 Ca 2+ 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.

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  • miR-335, miR-1202, miR-29b-3p, and miR-134-5p may regulate depression through inhibiting GRM4 expression, affecting Ca2+ influx into prefrontal cortex neurons and extracellular glutamate concentration.

    “MiR-335, miR-1202, miR-29b-3p, and miR-134-5p may regulate depression through inhibiting the expression of GRM4 gene (Fig. 5), that in turn affect the influx of Ca2+ into the prefrontal cortex neurons and the extracellular concentration of glutamate.277–283”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [282]

    The Results sections on GRM4 targeting and Ca2+ influx/glutamate release (pages unavailable) show that miR-29b-3p downregulated GRM4 in rat prefrontal cortex and primary neurons, increased Ca2+ influx, and increased extracellular glutamate. The Discussion mentions miR-1202 as a reported regulator of GRM4, but does not establish the claimed downstream effects for it. The cited passages do not support the same pathway for miR-335 or miR-134-5p. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The lncRNA Gm26917/miR29b-3p/GRM4 pathway may play a critical role in both fluoxetine and ketamine therapies in CUMS rats.

    “suggesting that the lncRNA Gm26917/miR29b-3p/GRM4 pathway may plays a critical role in both fluoxetine and ketamine therapies in CUMS rats.345”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [345]

    The Results sections on miR-29b-3p expression and GRM4 in CUMS rats support a possible role for miR-29b-3p/GRM4 in ketamine treatment. Our copy does not identify lncRNA Gm26917 or examine fluoxetine therapy, so it does not support the full pathway or its proposed role in both therapies. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Ketamine can increase the expression of miR-29b-3p and result in lower levels of GRM4 in the prefrontal cortex of depressed rat model.

    “Ketamine can also increase the expression of miR-29b-3p and result in lower levels of metabotropic glutamate receptor 4 (GRM4) in the prefrontal cortex of depressed rat model, suggesting that the lncRNA Gm26917/miR29b-3p/GRM4 pathway may plays a critical role in both fluoxetine and ketamine therapies in CUMS rats.345”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [345]

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Cited by

Sorted by citations

Authors
Wan, Y.-Q., Feng, J.-G., Li, M., Wang, M.-Z., Liu, L., Liu, X., Duan, X.-X., Zhang, C.-X., & Wang, X.-B.
Affiliations
Southwest Medical University (CN)
ORCID
Liu, Xueru
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-10
Volume
50
Issue
10
Pages
1-14
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-018-0164-4
PMC
PMC6204429
OpenAlex
W2899176426
Cited by
60
References
2
Citations by year
2026: 4 · 2025: 4 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 16 · 2020: 5 · 2019: 3
FWCI
3.87
Type
journal article
Language
en
Update notices
correction (2022-11-28)
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Department of Science and Technology of Sichuan Province (14JC0093)
  • National Natural Science Foundation of China (81271478)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
miR-29b-3p, ketamine, antidepressant effects, prefrontal cortex, mGluR4, chronic unpredictable mild stress, depression, microRNA, calcium influx, extracellular glutamate, neuronal apoptosis, major depressive disorder
MeSH terms
Animals, Antidepressive Agents, Calcium, Cell Survival, Disease Models, Animal, Gene Expression Regulation, Ketamine, Male, Neurons, Stress, Psychological, Gene Expression, Apoptosis, Prefrontal Cortex, Glutamic Acid, 3' Untranslated Regions, Gene Silencing, RNA Interference, MicroRNAs, Rats

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