A key role of miR-132-5p in the prefrontal cortex for persistent prophylactic actions of (R)-ketamine in mice
Li Ma, Long Wang, Lijia Chang, Jiajing Shan, Y. Qu, Xingming Wang, X. Wan, Yuko Fujita, Kenji Hashimoto
Translational Psychiatry September 28, 2022 DOI: 10.1038/s41398-022-02192-6 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice exposed to chronic restraint stress |
| Interventions | (R)-ketamine agomiR-132-5p antagomiR-132-5p |
| Dose | 10 mg/kg |
| Duration | 1 day before chronic restraint stress |
| Measures | forced swimming test, sucrose preference test, RNA-sequencing, quantitative RT-PCR |
| Topics | Esketamine Ketamine |
| Key points | (R)-ketamine pretreatment (10 mg/kg) prevented depression-like behaviors and normalized prefrontal cortex expression of miR-132-5p and related genes/proteins in chronically stressed mice. Manipulating miR-132-5p bidirectionally altered depression-like behaviors, indicating it mediates both the stress-induced phenotype and ketamine's sustained prophylactic effects. |
Abstract
( R,S )-ketamine is known to elicit persistent prophylactic effects in rodent models of depression. However, the precise molecular mechanisms underlying its action remain elusive. Using RNA-sequencing analysis, we searched for novel molecular target(s) that contribute to the prophylactic effects of ( R )-ketamine, a more potent enantiomer of ( R,S )-ketamine in chronic restraint stress (CRS) model. Pretreatment with ( R )-ketamine (10 mg/kg, 1 day before CRS) significantly ameliorated body weight loss, increased immobility time of forced swimming test, and decreased sucrose preference of sucrose preference test in CRS-exposed mice. RNA-sequencing analysis of prefrontal cortex (PFC) revealed that several miRNAs such as miR-132-5p might contribute to sustained prophylactic effects of ( R )-ketamine. Methyl CpG binding protein 2 (MeCP2) is known to regulate brain-derived neurotrophic factor (BDNF) expression. Quantitative RT-PCR confirmed that ( R )-ketamine significantly attenuated altered expression of miR-132-5p and its regulated genes ( Bdnf, Mecp2, Tgfb1, Tgfbr2 ) in the PFC of CRS-exposed mice. Furthermore, ( R )-ketamine significantly attenuated altered expression of BDNF, MeCP2, TGF-β1 (transforming growth factor β1), and synaptic proteins (PSD-95, and GluA1) in the PFC of CRS-exposed mice. Administration of agomiR-132-5p decreased the expression of Bdnf and Tgfb1 in the PFC, resulting in depression-like behaviors. In contrast, administration of antagomiR-132-5p blocked the increased expression of miR-132-5p and decreased expression of Bdnf in the PFC of CRS-exposed mice, resulting in antidepressant-like effects. In conclusion, our data show a novel role of miR-132-5p in the PFC underlying depression-like phenotypes in CRS model and the sustained prophylactic effects of ( R )-ketamine.
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 24
- The Antidepressant Actions of Ketamine and its Enantiomers Pharmacology & Therapeutics May 1, 2023
- Inflammation, stress and depression: an exploration of ketamine’s therapeutic profile Drug Discovery Today February 1, 2023
- Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions Journal of Anesthesia and Translational Medicine July 11, 2024
- (R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders. International Journal of Molecular Sciences June 20, 2024
- Role of the gut-brain axis via the subdiaphragmatic vagus nerve in stress resilience of 3,4-methylenedioxymethamphetamine in mice exposed to chronic restrain stress. Neurobiology of Disease December 1, 2023
and 19 more in the library
Cites 38
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