A key role of miR-132-5p in the prefrontal cortex for persistent prophylactic actions of (R)-ketamine in mice

• Published in: Translational psychiatry 2022-09, Vol.12 (1), p.417-417, Article 417
• Main Authors: Ma, Li, Wang, Long, Chang, Lijia, Shan, Jiajing, Qu, Youge, Wang, Xingming, Wan, Xiayun, Fujita, Yuko, Hashimoto, Kenji
• Format: Article
• Language: English
• Subjects: 38/1; 38/91; 631/154/436/2388; 64/60; 692/699/476/1414; 82/80; Antidepressants; Behavioral Sciences; Biological Psychology; Brain-derived neurotrophic factor; Gene expression; Ketamine; Laboratory animals; Medicine; Medicine & Public Health; Mental depression; MicroRNAs; Neurosciences; Pharmacotherapy; Post traumatic stress disorder; Psychiatry; Sucrose
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-022-02192-6

( 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.