行为绝望测验
神经营养因子
氯胺酮
前额叶皮质
脑源性神经营养因子
MECP2
开阔地
海马体
NMDA受体
药理学
社会失败
内分泌学
内科学
医学
抗抑郁药
神经科学
化学
心理学
受体
认知
基因
生物化学
表型
作者
Li Ma,Long Wang,Lijia Chang,Jiajing Shan,Youge Qu,Xingming Wang,Xiayun Wan,Yūkō Fujita,Kenji Hashimoto
标识
DOI:10.1038/s41398-022-02192-6
摘要
(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.
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