A role of microRNA-149 in the prefrontal cortex for prophylactic actions of (R)-ketamine in inflammation model

• Published in: Neuropharmacology 2022-11, Vol.219, p.109250-109250, Article 109250
• Main Authors: Ma, Li, Wang, Long, Chang, Lijia, Shan, Jiajing, Qu, Youge, Wang, Xingming, Fujita, Yuko, Hashimoto, Kenji
• Format: Article
• Language: English
• Subjects: Gut microbiota; microRNAs; NFATc4; Prophylactic effect: resilience
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2022.109250

MicroRNAs (or miRNAs) are short, regulatory RNAs that act as post-transcriptional repressors of gene expression. Recently, we reported that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of new antidepressant (R)-ketamine in lipopolysaccharide (LPS)-treated inflammation model of depression. In this study, we examined the role of miRNAs (miR-149 and miR-7688–5p) which can regulate NFATc4 in the prefrontal cortex (PFC) of male mice after administration of LPS (1.0 mg/kg). There was a positive correlation between the expression of Nfatc4 and the expression of miR-149 in the PFC. There was also a negative correlation between gene expression of Nfatc4 and gene expression of miR-7688-5p in the PFC. Gut microbiota analysis showed that pretreatment with (R)-ketamine (10 mg/kg) could restore altered composition of gut microbiota in LPS-treated mice. A network analysis showed that gut microbiota may regulate gene expression of Nfatc4 and miR-149 (or miR-7688-5p) in the PFC. Finally, inhibition of miR-149 by antagomiR-149 blocked LPS-induced depression-like behavior by attenuating LPS-induced expression of NFATc4 in the PFC. These findings suggest that the regulation of NFATc4 signaling by miR-149 might play a role in persistent prophylactic effects of (R)-ketamine, and that gut microbiota may regulate the gene expression of miRNAs in the PFC through gut–microbiota–brain axis. This article is part of the Special Issue on ‘Ketamine and its Metabolites’. •MiR-149 can regulate NFATc4 in the prefrontal cortex (PFC).•MiR-149 plays a role in prophylactic effects of (R)-ketamine.•Gut microbiota may regulate the gene expression of miRNAs in the PFC.