A Role of Microrna-149 in the Prefrontal Cortex for Prophylactic Actions of (R)-Ketamine in Inflammation Model

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.