Downregulation of microRNA-124-3p suppresses the mTOR signaling pathway by targeting DDIT4 in males with major depressive disorder

Recent investigations have suggested that microRNAs (miRNAs or miRs) are involved in several pathways that may contribute to the pathomechanism of major depressive disorder (MDD). Sex may not only act as a demographic factor in clinical practive, but may also play a vital role in the molecular heterogeneity of MDD. Although many molecular changes correlated with MDD are found in males, the molecular mechanisms of MDD remain poorly understood. The present study performed bioinformatics analysis to investigate the pathomechanism of MDD in males. The present study identified miR-124-3p as one of the most dysregulated miRNAs in MDD, with decreased expression in the post-mortem BA44 brain area of male patients with MDD. In addition, miR-124-3p targets DNA damage-inducible transcript 4 (DDIT4) and specificity protein 1 (SP1), a DDIT4 transcription factor, in the validated target module of the miRWalk 2.0 database. This is concurrent with an increase in the expression level of DDIT4, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway. It was also demonstrated that miR-124-3p expression was positively associated with mTOR signaling and this relationship was dependent on the tuberous sclerosis proteins 1/2 complex. Taken together, these results provided a novel insight on miR-124-3p involvement in the biological alterations of male patients with MDD and suggested that this miRNA may also serve as a male-specific target for antidepressant treatment.