MicroRNA-Mediated Regulation of and Is Implicated in SSRI Action.

Selective serotonin reuptake inhibitor (SSRI) antidepressant drugs are the first-line of treatment for major depressive disorder (MDD) but are effective in <70% of patients. Our earlier genome-wide studies indicated that two genes encoding for cell adhesion proteins, close homolog of L1 () and integrin beta-3 (), and microRNAs, miR-151a-3p and miR-221/222, are implicated in the variable sensitivity and response of human lymphoblastoid cell lines (LCL) from unrelated individuals to SSRI drugs. The microRNAs miR-221, miR-222, and miR-151-a-3p, along with their target gene binding sites, were explored using miRBase, TargetScan, microRNAviewer, and the UCSC Genome Browser. Luciferase reporter assays were conducted for demonstrating the direct functional regulation of and expression by miR-221/222 and miR-151a-3p, respectively. A human LCL exhibiting low sensitivity to paroxetine was utilized for studying the phenotypic effect of regulation by miR-151a-3p on SSRI response. By showing direct regulation of and by miR-151a-3p and miR-221/222, respectively, we link these microRNAs and genes with cellular SSRI sensitivity phenotypes. We report that miR151a-3p increases cell sensitivity to paroxetine via down-regulating expression. miR-151a-3p, miR-221/222 and their (here confirmed) respective target-genes, and , are implicated in SSRI responsiveness, and possibly in the clinical response to antidepressant drugs.