Specific miRNAs associated with treatment response during hospitalization for suicidal ideation

Abstract Brain epigenetic microRNAs (miRNA) can provide integrated and rapid brain regulation during recovery from suicidal ideation (SI), and because brain miRNA enter the circulation, plasma miRNA may be markers for SI recovery. Therefore, we used genome-wide miRNA expression profiling to measure plasma miRNA changes during resolution of SI and assessed mRNA-targets using functional annotation analyses. We correlated plasma miRNA with Columbia-Suicide Severity Rating Scores (C-SSRS), depression and anxiety in 42 SI and 26 non-SI inpatients at admission and 4–6 weeks later in recovery (C-SSRS = 0). The 42 SI patients showed down-regulation of four miRNAs (hsa-miR-424-5p, hsa-miR-378i, hsa-miR-6724-5p, and hsa-miR-10b-5p) after recovery from SI, while these four miRNAs showed no change for non-SI patients. We validated these differentially expressed (DE) miRNAs by qRT-PCR, and luciferase assays confirmed miRNA functional activity in Clusterin for miR-424-5p and in SDC1 for miR-10b-5p. Depression and anxiety improved and correlated with changes in miR-6724-5p and miR-378i, respectively. The serum protein Clusterin also increased in the plasma of the 42 recovered patients. mRNA target prediction for miR-378i, miR-10b-5p, and miR-424-5p yielded 37 hub genes. KEGG analyses showed enrichment in 5 to 15 hub genes within six neuronal pathways previously identified as critical in depression and suicidality: MAPK, ErbB, AMPK, Ras, p53, and PI3K-Akt. Thus, these four plasma miRNA changes and the associated modulation of six depression and suicidality pathways in brain may reflect brain-related epigenetic changes specifically involved in recovery from SI rather than reflecting non-specific changes in miRNA also found among non-SI inpatients.