These investigators further showed that fluoxetine treatment induced the secretion of various signaling molecules such as BDNF, Wnt2, and 15d-PGJ2 from raphe serotonergic neurons and acted cooperatively on the hippocampus, whereas
S100β controlled the locus coeruleus-dependent hippocampal response to fluoxetine.147 These signals relayed the action of fluoxetine on adult hippocampal neurogenesis by downregulating miR-16 in the hippocampus in a region-specific manner. In a complementary fashion, these signaling molecules were found to be increased in the cerebrospinal Inhibitors,research,lifescience,medical fluid of depressed patients upon fluoxetine treatment.147 O’Connor et al149 investigated whether early-life stress in rats induced changes in hippocampal miRNA levels and whether the rapidly acting NMDA receptor antagonist ketamine, electroconvulsive therapy (ECT), or Inhibitors,research,lifescience,medical fluoxetine treatment could reverse these changes. They found that early-life stress affected MEK inhibitor expression of multiple hippocampal miRNAs. Antidepressant treatments reversed some of these effects including a stress-induced change to miR-451. Ketamine Inhibitors,research,lifescience,medical and ECT possessed the highest number of common targets, suggesting convergence on common pathways. Interestingly, all three treatments possessed miR-598-5p as a common target. This demonstrates that changes to
hippocampal miRNA expression may represent an important component of stress-induced pathology, and antidepressant action may reverse these. In this context, Ryan et al150 examined Inhibitors,research,lifescience,medical ECT-induced BDNF expression and BDNFassociated miRNAs. Following acute or chronic electroconvulsive stimulation (ECS), they found that the level of selective miR-212 was significantly increased in dentate gyrus. miR-2f 2 level was also increased in parallel in whole blood following chronic ECS and
was positively correlated with miR-212 level Inhibitors,research,lifescience,medical in the dentate gyrus, suggesting that miR-212 may be crucial in the mechanism of action of ECT and that it can be used as a biomarker. Using genome-wide expression profiling of human lymphoblastoid cell lines (LCLs), Morag et al151 identified CHL1 as a selective serotonin reuptake inhibitor (SSRI) sensitivity biomarker. The same group reported much that specific miRNAs may be implicated in SSRI sensitivity of LCLs.152 They examined genome-wide expression profiling with miRNAs in LCLs exhibiting high or low sensitivities to paroxetine. They found that miR-1513p had a 6.7-fold higher basal expression in paroxetinesensitive LCLs, which was correlated with lower expression of CHL1, a target of miR-151-3p. The additional miRNAs miR-212, miR-132, miR-30b*, let-7b, and let-7c also differed by > 1.5-fold between the two LCL groups. These results suggest a possible therapeutic value of miRNAs in responders vs nonresponders to antidepressant treatment in MDD patients.