MiR-186-5p Dysregulation Leads to Depression-like Behavior by De-repressing SERPINF1 in Hippocampus

Diagnosis of major depressive disorder (MDD) is perplexing due to its multifactorial etiologies. Here, we isolated exosomes from the peripheral blood of MDD patients and healthy control subjects for mass spectrometry-based label-free quantitative proteomics. We identified that SERPINF1 is significantly diminished in the peripheral blood-derived exosomes of MDD patients compared to the healthy control subjects. Through RNA immunoprecipitation and luciferase reporter assays, we validated that SERPINF1 is a target of miR-186-5p that is upregulated in MDD patients' blood. In vivo studies in the chronic unpredictable mild stress (CUMS) mice further demonstrated that SERPINF1 in hippocampus is suppressed by miR-186-5p. Inhibiting the microRNA significantly restores the hippocampal SERPINF1 mRNA and protein expression, and ameliorates the depressive-like behaviors including sucrose preference and extended immobility time in the forced swim test. Instead, overexpressing miR-186-5p through tail intravenous injection of the mimics molecularly and behaviorally phenocopies the CUMS mice in wild-type mice. Our results indicate that the exosomal SERPINF1 in peripheral blood could serve as a reliable biomarker indicating MDD development, and miR-186-5p is a potential therapeutic target for the disease.