Early life stress-induced miR-708-5p affects bipolar disorder-associated phenotypes through neuronatin downregulation

The underlying physiological and molecular mechanisms of bipolar disorder (BD) remain largely unknown. Here, by using unbiased small RNA sequencing in peripheral blood mononuclear cells (PBMCs), we found that miR-708-5p, a microRNA that was previously associated with BD, is the most strongly upregulated microRNA in peripheral blood of both healthy human subjects with a high genetic or environmental predisposition to develop mood disorders (MDs). Furthermore, miR-708-5p is strongly upregulated in patients diagnosed with BD and has potential in conjunction with the previously identified miR-499-5p to differentiate BD patients from patients suffering from major depressive disorder (MDD) and healthy controls. miR-708 is also upregulated in the hippocampus of wild type juvenile rats that underwent social isolation, as well as in juvenile rats heterozygous for the BD risk gene Cacna1c . Furthermore, ectopic overexpression of miR-708-5p in the hippocampus of adult male mice leads to BD-associated endophenotypes, such as reduced behavioral despair, enhanced compulsivity, and short-term memory impairments. miR-708-5p directly targets Neuronatin (Nnat), an endoplasmic reticulum (ER) resident protein involved in calcium homeostasis. Restoring Nnat expression in the hippocampus of miR-708-5p overexpressing mice rescues BD-associated endophenotypes. In summary, we functionally link miR-708-5p dependent regulation of Nnat to BD, with potential implications for BD diagnosis and therapy.