Gilardi Carlotta, Martins Helena C, Levone Brunno Rocha, Bianco Alessandra Lo, Bicker Silvia, Germain Pierre-Luc, Gross Fridolin, Sungur Ayse Özge, Kisko Theresa M, Stein Frederike, Meinert Susanne, Schwarting Rainer K W, Wöhr Markus, Dannlowski Udo, Kircher Tilo, Schratt Gerhard
Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, ETH Zurich, 8057, Zurich, Switzerland.
Laboratory of Molecular and Behavioural Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, ETH Zurich, 8057, Zurich, Switzerland.
EMBO Rep. 2025 Apr;26(8):2121-2145. doi: 10.1038/s44319-025-00410-y. Epub 2025 Mar 10.
Mood disorders (MDs) are caused by an interplay of genetic and environmental (GxE) risk factors. However, molecular pathways engaged by GxE risk factors are poorly understood. Using small-RNA sequencing in peripheral blood mononuclear cells (PBMCs), we show that the bipolar disorder (BD)-associated microRNA miR-708-5p is upregulated in healthy human subjects with a high genetic or environmental predisposition for MDs. miR-708-5p is further upregulated in the hippocampus of rats which underwent juvenile social isolation, a model of early life stress. Hippocampal overexpression of miR-708-5p in adult male mice is sufficient to elicit MD-associated behavioral endophenotypes. We further show that miR-708-5p directly targets Neuronatin (Nnat), an endoplasmic reticulum protein. Restoring Nnat expression in the hippocampus of miR-708-5p-overexpressing mice rescues miR-708-5p-dependent behavioral phenotypes. Finally, miR-708-5p is upregulated in PBMCs from patients diagnosed with MD. Peripheral miR-708-5p expression allows to differentiate male BD patients from patients suffering from major depressive disorder (MDD). In summary, we describe a potential functional role for the miR-708-5p/Nnat pathway in MD etiology and identify miR-708-5p as a potential biomarker for the differential diagnosis of MDs.
情绪障碍（MDs）是由遗传和环境（基因与环境相互作用，GxE）风险因素共同作用引起的。然而，对于GxE风险因素所涉及的分子途径，我们了解甚少。通过对外周血单核细胞（PBMCs）进行小RNA测序，我们发现，在具有较高MDs遗传或环境易感性的健康人类受试者中，与双相情感障碍（BD）相关的微小RNA miR-708-5p上调。在经历幼年社会隔离（一种早期生活应激模型）的大鼠海马中，miR-708-5p进一步上调。成年雄性小鼠海马中miR-708-5p的过表达足以引发与MD相关的行为内表型。我们进一步表明，miR-708-5p直接靶向内质网蛋白神经毡蛋白（Nnat）。在miR-708-5p过表达小鼠的海马中恢复Nnat表达可挽救miR-708-5p依赖性行为表型。最后，在被诊断患有MD的患者的PBMCs中，miR-708-5p上调。外周血miR-708-5p表达能够区分男性BD患者和重度抑郁症（MDD）患者。总之，我们描述了miR-708-5p/Nnat途径在MD病因学中的潜在功能作用，并将miR-708-5p确定为MDs鉴别诊断的潜在生物标志物。
