Major depressive disorder (MDD) seriously endangers adolescent mental and physical health. Extracellular vesicles (EVs) are mediators of cellular communication and are involved in many physiological brain processes. Although EV miRNAshave been implicated in adults with major psychiatric disorders, investigation into their effects in adolescent MDDremains scarce. In discovery set, we conducted a genome-wide miRNA sequencing of serum EVs from 9 untreated adolescents with MDD and 8 matched healthy controls (HCs), identifying 32 differentially expressed miRNAs (18 upregulated and 14 downregulated). In the validation set, 8 differentially expressed and highly enriched miRNAs were verified in independent samples using RT-PCR, with 4 (miR-450a-2-3p, miR-3691-5p, miR-556-3p, and miR-2115-3p) of the 8 miRNAs found to be significantly elevated in 34 untreated adolescents with MDD compared with 38 HCs and consistent with the sequencing results. After the Bonferroni correction, we found that three miRNAs (miR-450a-2-3p, miR-556-3p, and miR-2115-3p) were still significantly different. Among them, miR-450a-2-3p showed the most markeddifferential expression and was able to diagnose disease with 67.6% sensitivity and 84.2% specificity. Furthermore, miR-450a-2-3p partially mediated the associations between total childhood trauma, emotional abuse, and physical neglect and adolescent MDD. We also found that the combination of miR-450a-2-3p and emotional abuse could effectively diagnose MDD in adolescents with 82.4% sensitivity and 81.6% specificity. Our data demonstrate the association of serum EV miRNA dysregulation with MDD pathophysiology and, furthermore, show that miRNAs may mediate the relationship between early stress and MDD susceptibility. We also provide a valid integrated model for the diagnosis of adolescent MDD.

中文翻译：

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重度抑郁症青少年血清细胞外囊泡 microRNA 失调和童年创伤。

重度抑郁症（MDD）严重危害青少年身心健康。细胞外囊泡 (EV) 是细胞通讯的介质，参与许多大脑生理过程。尽管 EV miRNA 与患有严重精神疾病的成年人有关，但对其在青少年 MDD 中的影响的研究仍然很少。在发现集中，我们对来自 9 名未经治疗的 MDD 青少年和 8 名匹配的健康对照 (HC) 的血清 EV 进行了全基因组 miRNA 测序，鉴定了 32 种差异表达的 miRNA（18 种上调和 14 种下调）。在验证集中，使用 RT-PCR 在独立样本中验证了 8 个差异表达和高度富集的 miRNA，其中 4 个（miR-450a-2-3p、miR-3691-5p、miR-556-3p、和 miR-2115-3p) 的 8 种 miRNA 在 34 名未经治疗的 MDD 青少年中显着升高，而 38 名 HC 则与测序结果一致。经过 Bonferroni 校正后，我们发现三个 miRNA（miR-450a-2-3p、miR-556-3p 和 miR-2115-3p）仍然存在显着差异。其中，miR-450a-2-3p差异表达最显着，诊断疾病的敏感性为67.6%，特异性为84.2%。此外，miR-450a-2-3p 部分介导了总体童年创伤、情感虐待和身体忽视与青少年 MDD 之间的关联。我们还发现，miR-450a-2-3p 和情绪虐待的结合可以有效诊断青少年的 MDD，灵敏度为 82.4%，特异性为 81.6%。我们的数据证明了血清 EV miRNA 失调与 MDD 病理生理学的关联，此外，表明 miRNA 可能介导早期应激与 MDD 易感性之间的关系。我们还为青少年 MDD 的诊断提供了一个有效的综合模型。