Cross-species identification of DLPFC-specific miR-130a-3p as a causal driver of major depressive disorder implicating microglial neuroimmune suppression

MicroRNAs (miRNAs) are postulated as pivotal epigenetic regulators in Major Depressive Disorder (MDD), yet distinguishing causal drivers from secondary associations remains a significant challenge due to cross-species barriers and tissue specificity. Here, we present a cross-species integrative framework rooted in human genetics and functionally validated in rodents to identify pathogenic miRNAs. By integrating large-scale cis-eQTLs and MDD GWAS data using Mendelian Randomization, we identified miR-130a-3p as a robust causal risk factor. Multivariable MR and neuroimaging integration further pinpointed the Dorsolateral Prefrontal Cortex (DLPFC) as the primary mediator of its pathogenic effects, characterized by disrupted related functional connectivity. Validating these findings, viral-mediated overexpression of miR-130a-3p in the murine medial prefrontal cortex (the functional homolog of human DLPFC) was sufficient to induce core depressive-like behaviors, including anhedonia and despair. Transcriptomic profiling revealed that miR-130a-3p predominantly downregulated genes enriched in immune-related pathways and specifically in microglia, suggesting a suppression of local neuroimmune signaling and an interruption of microglia-driven homeostasis. Finally, integrating these results with human Transcriptome-Wide Association Studies (TWAS) revealed that the expression levels of some miR-130a-3p downstream genes in the human DLPFC are significantly associated with MDD risk, completing a translational closed-loop that reinforces the relevance of the identified pathway. Collectively, our study identifies miR-130a-3p as a causal neuroimmune modulator in MDD and demonstrates the utility of a genetics-anchored, cross-species pipeline for dissecting the molecular etiology of psychiatric disorders.