Profiling Transcriptomic Changes Across Frontal Cortical Subregions in Major Depressive Disorder

Major depressive disorder (MDD) involves frontal cortical dysfunction, with emerging evidence implicating gliovascular and immune mechanisms, yet its transcriptional signatures across subregions, cell-types, and molecular layers remain poorly defined. Here, we integrated bulk-tissue RNA-seq data from dlPFC, mPFC, and dACC (n = 286) to identify a conserved core transcriptional profile, anchored in downregulated interneuron markers, and upregulated immune and vascular genes, spatially enriched in leptomeninges and white matter. Concordantly, multiomic factor analysis revealed immune activation, stress-response, and accelerated aging in MDD. Analysis of snRNA-seq data from dlPFC, mPFC, and oFC (863,511 nuclei; n = 204) revealed most pronounced MDD signatures in excitatory neurons, accompanied by coordinated disruption of glucocorticoid receptor machinery across cell-types, including FKBP5 upregulation. Glial, immune, and perivascular populations exhibited signatures of oxidative stress, ECM remodeling, and reduced neuronal support, and greater concordance with bulk-tissue MDD signals than neurons. A global reduction in cell-to-cell communications in MDD revealed a shift from homeostatic neuronal signaling toward endothelial and myelination-associated pathways. Ephrin-Eph signaling was consistently dysregulated, implicating disrupted axonal guidance, synaptic remodeling, and neurovascular integrity. Notably, MDD signatures were shared between MDD-only and PTSD comorbid cases at bulk-tissue analyses, while diverging at single-cell resolution. Together, these findings reframe MDD as a distributed frontal cortex disorder, driven by disrupted neuroglial and neurovascular communication.