INTEGRATED SCRNA-SEQ ANALYSIS OF CEREBRAL AND PERIPHERAL TISSUES CHARACTERIZES INTRICATE NEUROIMMUNE CROSSTALK ELICITED BY GATA1

GATA1 is a master transcriptional regulator of hematopoiesis, traditionally recognized for its pivotal role in immune cell development. However, recent clinical evidence has highlighted its upregulation in the dorsolateral prefrontal cortex of patients with major depressive disorder (MDD), where it triggers microglial activation associated with depressive-like behaviors. Despite these findings, the precise mechanisms underlying GATA1-mediated neuroimmune interactions remain largely elusive. To address this, we delivered adeno-associated virus (AAV)-GATA1 into the medial prefrontal cortex of mice and performed single-cell RNA sequencing on brain-resident immune cells and peripheral blood mononuclear cells (PBMCs). GATA1 overexpression markedly induced gene signatures associated with type I interferon (IFN)-responsive signaling within the brain. Notably, the plasmacytoid dendritic cell (pDC) cluster exhibited enhanced intercellular ligand–receptor interactions with multiple neural cell types. We identified a distinct microglial activation profile following GATA1 overexpression, characterized by expansion of IFN-responsive microglial subtypes expressing MHC-I, pro-inflammatory cytokines, complement components, and the exosome marker Cd63. Elevated exosome module scores in these microglia suggest a potential mechanism for exosome-mediated inflammatory signal transmission to the periphery. Furthermore, we observed an increased proportion of effector memory CD8⁺ T cells in the brain, indicating enhanced infiltration and memory formation. In the peripheral blood, activated CD8⁺ T cells demonstrated upregulated gene expression related to cell motility and an increased predicted velocity toward the brain. Collectively, GATA1 appears to orchestrate systemic neuroimmune crosstalk through microglia-mediated inflammatory signaling and CD8⁺ T cells. These findings suggest GATA1 as a promising therapeutic target for modulating neuroimmune dysfunction in the pathophysiology of MDD.