Cross-species single-nucleus transcriptomics identifies microglial Arhgap22 as a conserved modulator of synaptic phagocytosis and depression-related behaviors

Abstract Microglia-regulated neuroinflammation is associated with major depressive disorder (MDD), yet the molecular drivers of pathological microglia-neuron interactions remain poorly defined. Here, we conducted single-nucleus RNA sequencing (snRNA-seq) of the prefrontal cortex (PFC) in mice susceptible to chronic social defeat stress (CSDS) and identified a distinct microglial transcriptional signature that is enriched for phagocytic and immune activation pathways. Gene module analysis revealed a coordinated dysregulation linking microglia-specific programs to excitatory neuronal dysfunction. Morphological and ultrastructural analyses revealed enhanced microglial synaptic engulfment accompanied by synaptic alterations in the medial PFC of susceptible mice. By comparing data from MDD patients, a non-human primate model of depression, and a depression mouse model, we identified microglial Arhgap22 (Rho GTPase Activating Protein 22) downregulation as a conserved alteration in depression models across species. Arhgap22 overexpression in microglia attenuated CSDS-associated synaptic phagocytosis and synaptic damage, while partially ameliorating depression-related behavioral phenotypes. Collectively, these findings provide microglia-centered, cross-cell-type, and cross-species insights and identify Arhgap22 as a conserved microglial modulator of synaptic phagocytosis and depression-related behavioral phenotypes.