Environmental stress insults in 2HIT model synergistically produce disorder-associated microglia and macrophages in the cerebellum

Abstract A pivotal role of microglia is the maintenance of brain homeostasis, but the function is severely altered in the brains with psychiatric disorders such as schizophrenia spectrum disorders. Previous pathological and physiological findings indicate a localized deficit in the cerebellum of the patients. However, it is unknown if the accumulation of inflammatory stress alters microglia morphology, localization, molecular expression pattern, and phenotype. Here, using translational mouse models that exploit known risk factors for mental disorders: maternal infection and repeated social defeat stress, we investigated the brain immune environment of psychiatric disorder models with multiple immune stress. The synergy of maternal immune activation and repeated defeat stress on mice brought forth reactive microglia specifically in the cerebellum. The increase in the reactive microglia in 2HIT correlated with cerebellar Purkinje neuron loss. Highly-multiplexed imaging mass cytometry with originally-customized 26 markers demonstrated a TREM2-positive immune-cell population of disease-associated microglia/macrophages (DAM IMC s) being close at near-vasculature. Single-cell proteomic clustering indicates sIL-6R- and TGFBR2-signaling with cell transition from progenitor cells to mature DAM IMC s, which implies synergistic disruption of neurophysiological properties and functioning in the 2HIT cerebellum. Our study identifies the distinct immune cells in the cerebellum, which may influence cognition and behavior.