Maternal immune activation and peripubertal stress synergistically produce reactive microglia and confine cerebellar cognitive function.

Abstract The functional alteration of microglia emerges in the brains exposed to extrinsic stress insults during early development. Pathophysiological findings of psychiatric disorders such as schizophrenia and autism implied a localized deficit of the cerebellum. However, the link between microglia reactivity and cerebellar dysfunction is missing. Here, we investigated the developmental immune environment of translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (i.e., 2HIT). We found synergy of inflammatory stress insults produced reactive microglia, specifically in the cerebellum in both sexes. The microglial proliferation correlated with the Purkinje neuron loss in 2HIT mice. Highly multiplexed imaging-mass-cytometry demonstrated a TREM2-positive population of stress-associated microglia in the cerebellum. Single-cell-proteomic clustering revealed IL-6- and TGFβ-signaling association with microglial cell transition. Purkinje cells reduced excitability, cerebellum-involved brain-wide functional dysconnectivity, and behavioral anomalies underpin the cerebellar cognitive dysfunctions in 2HIT animals, ameliorated by cerebellum-specific microglia replacement.