Abstract

Early-life adversity, including prenatal stress exposure, has enduring effects on stress responsivity later in life. Yet the impact of maternal stress on offspring susceptibility to stress and its underlying biological mechanisms remain to be elucidated. Here, we established a “2-hit” stress model to investigate whether maternal chronic unpredictable stress (E9.5 to E18) increases offspring susceptibility to social isolation during adolescence (P28 to P49). Our study reveals that maternal stress increases susceptibility to adolescent social isolation in male—but not female—offspring, manifested as increased anxiety- and depressive-like behaviors. This vulnerability is mediated by the priming of hippocampal dentate gyrus microglia through the complement C3–C3aR signaling pathway, which promotes the aberrant phagocytosis of excitatory synapses and reduces glutamatergic neuronal activity. Notably, pharmacological blockade of C3aR or chemogenetic activation of glutamatergic neurons in the dentate gyrus during adolescence effectively alleviated stress susceptibility. Therefore, our findings identify a targetable immune-mediated mechanism in the hippocampus that underlies stress vulnerability in offspring exposed to gestational maternal stress, offering new avenues for preventing adolescent-onset mood disorders.