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Epidemiological evidence suggests that prenatal maternal immune activation (MIA) is a risk factor for autism spectrum disorders (ASD). Yet, because not all human MIA offspring develop ASD, we hypothesize that “second hits” may be needed to induce severe brain damage and disruption of the neural network. We tested this hypothesis using an established MIA model with Poly I: C (20 mg/kg) intraperitoneally injected at mid pregnancy (E12. 5) in C57BL/6 mice. The offspring were challenged by mild hypoxia-ischemia (HI) at P10 as the second hit. We found that MIA alone infrequently caused clusters of amoeboid microglial cells (AMCs) expressing a high level of Complement component 3 (C3) in the offspring brains. Elevated NFkB signaling and a higher basal level of IL-6, IL-17 and MMP9 mRNA were also detected in the P11 MIA offspring brains. When challenged by HI, the MIA offspring showed significantly …