Abstract
Abstract 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 greater NFkB activity, TUNEL-positive apoptosis, and mRNAs for pro-inflammatory cytokines including IL-6, IL-17, TNFα, IL-23, TSPO and MCP-1 at 24 h post-injury, when compared to those injured by HI alone. At 7 d recovery, the MIA/HI-injured mice showed more AMCs, monocyte infiltration, and greater brain atrophy than singularly MIA- or HI-injured mice. Finally, the MIA/HI-injured mouse brains showed a significant reduction of PSD95 and synaptotagmin/PSD-96 punctates, correlated with greater C3 expression in the hippocampal CA2/3 region than MIA alone or HI-injured counterparts. Together, these results suggest that MIA elevates the inflammatory activity in the offspring brain, and acts as a primer to sensitize the neuroinflammatory responses to a secondary insult, leading to greater brain damage, and potentially ASD-like cognitive deficits.
Published Version
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