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Preeclampsia promotes autism in offspring via maternal inflammation and fetal NFκB signaling

Xueyuan Liu,Haiyan Liu,Nihao Gu,J. Pei,Xianhua Lin,Wenlong Zhao

Published 2023 in Life Science Alliance

ABSTRACT

This study highlights elevated TNFα in maternal serum contributes to autism-like phenotypes in offspring exposed to preeclampsia and gives a therapeutic target to prevent it. Preeclampsia (PE) is a risk factor for autism spectrum disorder (ASD) in offspring. However, the exact mechanisms underlying the impact of PE on progeny ASD are not fully understood, which hinders the development of effective therapeutic approaches. This study shows the offspring born to a PE mouse model treated by Nω-nitro-L-arginine methyl ester (L-NAME) exhibit ASD-like phenotypes, including neurodevelopment deficiency and behavioral abnormalities. Transcriptomic analysis of the embryonic cortex and adult offspring hippocampus suggested the expression of ASD-related genes was dramatically changed. Furthermore, the level of inflammatory cytokines TNFα in maternal serum and nuclear factor kappa B (NFκB) signaling in the fetal cortex were elevated. Importantly, TNFα neutralization during pregnancy enabled to ameliorate ASD-like phenotypes and restore the NFκB activation level in the offspring exposed to PE. Furthermore, TNFα/NFκB signaling axis, but not L-NAME, caused deficits in neuroprogenitor cell proliferation and synaptic development. These experiments demonstrate that offspring exposed to PE phenocopies ASD signatures reported in humans and indicate therapeutic targeting of TNFα decreases the likelihood of bearing children with ASD phenotypes from PE mothers.

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