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

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Preeclampsia (PE) is a known risk factor for autism spectrum disorder (ASD) in offspring.
• The precise mechanisms linking PE to ASD development remain unclear, limiting therapeutic interventions.

Purpose of the Study:

• To investigate the impact of PE on offspring neurodevelopment and behavior.
• To elucidate the molecular mechanisms, particularly inflammatory pathways, involved in PE-induced ASD-like phenotypes.
• To evaluate the therapeutic potential of targeting TNFα in mitigating these effects.

Main Methods:

• Utilized a mouse model of PE induced by Nω-nitro-L-arginine methyl ester (L-NAME).
• Conducted transcriptomic analysis of embryonic cortex and adult offspring hippocampus.
• Measured maternal serum TNFα levels and fetal cortex NFκB signaling.
• Administered TNFα neutralization during pregnancy.
• Assessed neuroprogenitor cell proliferation and synaptic development.

Main Results:

• Offspring from the PE mouse model exhibited ASD-like phenotypes, including neurodevelopmental deficits and behavioral abnormalities.
• Significant alterations in ASD-related gene expression were observed in the embryonic cortex and adult hippocampus.
• Elevated maternal serum TNFα and fetal cortex NFκB signaling were detected in the PE model.
• TNFα neutralization ameliorated ASD-like phenotypes and normalized NFκB activation in offspring.
• The TNFα/NFκB pathway, not L-NAME itself, was found to impair neuroprogenitor cell proliferation and synaptic development.

Conclusions:

• PE exposure in offspring leads to ASD-like signatures, mirroring human conditions.
• The TNFα/NFκB signaling axis plays a critical role in mediating PE's adverse effects on neurodevelopment.
• Targeting TNFα therapeutically during pregnancy offers a promising strategy to reduce the incidence of ASD phenotypes in offspring born to mothers with PE.