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Maternal immune activation in mice disrupts proteostasis in the fetal brain
Name
nihms-1648035.pdf
Description
Accepted version
Size
5.77 MB
Format
Adobe PDF
Checksum (MD5)
2eecdcdd91e1c9f04b4072479035bace
Author(s)
Kalish, Brian T
Kim, Eunha
Finander, Benjamin
Duffy, Erin E
Kim, Hyunju
Gilman, Casey K
Yim, Yeong Shin
Tong, Lilin
Kaufman, Randal J
Griffith, Eric C
Date Issued
2021
Journal
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
10.1038/s41593-020-00762-9
