Maternal immune activation in mice disrupts proteostasis in the fetal brain

Nat Neurosci. 2021 Feb;24(2):204-213. doi: 10.1038/s41593-020-00762-9. Epub 2020 Dec 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain / immunology*
  • Developmental Disabilities / genetics
  • Female
  • Fetus / immunology*
  • Gene Expression Profiling
  • Immunity, Innate / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Protein Biosynthesis / genetics
  • Proteome / biosynthesis
  • Proteostasis / genetics*
  • RNA / biosynthesis
  • RNA / genetics
  • RNA, Small Interfering
  • Sex Characteristics
  • Signal Transduction
  • Stress, Psychological / genetics
  • Stress, Psychological / psychology


  • Proteome
  • RNA, Small Interfering
  • RNA