The epitranscriptome in the maternal immune activation model of neurodevelopmental conditions

  • Awarded: 2022
  • Award Type: Pilot
  • Award #: 973285

Environmental perturbations that disrupt fetal neurodevelopment are strongly associated with autism spectrum disorder (ASD). Specifically, maternal infection and inflammation during pregnancy predispose offspring to neurodevelopmental and psychiatric conditions. The relationship between maternal immune activation (MIA) during pregnancy and neurodevelopmental and psychiatric conditions in offspring has been extensively studied in rodents. However, the molecular mechanisms underlying this link between maternal inflammation and disruption in fetal brain development are poorly understood.

MIA triggers the integrated stress response (ISR) selectively in the male fetal brain, resulting in the arrest of global protein translation^1. This sex-specific disruption in mRNA translation machinery is necessary for behavioral abnormalities in mice. Preliminary results from the labs of Brian Kalish and Yeong Shin Yim suggest that MIA is associated with similar sex-specific changes in the regulators of RNA modifications (the RNA “epitranscriptome”). The epitranscriptome shapes gene expression through the regulation of RNA stability, translation and noncoding transcript function, and it is necessary for memory consolidation, neurogenesis, dopaminergic signaling, and the neural stress response.

Kalish and Yim hypothesize that manipulation of the epitranscriptome may be a novel method of reversing MIA-associated neurodevelopmental conditions. The objective of this project is to identify mechanisms underlying sex-specific vulnerability to MIA and the subsequent development of behaviors associated with neurodevelopmental conditions. Results from these studies are expected to significantly advance our understanding of the fetal brain response to maternal inflammation, which may be broadly applicable to other ASD etiologies.


  1. Kalish B.T. et al. Nat. Neurosci. 24, 204-213 (2021) PubMed
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