Maternal Immune Activation Disrupts Proteostasis in the Fetal Brain

Maternal infection and inflammation during pregnancy is associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. We leveraged single-cell RNA sequencing to profile transcriptional changes in the rodent 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 specifically activated the integrated stress response (ISR) in male, but not female, MIA offspring, thereby reducing global mRNA translation and altering nascent proteome synthesis. Moreover, genetic blockade of ISR activation rescued the social behavior phenotype in MIA male offspring. Our data suggest that therapeutic targeting of the ISR may be beneficial in reducing maternal inflammation-associated neurodevelopmental disorders. Overall design: Two timepoints (E14 and E18), each with two bioreplicates of the following: PBS control male, PBS control female, maternal immune activation male, maternal immune activation female. RNA-seq and ribosome profiling of one timepoint (E18) with replicates of the following conditions: PBS control male, PBS control female, maternal immune activation male, maternal immune activation female.