Maternal immune activation in mice disrupts proteostasis in the fetal brain.
Brian T KalishEunha KimBenjamin FinanderErin E DuffyHyunju KimCasey K GilmanYeong Shin YimLilin TongAlexandre Rosa CamposEric C GriffithGloria B ChoiMichael Eldon GreenbergJun R HuhPublished in: Nature neuroscience (2020)
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.
Keyphrases
- single cell
- birth weight
- high fat diet
- pregnancy outcomes
- oxidative stress
- white matter
- gene expression
- resting state
- type diabetes
- high throughput
- metabolic syndrome
- pregnant women
- adipose tissue
- functional connectivity
- subarachnoid hemorrhage
- insulin resistance
- cerebral ischemia
- transcription factor
- heat stress
- deep learning
- data analysis
- heat shock protein
- high fat diet induced