Maternal immune activation in mice disrupts proteostasis in the fetal brain

Abstract

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. 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, thereby reducing global mRNA translation and altering nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as an increase in cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.

Inflammation stresses out brain development

“…In the current issue of Nature Neuroscience, Kalish et al find, in mice, that sex-dependent induction of the integrated stress response in developing cortical cells contributes to altered neurodevelopment and precipitates autistic-related behaviors in offspring exposed to maternal inflammation. These findings expand our understanding of the sex bias and etiology of autism-related neurodevelopmental disorders 12 .…”

Moderately pathogenic maternal influenza A virus infection disrupts placental integrity but spares the fetal brain

“…Respiratory IAV infection has downstream consequences for maternal intestinal health. Since maternal IL-17A signaling has been associated with neurodevelopmental and behavioral abnormalities in offspring 9,20,22 , we sought to investigate whether downstream maternal IL-17A signaling is evident during IAV infection. We thus examined the maternal intestine for indications of intestinal immune injury and TH17 cell activation.…”

“…Similarly, IL-17A blockade in pregnant dams protects the developing fetal brain from MIA-induced disruptions in morphology and proteostasis, and normalizes behavioral outcomes 9,22,24 . The majority of TH17 cells reside in the intestine, and endogenous segmented filamentous intestinal bacteria (SFB), which promote TH17 cell development 25 , have been shown to be required for the emergence of MIA-associated offspring phenotypes 20,22,24 . Notably, respiratory IAV infection also promotes TH17 cell development and IL-17A-dependent intestinal injury in reports studying non-pregnant male mice 26 .…”

“…Genetic knock out of transcription factor retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), expressed by IL-17producing cells and a master regulator of TH17 cell development 23 , can rescue MIA-induced cortical malformations 9 . Similarly, IL-17A blockade in pregnant dams protects the developing fetal brain from MIA-induced disruptions in morphology and proteostasis, and normalizes behavioral outcomes 9,22,24 . The majority of TH17 cells reside in the intestine, and endogenous segmented filamentous intestinal bacteria (SFB), which promote TH17 cell development 25 , have been shown to be required for the emergence of MIA-associated offspring phenotypes 20,22,24 .…”

“…While essential progress continues to be made in elucidating potential etiologies of disrupted fetal neurodevelopment during MIA, these mechanisms have yet to be confirmed in models that use live pathogen infections. In particular, recent evidence implicates maternal T helper 17 (TH17) cells and interleukin (IL)-17A as primary drivers of altered fetal brain development during poly I:C-induced MIA 9,[20][21][22] . Genetic knock out of transcription factor retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), expressed by IL-17producing cells and a master regulator of TH17 cell development 23 , can rescue MIA-induced cortical malformations 9 .…”