Journal Article

Maternal immune activation in mice disrupts proteostasis in the fetal brain

Gilman, Casey K., Yim, Yeong Shin, Kaufman, Randal J., Kim, Hyunju, Choi, Gloria B., Kalish, Brian T., Finander, Benjamin, Kim, Eunha, Duffy, Erin E., Griffith, Eric C., Tong, Lilin, Huh, Jun R., Greenberg, Michael E.

2021

Overview

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. This paper shows that maternal immune activation in mice induces changes in the mRNA translation machinery in the fetal brain and activates the integrated stress response in male fetuses, which mediates neurobehavioral abnormalities.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/51 / 38/39 / 631/337 / 631/378 / 631/378/1831 / 64/60 / 82/29 / 82/80 / 96/95 / Abnormalities / Animal Genetics and Genomics / Animals / Behavior, Animal / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain / Brain - immunology / Brain research / Cytokines / Development and progression / Developmental Disabilities - genetics / Disorders / Epidemiology / Female / Females / Fetal brain / Fetus - immunology / Fetuses / Gender differences / Gene expression / Gene Expression Profiling / Gene sequencing / Genetic translation / Health aspects / Immune response / Immune system / Immunity, Innate - genetics / Inflammation / Interleukins / Male / Males / Mental illness / Messenger RNA / Mice / Mice, Inbred C57BL / Molecular modelling / Nervous system diseases / Neurobiology / Neurodevelopmental disorders / Neurosciences / Offspring / Physiological aspects / Pregnancy / Prenatal influences / Protein Biosynthesis - genetics / Proteins / Proteome - biosynthesis / Proteomes / Proteostasis - genetics / Risk factors / RNA - biosynthesis / RNA - genetics / RNA, Small Interfering / Sex Characteristics / Signal Transduction / Stress, Psychological - genetics / Stress, Psychological - psychology / Transcription / Transfer RNA / Translation