news & views NEURODEVELOPMENT Infammation stresses out brain development A new study reveals that maternal immune activation promotes sex-biased activation of the integrated stress response in the developing mouse brain and that this mechanistically contributes to the onset of autism-related behaviors uniquely in male ofspring. Kristine E. Zengeler and John R. Lukens A utism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders, with current estimates identifying a diagnosis of one child out of every 54 in the US 1 . Epidemiological reports and recent experimental evidence together suggest that activation of a mother’s immune response during pregnancy may contribute to the etiology of neurodevelopmental disorders 2–4 . Indeed, various triggers of maternal immune activation (MIA)— including multiple pathogen-derived stimuli, environmental irritants and autoinflammatory conditions—have been reported to induce cortical abnormalities, circuit dysfunction and behavioral changes in animal models 5–11 . While there is emerging evidence that gestational inflammation can perturb fetal brain development, the cellular and molecular events that promote neural dysfunction in MIA offspring remain incompletely understood. 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 . To interrogate a connection between maternal inflammation and altered neurodevelopment, the authors employed a mouse MIA model whereby pregnant mothers were injected with polyinosinic:polycytidylic acid (polyI:C; a mimic of viral infection) or saline as a control. The authors first conducted single-cell RNA sequencing (scRNA-seq) on cortices of embryos from polyI:C- or saline-injected mothers to gain an unbiased and comprehensive picture of changes to the fetal brain that occur shortly after the onset of maternal inflammation. Analysis of differential gene expression 2 and 6 days after the induction of maternal inflammation revealed substantial changes in the transcriptional states of a variety of cortical cell types following MIA. Unlike the roles of MIA in neurodevelopmental disorders, which have only recently emerged, the sex bias in ASD has long been appreciated, with ASD cases in males outnumbering those in females by approximately 4:1 (ref. 13 ). This sex bias in the human condition is also mirrored in the MIA model used in this study, since only male offspring developed behavioral polyI:C Maternal immune activation Female Male Neurotypical development and behavior Neurotypical development and behavior Male eIF2α P PERK P ER stress Integrated stress response Abnormal neurodevelopment T cell IL-17a IL-17a Repetitive behaviors Impaired sociability Normal proteostasis eIF2α inhibition ↓ Protein synthesis Fig. 1 | The integrated stress response contributes to maternal immune activation (MIA)-induced neurodevelopmental changes. Induction of MIA following injection of pregnant mice with the viral mimetic polyI:C provokes production of IL-17a by maternal T cells, and this leads to altered neurodevelopment and autism-related behaviors in male but not female offspring. The development of autism-related phenotypes in male MIA-exposed offspring is associated with a sex-specific induction of the integrated stress response (ISR). Namely, the sexually dimorphic ISR in the brains of male MIA-exposed offspring is characterized by activation of PERK and eIF2α signaling, both of which are hallmarks of ER stress and lead to an attenuation of protein synthesis. Blockade of the ISR via either genetic or pharmacological inhibition of eIF2α protects against the development of autism-like behavioral abnormalities and altered brain maturation in MIA offspring. Figure created with https:// biorender.com. NATURE NEUROSCIENCE | www.nature.com/natureneuroscience