Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by a period of massive cell death where over half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and byproducts of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signaling. How the immune response to this collateral damage influences brain maturation and function currently remains poorly understood. Here we show that the AIM2 inflammasome contributes to proper brain development and that disruptions in this immune sensor of genotoxic stress lead to behavioral abnormalities. The AIM2 inflammasome has been most extensively studied in the context of infection, where its activation in response to double-stranded DNA (dsDNA) is known to trigger cytokine production as well as a Gasdermin-D-mediated form of cell death commonly referred to as pyroptosis 1-4 . We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this DNA damage surveillance sensor result in anxiety-related behaviors. We further show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of the cell death executioner Gasdermin-D, and not via its involvement in IL-1 and/or IL-18 production. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signaling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, we report that

Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome-immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.

Recent studies suggest that autism is often associated with altered microbiota composition and gastrointestinal inflammation. This work has led to growing speculation of a potential role for the microbiome in autism spectrum disorder (ASD). However, how microbiota diversity mechanistically influences the development of autistic phenotypes has not been studied in great detail to date. To formally investigate this, we evaluated how environmentally induced changes in gut microbiota landscape influence the incidence and severity of MIA-induced neurodevelopmental disorders. Herein, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a MIA mouse model of autism. Mechanistically, we show that microflora-dependent calibration of the immune response underlies the effects of the microbiome on inflammation-induced ASD-like phenotypes. Specifically, we find that neutralization of IL-17a ameliorates the ability of the microbiome to affect the development of autism-related behaviors. Our results identify the immune system as a link between gut microbiota and the brain in neurodevelopmental disorders, and suggest that targeting the microbiome and maternal immune responses during gestation may offer strategies to limit autism development in at-risk pregnancies.

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