Fetal immunity and the developing brain: implications for neurodevelopmental disorders.
The brain has innate immune myeloid cells (including microglia and border-associated macrophages) that have dynamic roles in homeostasis and the response to tissue injury and infection. Given the ability of brain myeloid cells to sense a variety of environmental cues, several studies have investigated their roles in neurodegenerative disease onset and progression. But, the impact of fetal myeloid cells on neurodevelopmental disorders is relatively unexplored in comparison. We used two mouse models of neurodevelopmental disorders to uncover the impact of fetal myeloid cell immunity to both normal and abnormal brain development. We found that an inflammatory lytic form of cell death, termed pyroptosis, in microglia may be required for establishing certain normal behavioral circuits. With genetic deficiency in the pyroptosis pathway, or upon pharmacological inhibition thereof, mice have attention-deficit/hyperactivity disorder (ADHD)-like behavior changes. Using the maternal immune activation (MIA) model of autism spectrum disorder (ASD), we identified a fetal myeloid responder population, likely to be border-associated macrophages, which directly sense MIA challenge. Thus, we learned that fetal immunity, mediated by myeloid cells, has important consequences for brain formation. Disruption or activation of these roles may constitute an upstream arm in neurodevelopmental disorder etiology.