Human epidemiological studies suggest that fetuses exposed to maternal inflammation during the late first or the second trimester have an increased likelihood of neurodevelopmental disorders. Studies are needed to define the molecular and cellular mechanisms by which immune activation during pregnancy translates into neurodevelopmental and behavioral abnormalities in children. Using a mouse model of maternal immune activation (MIA), we demonstrated that Th17 cells are critical mediators that induce neurodevelopmental disorder-like phenotypes in the affected offspring exposed to prenatal inflammation. We also demonstrated that inflammation-induced neurodevelopmental disorder phenotypes in the offspring require maternal intestinal bacteria such as segmented filamentous bacteria (SFB) that promote Th17 cell differentiation. Moreover, we have spatially and functionally mapped the brain regions that mediate behavioral abnormalities. Inflammation during pregnancy in humans, however, does not always lead to the birth of children with neurodevelopmental disorders, suggesting that there are factors that suppress maternal Th17 cell-dependent, neurodevelopmental disorder-like phenotypes in the affected offspring. We hypothesize that pregnancy- associated changes in immune cell function and the composition of commensal bacteria favor anti- inflammatory responses that dictate both the amplitude and specificity of immune responses against infection and other inflammatory conditions. In the proposed application, we will first determine the pregnancy-induced changes in immune cell function and their impact on MIA-like phenotypes in offspring. Secondly, we will investigate if pregnancy-associated changes in the bacterial community of the maternal guts contribute to anti-inflammatory responses. Lastly, we propose that by harnessing pregnancy-associated anti-inflammatory responses we can develop preventive ways to suppress neuronal and behavioral changes in the MIA-affected offspring.
Our proposal will define the process by which immune activation during pregnancy leads to neurodevelopmental disorders in children. We will determine the key changes in immune cell function and maternal bacteria that occur during pregnancy and how these changes may impact the brain development of the fetus. These studies can help identify new targets and therapies to prevent inflammation-induced neurodevelopmental disorders.