Maternal immune mechanisms and offspring neurodevelopment

Inflammation during pregnancy occurs in gestational diabetes, preeclampsia, maternal stress, and other conditions. Convergent evidence from the human literature has associated gestational inflammation with increased risk for offspring neuropsychiatric disorders, including autism spectrum disorder, ADHD, anxiety and mood disorders, and others. To minimize this risk and develop new treatments, an understanding of the underlying mechanisms and specific mediators is critical. Using multiple preclinical models of prenatal inflammation, we examined the maternal and offspring mechanisms underlying offspring neurodevelopmental risk. In a chronic restraint model of prenatal maternal stress, we found that the pro-inflammatory cytokine IL-6 mediated some but not all stress impacts on offspring (e.g., pre- and postnatal cortical microglia phenotypes but not GABAergic or behavior changes). Similarly, we found that chronically elevated maternal IL-17 was sufficient to cause some ASD-like offspring phenotypes (e.g., dysregulated cell cycle genes, synaptic development, and behavior) in male but not female offspring. Finally, in a pro-inflammatory murine model of preeclampsia (created by the Grobe and Santillan labs), we found that hypovolemic mechanisms but not cell death or atrophy likely mediated offspring brain growth and behavior changes. These findings demonstrate that altered maternal levels of single cytokines (e.g., IL-6 and IL-17) can change the developing brain in lasting ways. This work also suggests that complex inflammatory states such as preeclampsia and maternal stress impact offspring neurodevelopment and behavior at multiple levels. No single target mediates these impacts, but rather many cytokines/inflammatory proteins are involved. It is our hope that delineating these targets and the underlying pathophysiology will promote the future development of treatment and prevention strategies.