Manipulation of placental IGF1 and impacts on phenotypes relevant to neurodevelopmental disorders

During pregnancy, placental hormones can influence fetal brain growth and development. Despite recent studies identifying links between placental genetics and fetal brain, the role of the placenta in neurodevelopment is understudied. The production of the placental hormone, insulin-like growth factor 1 (IGF1), is often dysregulated in preterm birth, placental insufficiency, and gestational diabetes. These conditions are linked to elevated neurodevelopmental disorder (NDD) risk with marked sex differences. While IGF1 is required for fetal neurodevelopment, the role of placental IGF1, especially with respect to sex differences, remains poorly understood. I hypothesized that dysregulated placental IGF1 production would sex-specifically alter placental function, subsequently impacting neurodevelopment and behavior. To define placental IGF1’s role in fetal neurodevelopment, I developed a placental-targeted method to genetically manipulate Igf1 in mice. Using this technique, placental Igf1 expression was decreased or increased. After manipulation, placental function, morphological changes in brain development, and behavior were assessed. Outcomes after placental Igf1 manipulation were highly sex dependent. Placental Igf1 overexpression and insufficiency resulted in the expected embryonic striatal overgrowth and undergrowth, respectively, in males and females. Interestingly, males demonstrated placental compensations against the overexpression of Igf1 and subsequently had less severe changes than females in postnatal brain and behavior. Offspring with placental Igf1 insufficiency had sex-specific changes in embryonic forebrain gene expression that were associated with NDD-risk. Sex-specific behavioral changes relevant to NDDs were found in both sexes after increased or decreased placental Igf1. The findings demonstrate that placental IGF1 production can persistently influence brain and behavior development relevant to NDDs.