Double-hit of MIA and Nod2 deficiency induces sex-specific offspring behavioral abnormalities through placental dysregulation

The pathogenesis of neuropsychiatric disorders, including autism spectrum disorder and schizophrenia, originates from complex interactions between genetic susceptibility and early environmental exposure. Infectious challenges during pregnancy are well-known environmental risk factors for neurodevelopmental disorders. Our previous research reported the interplay between maternal immune activation (MIA) and nucleotide-binding oligomerization domain-containing protein 2 (Nod2) signaling deficiency as potential genetic and environmental risk factors for schizophrenia pathogenesis. However, the mechanisms underlying this double-hit interaction—specifically regarding maternal-fetal interface homeostasis—remain unclear. In this study, we used the novel double-hit murine model that combines Nod2 knockout (Nod2^−/−) with polyinosinic:polycytidylic acid-induced MIA to systematically assess maternal metabolic profiles, placental developmental dynamics, and offspring behavioral phenotypes. We demonstrated that double-hit exposure has a significant effect on maternal metabolism and offspring development, characterized by sex-specific functional alterations in the placenta and increased susceptibility to neurodevelopmental disorders in male offspring. These results confirmed that the maternal environment modulates offspring neurodevelopment through placental mediation, highlighting the potential of modulating maternal immune-metabolic homeostasis as a preventive strategy against neurodevelopmental disorders.