Embryonic and placental factors are linked with the development of autism-like behaviors in the BTBR mouse model.

Neurodevelopmental disorders arise from the interplay between genetic and maternal influences during prenatal life. Using the BTBR T+Itpr3tf/J (BTBR) mouse model of idiopathic autism and the C57BL/6J (B6) control strain, we examined how embryonic genotype and maternal environment interact to shape placental development, fetal growth, and postnatal behavior. Quantitative analyses of fetal and placental weights confirmed strain- and stage-specific growth restriction in BTBR conceptuses (n = 18-35 conceptuses from 3 litters per strain). Morphological assessment further demonstrated a substantial strain effect on placental layers, characterized by enlarged labyrinth compartments and reduced glycogen stores in BTBR placentas. Through reciprocal embryo transfers (n = 3 litters per strain combination), we found that maternal strain predominantly determined placental morphology: BTBR and B6 conceptuses developed placentas that mirrored the histological architecture of their foster mothers. In contrast, autism-like behaviors remained specific to BTBR offspring, regardless of the maternal strain, indicating a prevalent embryonic genotype effect on behavioral outcomes. Placental transcriptomic profiling (n = 4 conceptuses per strain) revealed an enrichment in lipid metabolism, nutrient transport, and extracellular matrix remodeling pathways. Together, these findings indicate that maternal factors primarily shape placental architecture, whereas embryonic determinants are linked with the development of autism-like behaviors in the BTBR mouse model. These insights advance our understanding of early-life determinants of autism and suggest placental metabolism as a potential target for early diagnosis of neurodevelopmental risk.