High-Level Exposure of Testosterone During Mouse Pregnancy Impairs the Offspring Social Behavior by Interrupting Neurexin–Neuroligin Binding

Background/Objectives: The onset of autism spectrum disorder (ASD) is thought to be related to fetal testosterone (TSTN) levels or the binding of neurexin (Nrxn) to neuroligin (Nlgn), as per some studies. However, the underlying molecular mechanisms remain unclear. We found that high concentrations of TSTN interrupt Nrxn–Nlgn binding in the neonatal brain, causing impaired social behavior. Methods: We reproduced high concentrations of TSTN in the womb by injecting TSTN into pregnant mice, followed by the quantification of Nrxn–Nlgn binding in the neonatal brain. We also explored the sociability and social novelty preferences of male and female offspring. Results: Nrxn–Nlgn binding in the neonatal brain decreased after TSTN injection. Furthermore, male mice showed impairment in social novelty, whereas female mice showed impairments in both social novelty and sociability following TSTN injection. Conclusions: This study revealed that high concentrations of TSTN during brain development interrupted Nrxn–Nlgn binding and led to impairments in social behavior.