The role of HIF-1α silencing in late pregnancy hypoxia-induced autism-like behavior in rat offspring

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can be caused by a variety of factors. Our previous study indicated that hypoxia-inducible factor 1 alpha (HIF-1α) plays a role in hypoxia-caused autism-like behavior. In this study, we investigated the mechanism by which HIF-1α contributes to prenatal hypoxia-induced autism-like behavior in vivo to provide an experimental basis for the treatment of ASD. We established a prenatal hypoxia model of pregnant rats by placing 17-day pregnant rats into a self-made hypoxia chamber filled with a nitrogen containing 10%±0.5% oxygen. Within 24 h after birth, the lateral ventricles of the prenatal hypoxia offspring rats were injected with a recombinant adeno-associated virus designed to silence HIF-1α expression. The autistic behavior of offspring rats in the HIF-1α silenced group was significantly alleviated compared with that of the prenatal hypoxia group. With the silencing of HIF-1α, the activity of phosphatase and tensin homolog (PTEN) increased and the PI3K/AKT pathway was inhibited by negative feedback. The mRNA expression level of vascular endothelial growth factor (VEGF) was decreased in the Si-HIF-1α silenced group and N-methyl D-aspartate receptor subtype 2 (NR2A) expression was downregulated. Thus, our study indicates that HIF-1α plays a role in hypoxia-induced autism-like behavior, and its regulatory effect may be achieved by inhibiting the activity of PTEN, resulting in activation of the PI3K signaling pathway. Synaptic plasticity regulation may also be involved.