GR / HDAC3 Regulates Npas4 Signaling Pathway and Mediates Cognitive Impairment in Prenatal Hypoxia Male Offspring

Prenatal hypoxia (PH) is a common pregnancy complication that can lead to cognitive impairment in the offspring, but the underlying mechanisms remain unclear. In this study, we established a model of PH by exposing C57 mice to hypoxia (10.5% oxygen) environment from gestational day (GD) 12.5-17.5. We found that PH resulted in cognitive impairment and reduced hippocampal neurogenesis in male offspring compared to control offspring. Mechanistically, PH is a form of prenatal stress that promotes placental transfer of maternal glucocorticoids (GC), which induces hyperactivity of the fetal hypothalamic-pituitary-adrenal (HPA) axis, leading to downregulation of the hippocampal glucocorticoid receptor (GR) in the offspring. In addition, PH promotes increased nuclear translocation of the GR and histone deacetylase 3 (HDAC3) complex, which represses the expression of immediate-early gene Npas4. By acting as a GR receptor antagonist, Mifepristone (MIF) mitigates ameliorated neurogenesis and cognitive impairment in the hippocampus of PH male offspring through the GR/HDAC3-Npas4 pathway. Thus, our study reveals that the GR/HDAC3-Npas4 signaling pathway is implicated in reduced hippocampal neurogenesis and cognitive impairment in PH male offspring. This research provides support for the pathogenesis of fetal cognitive impairment caused by PH.