Prednisone Exposure During Pregnancy Increases Susceptibility to Epilepsy in Adult Offspring Mice

Prenatal glucocorticoid exposure is associated with multiple long-term health risks in offspring. Prednisone is the most commonly used oral glucocorticoid. Although prior studies have shown that prenatal prednisone exposure (PPE) induces renal abnormalities in offspring rats and genital developmental abnormalities in offspring mice, its effects on brain development remain poorly understood. Our results showed that PPE impairs the proliferation and differentiation of neural progenitor cell, reduces neurogenesis, induces synaptic dysfunction, and affects microglial proliferation in offspring mice. These impairments were observed in female offspring during gestational days 0 to 9 (GD0-9) and GD0-18, whereas in male offspring, they were observed during GD0-18. We further identified that transient receptor potential vanilloid 1 (TRPV1) is upregulated in PPE offspring mice, and the epileptic phenotype was significantly attenuated in TRPV1^-/- mice. Mechanistically, this attenuation was mediated by glucocorticoid receptor activation, which subsequently triggered intracellular cyclic adenosine monophosphate (cAMP) signaling. Collectively, our study identifies a specific time window of neurotoxicity associated with PPE and provides evidence supporting the developmental origin of epilepsy in this context.