Maternal immune activation induces epilepsy- patent foramen ovale comorbidity in offspring.

Abstract

Clinical evidence suggests that patent foramen ovale (PFO) is a common comorbidity in patients with epilepsy, but shared etiology remains unclear. Maternal immune activation (MIA) is a known risk factor for neurodevelopmental disorders in offspring, including epilepsy. However, its impact on cardiac development remains largely unexplored. Here, we employed a poly(I:C)-induced severe MIA rat model and found a single MIA insult concurrently increases seizure susceptibility and PFO prevalence in offspring. Integrated transcriptomic analyses revealed convergent upregulation and functional enrichment of the Hippo signaling pathway in both the brain tissues of MIA offspring and in atrial septa from PFO  rats. Critically, as the terminal effector of the Hippo pathway, Yap1 was downregulated in nucleus of endothelial cells from human epileptic brain samples by snRNA-seq analysis. We demonstrated the role of Yap1 in the pathogenesis of PFO formation using both in vivo and in vitro models. The inhibition of Yap1 on neonatal pups and HUVECs causes impaired endothelial-to-mesenchymal transition (EndMT), recapitulating the cellular defect hypothesized to underlie PFO. Collectively, these findings suggest MIA as a common etiological factor for epilepsy and PFO, implicating Hippo pathway activation and the functional repression of Yap1 as a pivotal shared mechanism that concurrently disrupts neurodevelopment and cardiac development, ultimately leading to this comorbidity.