Gestational Hypoxia Disrupts Medial Ganglionic Eminence Progenitor Dynamics and Interneuron Development in Schizophrenia
TL;DR
It is demonstrated that developmental redox disruption directly impairs GABAergic circuit assembly, while supporting targeted antioxidant pharmacotherapy during gestation as a translatable strategy to mitigate neurodevelopmental risk.
Abstract
ABSTRACT Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by heterogeneous symptoms and multifactorial etiologies. Medial ganglionic eminence (MGE) spheroids generated from first‐episode schizophrenia (FES) patients revealed accelerated neurodevelopmental trajectories and enhanced hypoxia responses via single‐cell transcriptomics. Notably, FES patient‐derived MGE spheroids exhibited defective interneuron migration, disrupted synaptic ultrastructure, and diminished network synchronization. To establish causal links, the gestational hypoxia mouse model recapitulated key pathologies, including reduced progenitor proliferation, abbreviated cell cycles, mismatched interneuron subtypes, and schizophrenia‐like behavioral deficits in offspring. Critically, maternal administration of N‐acetylcysteine (NAC) restored redox homeostasis and rescued both cellular and behavioral phenotypes. Collectively, these results demonstrate that developmental redox disruption directly impairs GABAergic circuit assembly, while supporting targeted antioxidant pharmacotherapy during gestation as a translatable strategy to mitigate neurodevelopmental risk.