N-acetylcysteine Restores Impaired Dentate Gyrus Neurogenesis in a Neonatal Maternal Separation Rat Model.

Early-life stress (ELS) is a major contributor to neurodevelopmental vulnerability, particularly within the dentate gyrus (DG), where oxidative burden and microglial activation disrupt adult neurogenesis. Here, we examined whether N-acetylcysteine (NAC), a cysteine prodrug and glutathione precursor, could counteract impaired neurogenesis induced by neonatal maternal separation (NMS). Adolescent NAC administration restored the number of Ki67⁺ proliferating progenitors and DCX⁺ immature neurons in the DG of NMS rats, accompanied by reduced reactive oxygen species, suppressed iNOS induction, and attenuated microglial activation. NAC also normalized EAAC1 expression, indicating enhanced neuronal antioxidant capacity. Notably, NAC rescued diminished neurogenesis in EAAC1 knockout mice, demonstrating its efficacy under both stress-induced and transporter-deficient redox imbalance. These findings identify NAC as a potent modulator of hippocampal neuroplasticity, acting through the restoration of redox and inflammatory homeostasis, and support its potential as an early therapeutic strategy to mitigate long-lasting neurodevelopmental consequences of ELS.