Dwir, DaniellaCabungcal, Jan-HarryXin, LijingGiangreco, BasilioParietti, EneaCleusix, MartineJenni, RaoulKlauser, PaulConus, PhilippeCuenod, MichelSteullet, PascalDo, Kim Q.2021-12-042021-12-042021-12-042021-11-0110.1093/schbul/sbab066https://infoscience.epfl.ch/handle/20.500.14299/183571WOS:000715376600026Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.Psychiatryantioxidantphysical exercicemechanismbrain developmentearly psychosiscognitioninduced developmental delaysconsensus cognitive batteryprefrontal cortexredox dysregulationperineuronal netsdouble-blindinhibitory interneuronsglutathione precursoraerobic exercisemr spectroscopytext::journal::journal article::research article