Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis

Schizophr Bull. 2021 Oct 21;47(6):1782-1794. doi: 10.1093/schbul/sbab066.


Research 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.

Keywords: antioxidant; brain development; cognition; early psychosis; mechanism; physical exercice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology*
  • Adult
  • Animals
  • Combined Modality Therapy
  • Disease Models, Animal
  • Exercise Therapy*
  • Female
  • Glutamate-Cysteine Ligase / deficiency
  • Humans
  • Interneurons / drug effects*
  • Interneurons / metabolism
  • Male
  • Matrix Metalloproteinase 9 / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress / drug effects*
  • Parvalbumins / metabolism
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / metabolism
  • Psychotic Disorders / therapy*
  • Receptor for Advanced Glycation End Products / drug effects*
  • Signal Transduction / drug effects
  • Translational Research, Biomedical


  • Parvalbumins
  • Receptor for Advanced Glycation End Products
  • Matrix Metalloproteinase 9
  • GCLM protein, mouse
  • Glutamate-Cysteine Ligase
  • Acetylcysteine