MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients

• Type of Material: Article
• Authors: Daniella Dwir, University of Lausanne; Basilio Giangreco, University of Lausanne; Lijing Xin, Ecole Polytechnique Fédérale de Lausanne; Liliane Tenenbaum, Centre Hospitalier Universitaire Vaudois; Jan-Harry Cabungcal, University of Lausanne; Pascal Steullet, University of Lausanne; Audrey Goupil, University of Lausanne; Martine Cleusix, University of Lausanne; Raoul Jenni, University of Lausanne; Abdelwahed Chtarto, Université Libre de Bruxelles; Philipp S. Baumann, University of Lausanne; Paul Klauser, University of Lausanne; Philippe Conus, University of Lausanne; Rabindra Tirouvanziam, Emory University; Michel Cuenod, University of Lausanne; Kim Q. Do, University of Lausanne
• Language: English
• Date: 2020-11-01
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41380-019-0393-5
• Title of Journal or Parent Work: MOLECULAR PSYCHIATRY
• Volume: 25
• Issue: 11
• Start Page: 2889
• End Page: 2904
• Grant/Funding Information: This work was supported by the Swiss National Science Foundation (320030_122419 to PC. and KQD), National Center of Competence in Research (NCCR) “SYNAPSY—The Synaptic Bases of Mental Diseases” financed by the Swiss National Science Foundation (n°51NF40 – 185897). Magnetic resonance spectroscopy was performed in the Centre d’Imagerie BioMédicale (CIBM) of the UNIL, UNIGE, HUG, CHUV, EPFL and the Leenaards and Jeantet Foundations. We are grateful for support from the Damm-Etienne Foundation, Pro Scientia et Arte, Avina Foundation and Alamaya Foundation.
• Keywords: PREFRONTAL CORTEX; Neurosciences; NADPH-OXIDASE; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; OXIDATIVE STRESS; MATRIX-METALLOPROTEINASE-9 MMP-9; GLUTATHIONE DEFICIT; GLYCATION END-PRODUCTS; PERINEURONAL NETS; MR SPECTROSCOPY; Science & Technology; Neurosciences & Neurology; PARVALBUMIN INTERNEURONS; MATRIX METALLOPROTEINASES; Psychiatry
• Research Categories: Psychology, Cognitive; Biology, Neuroscience

Abstract

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress “hub” affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258–70); (Nat Rev Neurosci. 2016;17:125–34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm−/−), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721–8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets.