Journal Article

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

Klauser, Paul, Baumann, Philipp S, Cleusix Martine, Abdelwahed, Chtarto, Do, Kim Q, Conus Philippe, Cuenod Michel, Dwir Daniella, Tenenbaum Liliane, Steullet Pascal, Goupil Audrey, Jan-Harry, Cabungcal, Giangreco Basilio, Xin Lijing, Tirouvanziam Rabindra, Jenni Raoul

2020

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Acetylcysteine / Advanced glycosylation end products / Antioxidants / Cortex (cingulate) / Cytokines / Gelatinase B / Glutamic acid receptors (ionotropic) / Glutathione / Glycosylation / Inflammation / Interneurons / Matrix metalloproteinase / Mental disorders / Metalloproteinase / Microglia / N-Methyl-D-aspartic acid receptors / NF-κB protein / Oxidative stress / Perineuronal nets / Schizophrenia / Therapeutic targets / Transgenic mice / Translation / γ-Aminobutyric acid