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.
Highlights
The pathophysiology of schizophrenia (SZ) was shown to be neurodevelopmental, involving both environmental and genetic factors which converge at redox imbalance and immune dysregulation [1,2,3,4,5]
We investigated the impact of matrix metalloproteinase 9 (MMP9) on oxidative stress (OxS) and neuroinflammation propagation, followed by an investigation of its effect on the alteration of perineuronal nets (PNN), the first components affected by OxS due to their role as a protective shield for Parvalbumin-expressing fast-spiking interneurons (PVI) [19], observed at PND40 in the Gclm knockout (Gclm-KO) mice [18]
Our results suggest a feedforward potentiation loop between OxS and neuroinflammation involving the following steps: activation of MMP9 by OxS, leading to receptor for advanced glycation end-products (RAGE) shedding, followed by NFkB activation, secretion of pro-inflammatory cytokines, microglia activation and further reactive oxygen species (ROS) production and OxS during juvenile postnatal development (Fig. 5a)
Summary
The pathophysiology of schizophrenia (SZ) was shown to be neurodevelopmental, involving both environmental and genetic factors which converge at redox imbalance and immune dysregulation [1,2,3,4,5]. Extended author information available on the last page of the article neuroinflammation may persistently affect brain development, and the redox-sensitive Parvalbumin-expressing fast-spiking interneurons (PVI). Recent studies suggest that OxS-induced parvalbumin interneurons impairments represents a pathophysiological hub, on which converge various causal genetic and environmental risk factors during neurodevelopment. The genetic vulnerability factors involve either redox regulation genes directly, affecting glutathione (GSH)
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