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Potential Roles of Redox Dysregulation in the Development of Schizophrenia.

ABSTRACT: Converging evidence implicates redox dysregulation as a pathological mechanism driving the emergence of psychosis. Increased oxidative damage and decreased capacity of intracellular redox modulatory systems are consistent findings in persons with schizophrenia as well as in persons at clinical high risk who subsequently developed frank psychosis. Levels of glutathione, a key regulator of cellular redox status, are reduced in the medial prefrontal cortex, striatum, and thalamus in schizophrenia. In humans with schizophrenia and in rodent models recapitulating various features of schizophrenia, redox dysregulation is linked to reductions of parvalbumin containing gamma-aminobutyric acid (GABA) interneurons and volumes of their perineuronal nets, white matter abnormalities, and microglia activation. Importantly, the activity of transcription factors, kinases, and phosphatases regulating diverse aspects of neurodevelopment and synaptic plasticity varies according to cellular redox state. Molecules regulating interneuron function under redox control include NMDA receptor subunits GluN1 and GluN2A as well as KEAP1 (regulator of transcription factor NRF2). In a rodent schizophrenia model characterized by impaired glutathione synthesis, the Gclm knockout mouse, oxidative stress activated MMP9 (matrix metalloprotease 9) via its redox-responsive regulatory sites, causing a cascade of molecular events leading to microglia activation, perineural net degradation, and impaired NMDA receptor function. Molecular pathways under redox control are implicated in the etiopathology of schizophrenia and are attractive drug targets for individualized drug therapy trials in the contexts of prevention and treatment of psychosis.

SUBMITTER: Perkins DO

PROVIDER: S-EPMC7395886 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix-PAS heterodimeric transcription factor that dimerizes with other basic helix-loop-helix-PAS proteins to mediate biological responses. The function of ARNT2 is poorly understood. Here we provide an initial characterization of the zebrafish arnt2 null (arnt2(-/-)) mutant to identify functions of Arnt2 during development. Arnt2(-/-) mutant zebrafish develop normally until 120 hours postfertilization (hpf ) when morphological changes and functional deficits occur. The C-start escape response initiated by either touch or startle stimuli is absent in the mutants. Brain ventricle size is markedly increased at 120 hpf. Heart ventricles are enlarged, with decreased ventricle wall thickness. A cardiac arrhythmia, characterized by missing beats, is also observed in the mutants. This is associated with bradycardia in arnt2(-/-) larvae. Dilated liver sinusoids merge abnormally to form an extensive, labyrinth-like network of vascular channels. External appearance of arnt2(-/-) larvae at 120 hpf is indistinguishable from wild type except that the swim bladder is not inflated. The arnt2(-/-) mutants are not debilitated when phenotypic effects are first detected at 120 hpf that culminate in mortality, 4 days later around 216 hpf. Gross morphological assessment of the development of forebrain, midbrain, and hindbrain regions, neuromasts and Mauthner neurons, inner ear semicircular canals and otoliths, primary motor neurons, trigeminal ganglia, and trunk skeletal muscles, before or when the arnt2(-/-) phenotype was observed, failed to demonstrate a difference from wild type. The only effect in arnt2(-/-) larvae that occurred before 120 hpf was a decrease in expression of sim1, an Arnt2 dimerization partner, in the hypothalamus and ventral thalamus at 72 hpf. Further research is needed to determine if the primary functions of Arnt2 occur during the larval stage, when the phenotype is observed, or earlier in development.

Project description: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.

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Potential Roles of Redox Dysregulation in the Development of Schizophrenia.

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