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.

中文翻译：

---

氧化还原失调在精神分裂症发展中的潜在作用

越来越多的证据表明氧化还原失调是导致精神病出现的病理机制。氧化损伤增加和细胞内氧化还原调节系统能力降低是精神分裂症患者以及随后发展为明显精神病的临床高危人群的一致发现。谷胱甘肽是细胞氧化还原状态的关键调节剂，在精神分裂症患者的内侧前额叶皮层、纹状体和丘脑中，谷胱甘肽的水平会降低。在患有精神分裂症的人类和重现精神分裂症各种特征的啮齿动物模型中，氧化还原失调与含有 γ-氨基丁酸 (GABA) 中间神经元的小清蛋白及其周围神经元网、白质异常和小胶质细胞激活的体积减少有关。重要的是，转录因子的活性，调节神经发育和突触可塑性的不同方面的激酶和磷酸酶根据细胞氧化还原状态而变化。在氧化还原控制下调节中间神经元功能的分子包括 NMDA 受体亚基 GluN1 和 GluN2A 以及 KEAP1（转录因子 NRF2 的调节剂）。在以谷胱甘肽合成受损为特征的啮齿类精神分裂症模型中，Gclm 敲除小鼠，氧化应激通过其氧化还原反应性调节位点激活 MMP9（基质金属蛋白酶 9），引起一系列分子事件，导致小胶质细胞激活、神经周围网络降解和受损NMDA 受体功能。