Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients’ blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients’ group with mitochondrial dysfunction “Psy-D”, having high miR-137 and low COX6A2 levels in exosomes, and (b) a “Psy-ND” subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

精神分裂症的早期检测和干预需要基于机制的生物标志物来捕获神经回路功能障碍，从而更好地对患者进行分层、监测疾病进展和治疗。在前额叶皮层和氧化还原失调小鼠的血液中（Gclm-KO ± GBR)，氧化应激诱导 miR-137 上调，导致 COX6A2 和线粒体自噬标记物（NIX、Fundc1 和 LC3B）减少以及受损线粒体的积累，进一步加剧氧化应激和小清蛋白中间神经元 (PVI) 损伤。MitoQ 是一种靶向线粒体的抗氧化剂，拯救了所有这些过程。转化为早期精神病患者 (EPP)，血液外泌体 miR-137 增加和 COX6A2 减少，结合线粒体自噬标志物的改变，表明在动物模型中中心和外周进行的观察反映在患者的血液中。较高的外泌体 miR-137 和较低的 COX6A2 水平与 EEG 中 ASSR 伽马振荡的减少有关。由于 ASSR 需要适当的 PVI 相关网络，miR-137/COX6A2 血浆外泌体水平的改变可能代表 PVI 皮质微电路损伤的代理标志。EPP 可以分为两个亚组：(a) 具有线粒体功能障碍的患者组“Psy-D”，外泌体中具有高 miR-137 和低 COX6A2 水平，以及 (b) 没有/低线粒体损伤，包括 miR-137 和 COX6A2 水平在对照范围内的患者。Psy-D 患者表现出更多受损的 ASSR 反应与更差的精神病理学状态、神经认知表现以及全球和社会功能相关，这表明 PVI 线粒体的受损导致更严重的疾病概况。这种分层将允许以高选择性和特异性，