Background and Hypothesis Cognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia. Study Design Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (n = 27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n = 26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify (1) numbers of PVI across the cortical mantle (20 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2–4 (23 unaffected comparison, 18 schizophrenia). Study Results In schizophrenic patients, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2–4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and total DLPFC gray matter. Conclusions Our findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.

中文翻译：

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线粒体基质蛋白亲环蛋白 D 的升高与精神分裂症患者前额皮质中小清蛋白表达的减少相关

背景和假设精神分裂症的认知缺陷与背外侧前额叶皮质（DLPFC）的功能障碍有关，包括表达小清蛋白（PV）的中间神经元（PVI）的改变。氧化还原失调和氧化应激可能代表精神分裂症病理学的汇聚点，导致 GABA 能中间神经元功能障碍和 PV 损失。在这里，我们发现线粒体基质蛋白亲环蛋白 D (CypD) 是线粒体通透性转换孔 (mPTP) 的关键引发剂和细胞内氧化还原状态的调节剂，在精神分裂症的 PVI 中发生了改变。研究设计 使用蛋白质印迹法测量精神分裂症患者 (n = 27) 和没有已知精神或神经系统疾病史的匹配对照受试者 (n = 26) 死后 DLPFC 标本中的 CypD 蛋白水平。在该队列的一个子集中，使用多标记免疫荧光共聚焦显微镜和无偏立体采样方法来量化（1）整个皮质套的 PVI 数量（20 个未受影响的比较，14 个精神分裂症）和（2）来自 PVI 的 PV 和 CypD 蛋白水平皮质层 2-4（23 个未受影响的比较，18 个精神分裂症）。研究结果 在精神分裂症患者中，DLPFC 中的 PVI 总数没有显着改变，但与未受影响的对照受试者相比，第 2-4 层的单个 PVI 中 PV 蛋白水平沿浅表到深部的梯度下降。这些层流特异性 PVI 改变与 PVI 和总 DLPFC 灰质中 CypD 的显着升高相互相关。结论 我们的研究结果支持先前报道的精神分裂症 PVI 异常，并表明 CypD 介导的 mPTP 形成可能是精神分裂症 PVI 功能障碍的潜在因素。