Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA.
Neuropsychopharmacology. 2022 Nov;47(12):2033-2041. doi: 10.1038/s41386-022-01310-8. Epub 2022 Mar 30.
Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding SCZ pathophysiology, are analyzing the drug effects. We hypothesized that comparing SCZ-altered and APD-influenced signatures derived from the same cohort can provide better insight into SCZ pathophysiology. For this, we performed LCMS-based proteomics on dorsolateral prefrontal cortex (DLPFC) samples from control and SCZ subjects and used statistical approaches to identify SCZ-altered and APD-influenced proteomes, validated experimentally using independent cohorts and published datasets. Functional analysis of both proteomes was contrasted at the biological-pathway, cell-type, subcellular-synaptic, and drug-target levels. In silico validation revealed that the SCZ-altered proteome was conserved across several studies from the DLPFC and other brain areas. At the pathway level, SCZ influenced changes in homeostasis, signal-transduction, cytoskeleton, and dendrites, whereas APD influenced changes in synaptic-signaling, neurotransmitter-regulation, and immune-system processes. At the cell-type level, the SCZ-altered and APD-influenced proteomes were associated with two distinct striatum-projecting layer-5 pyramidal neurons regulating dopaminergic-secretion. At the subcellular synaptic level, compensatory pre- and postsynaptic events were observed. At the drug-target level, dopaminergic processes influenced the SCZ-altered upregulated-proteome, whereas nondopaminergic and a diverse array of non-neuromodulatory mechanisms influenced the downregulated-proteome. Previous findings were not independent of the APD effect and thus require re-evaluation. We identified a hyperdopaminergic cortex and drugs targeting the cognitive SCZ-symptoms and discussed their influence on SCZ pathology in the context of the cortico-striatal pathway.
抗精神病药物（APD）在治疗精神分裂症（SCZ）的阳性症状方面非常有效。然而，它们对死后研究有很大的影响。由于大多数队列缺乏来自未经药物治疗的患者的样本，因此许多研究不是在了解 SCZ 病理生理学，而是在分析药物的影响。我们假设，比较来自同一队列的 SCZ 改变和 APD 影响的特征可以更好地了解 SCZ 病理生理学。为此，我们对来自对照和 SCZ 受试者的背外侧前额叶皮层（DLPFC）样本进行了基于 LCMS 的蛋白质组学分析，并使用统计方法来鉴定 SCZ 改变和 APD 影响的蛋白质组，使用独立的队列和已发表的数据集进行了实验验证。在生物途径、细胞类型、亚细胞突触和药物靶点水平上对这两种蛋白质组进行了功能分析。在计算机上验证表明，SCZ 改变的蛋白质组在 DLPFC 和其他大脑区域的几个研究中是保守的。在途径水平上，SCZ 影响了内稳态、信号转导、细胞骨架和树突的变化，而 APD 影响了突触信号、神经递质调节和免疫系统过程的变化。在细胞类型水平上，SCZ 改变和 APD 影响的蛋白质组与两种不同的调节多巴胺分泌的纹状体投射层 5 锥体神经元有关。在亚细胞突触水平上，观察到了代偿性的突触前和突触后事件。在药物靶点水平上，多巴胺能过程影响了 SCZ 改变的上调蛋白质组，而非多巴胺能和各种非神经调节机制影响了下调蛋白质组。以前的发现不受 APD 效应的影响，因此需要重新评估。我们确定了一个超多巴胺能皮层和针对认知 SCZ 症状的药物，并在皮质-纹状体通路的背景下讨论了它们对 SCZ 病理的影响。
