Background and Hypothesis Schizophrenia is characterized by a complex interplay between genetic and environmental risk factors converging on prominent signaling pathways that orchestrate brain development. The Akt/GSK3β/mTORC1 pathway has long been recognized as a point of convergence and etiological mechanism, but despite evidence suggesting its hypofunction, it is still not clear if this is already established during the first episode of psychosis (FEP). Study Design Here, we performed a systematic phosphorylation analysis of Akt, GSK3β, and S6, a mTORC1 downstream target, in fresh peripheral blood mononuclear cells from drug-naive FEP patients and control subjects. Study Results Our results suggest 2 distinct signaling endophenotypes in FEP patients. GSK3β hypofunction exhibits a promiscuous association with psychopathology, and it is normalized after treatment, whereas mTORC1 hypofunction represents a stable state. Conclusions Our study provides novel insight on the peripheral hypofunction of the Akt/GSK3β/mTORC1 pathway and highlights mTORC1 activity as a prominent integrator of altered peripheral immune and metabolic states in FEP patients.

中文翻译：

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GSK3β 和 mTORC1 代表未接受药物治疗的首发精神病患者外周血单核细胞中的 2 个不同信号标志物

背景和假设 精神分裂症的特征是遗传和环境风险因素之间复杂的相互作用，这些因素汇聚在协调大脑发育的重要信号通路上。Akt/GSK3β/mTORC1 通路长期以来一直被认为是一个聚合点和病因机制，但尽管有证据表明其功能减退，但仍不清楚这是否已经在精神病首发 (FEP) 期间建立。研究设计 在这里，我们对来自未接受药物治疗的 FEP 患者和对照受试者的新鲜外周血单核细胞中的 Akt、GSK3β 和 S6（mTORC1 下游靶标）进行了系统的磷酸化分析。研究结果 我们的结果表明 FEP 患者有 2 种不同的信号内表型。GSK3β 功能减退表现出与精神病理学的混杂关联，并且在治疗后正常化，而 mTORC1 功能减退代表稳定状态。结论 我们的研究提供了关于 Akt/GSK3β/mTORC1 通路外周功能减退的新见解，并强调 mTORC1 活性是 FEP 患者外周免疫和代谢状态改变的重要整合因子。