Department of Psychiatry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
Schizophr Bull. 2022 Sep 1;48(5):1136-1144. doi: 10.1093/schbul/sbac069.
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).
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.
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.
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.
精神分裂症的特征是遗传和环境风险因素的复杂相互作用，这些因素集中在协调大脑发育的突出信号通路。Akt/GSK3β/mTORC1 途径长期以来一直被认为是一个汇聚点和病因机制，但尽管有证据表明其功能低下，但目前尚不清楚这是否已经在精神病首次发作（FEP）期间确立。
在这里，我们对来自未经药物治疗的 FEP 患者和对照受试者的新鲜外周血单核细胞中的 Akt、GSK3β 和 mTORC1 下游靶标 S6 进行了系统磷酸化分析。
我们的结果表明 FEP 患者存在 2 种不同的信号内表型。GSK3β 功能低下与精神病理学具有混杂关联，并且在治疗后会恢复正常，而 mTORC1 功能低下则代表一种稳定状态。
我们的研究提供了 Akt/GSK3β/mTORC1 途径外周功能低下的新见解，并强调了 mTORC1 活性作为 FEP 患者外周免疫和代谢状态改变的主要整合者。
