Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia
Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia
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DOI：
10.1038/ng1296
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发表时间：
2004-02-01
期刊：
影响因子：
30.8
通讯作者：
Gogos, JA
中科院分区：
文献类型：
--
作者：
Emamian, ES;Hall, D;Gogos, JA
AKT-GSK 3 β信号传导是锂的靶点，因此与情绪障碍的发病机制有关。在这里，我们提供的证据表明，这种信号通路也有精神分裂症的作用。具体而言，我们目前收敛的证据表明，在AKT 1蛋白水平和水平的磷酸化GSK 3 β在Ser 9的外周淋巴细胞和精神分裂症患者的大脑;精神分裂症和AKT 1单倍型与较低的AKT 1蛋白水平的显着关联;和更大的敏感性，安非他明的感觉门控破坏性作用，赋予AKT 1缺乏症。我们的研究结果支持了AKT 1-GSK 3 β信号通路的改变与精神分裂症发病机制有关的观点，并将AKT 1确定为潜在的精神分裂症易感基因。与这一提议一致，我们还表明氟哌啶醇诱导治疗小鼠大脑中AKT 1调节磷酸化的逐步增加，这可以补偿精神分裂症中该信号通路的受损功能。
AKT-GSK3beta signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3beta at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3beta signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.