Behavioural Neuroscience Laboratory, The Florey Institute of Neuroscience & Mental Health, Parkville, Vic., Australia.
J Neurochem. 2014 May;129(3):377-87. doi: 10.1111/jnc.12622. Epub 2013 Dec 25.
The mammalian target of rapamycin (mTOR) signalling cascade is involved in the intracellular regulation of protein synthesis, specifically for proteins involved in controlling neuronal morphology and facilitating synaptic plasticity. Research has revealed that the activity of the mTOR cascade is influenced by several extracellular and environmental factors that have been implicated in schizophrenia. Therefore, there is reason to believe that one of the downstream consequences of dysfunction or hypofunction of these factors in schizophrenia is disrupted mTOR signalling and hence impaired protein synthesis. This results in abnormal neurodevelopment and deficient synaptic plasticity, outcomes which could underlie some of the positive, negative and cognitive symptoms of schizophrenia. This review will discuss the functional roles of the mTOR cascade and present evidence in support of a novel mTOR-based hypothesis of the neuropathology of schizophrenia. During neurodevelopment, genetic and epigenetic factors can disrupt mTOR signalling which affects synthesis of proteins essential for correct neuronal growth and network connectivity. This renders the CNS particularly vulnerable to the effects of secondary factors during adolescence which increases the risk of developing schizophrenia in adulthood. This review discusses the functional roles of the mTOR cascade and presents evidence in support of a novel mTOR-based hypothesis of the neuropathology of schizophrenia. Testing this hypothesis will advance our understanding of the aetiology of this illness and reveal novel therapeutic targets.
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路参与细胞内蛋白质合成的调节，特别是参与控制神经元形态和促进突触可塑性的蛋白质。研究表明，mTOR 级联的活性受几种与精神分裂症有关的细胞外和环境因素的影响。因此，有理由相信，这些因素在精神分裂症中的功能障碍或功能低下的一个下游后果是 mTOR 信号的中断，从而导致蛋白质合成受损。这导致异常的神经发育和突触可塑性不足，这些结果可能是精神分裂症阳性、阴性和认知症状的基础。本综述将讨论 mTOR 级联的功能作用，并提供支持精神分裂症神经病理学新的基于 mTOR 的假说的证据。在神经发育过程中，遗传和表观遗传因素会破坏 mTOR 信号，从而影响对正确神经元生长和网络连接至关重要的蛋白质的合成。这使得中枢神经系统特别容易受到青春期二次因素的影响，从而增加成年后患精神分裂症的风险。本综述讨论了 mTOR 级联的功能作用，并提供支持精神分裂症神经病理学新的基于 mTOR 的假说的证据。测试这一假设将增进我们对这种疾病病因的理解，并揭示新的治疗靶点。
