Stress during critical periods of development and risk for schizophrenia
Stress during critical periods of development and risk for schizophrenia
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DOI：
10.1016/j.schres.2019.01.030
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发表时间：
2019-11-01
影响因子：
4.5
通讯作者：
Grace, Anthony A.
中科院分区：
文献类型：
--
作者：
Gomes, Felipe, V;Zhu, Xiyu;Grace, Anthony A.
精神分裂症是一种具有遗传倾向的神经发育障碍，长期以来，压力与其病因有关。虽然压力影响疾病的所有阶段，但越来越多的证据表明，在发展的关键时期的压力可能特别有害，增加了个人对精神病的脆弱性。为了彻底了解压力的潜在致病作用，我们的小组一直专注于产前甲基偶氮甲醇乙酸酯（MAM）啮齿动物模型，并发现MAM后代在青春期前表现出异常的压力反应性和高度焦虑，在表现出高多巴胺能状态之前。此外，在青春期前对焦虑进行长期治疗可以防止成年后多巴胺功能障碍的出现。有趣的是，足够强的压力施加到正常大鼠选择性在早期发展可以概括多种精神分裂症相关的表型MAM大鼠，而相同的压力模式在成年期只产生短期抑郁症相关的赤字。总而言之，证据是趋同的：发育中断（遗传或环境）可能会使动物在关键时间窗口期间更容易受到压力的有害影响，在此期间，不受调节的压力可能导致以后生活中出现精神病。作为调节中脑多巴胺系统的重要区域，腹侧海马特别容易受到压力的影响，其快速尖峰小白蛋白中间神经元的独特成熟特征可能在很大程度上是这种脆弱性的基础。在这篇综述中，通过讨论跨越临床和基础科学研究的新证据，我们提出发展压力脆弱性作为精神分裂症病理生理学中早期易感性和环境触发事件之间的新联系。这一有前途的研究路线不仅可以提供对病因学的深入了解，还可以为疾病预防提供“路线图”。(C)2019爱思唯尔B.V.保留所有权利。
Schizophrenia is a neurodevelopmental disorder with genetic predisposition, and stress has long been linked to its etiology. While stress affects all stages of the illness, increasing evidence suggests that stress during critical periods of development may be particularly detrimental, increasing individual's vulnerability to psychosis. To thoroughly understand the potential causative role of stress, our group has been focusing on the prenatal methylazoxymethanol acetate (MAM) rodent model, and discovered that MAM offspring display abnormal stress reactivity and heightened anxiety prepubertally, prior to the manifestation of a hyperdopaminergic state. Furthermore, pharmacologically treating anxiety during prepuberty prevented the emergence of the dopamine dysfunction in adulthood. Interestingly, sufficiently strong stressors applied to normal rats selectively during early development can recapitulate multiple schizophrenia-related phenotypes of MAM rats, whereas the same stress paradigm during adulthood only produced short-term depression-related deficits. Altogether, the evidence is thus converging: developmental disruption (genetic or environmental) might render animals more susceptible to the deleterious effects of stress during critical time windows, during which unregulated stress can lead to the emergence of psychosis later in life. As an important region regulating the midbrain dopamine system, the ventral hippocampus is particularly vulnerable to stress, and the distinct maturational profile of its fast-spiking parvalbumin interneurons may largely underlie such vulnerability. In this review, by discussing emerging evidence spanning clinical and basic science studies, we propose developmental stress vulnerability as a novel link between early predispositions and environmental triggering events in the pathophysiology of schizophrenia. This promising line of research can potentially provide not only insights into the etiology, but also a "roadmap" for disease prevention. (C) 2019 Elsevier B.V. All rights reserved.