Gomes Felipe V, Zhu Xiyu, Grace Anthony A
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, PA, USA.
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, PA, USA.
Schizophr Res. 2019 Nov;213:107-113. doi: 10.1016/j.schres.2019.01.030. Epub 2019 Jan 30.
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.
精神分裂症是一种具有遗传易感性的神经发育障碍，长期以来应激一直与其病因相关联。虽然应激会影响疾病的各个阶段，但越来越多的证据表明，发育关键期的应激可能特别有害，会增加个体患精神病的易感性。为了全面了解应激的潜在致病作用，我们团队一直专注于产前醋酸甲基氧化偶氮甲醇（MAM）啮齿动物模型，并发现MAM后代在青春期前表现出异常的应激反应性和焦虑加剧，此时多巴胺能亢进状态尚未显现。此外，青春期前对焦虑进行药物治疗可预防成年期多巴胺功能障碍的出现。有趣的是，在正常大鼠早期发育期间选择性施加足够强烈的应激源，可以重现MAM大鼠的多种精神分裂症相关表型，而成年期相同的应激模式只会产生短期的抑郁相关缺陷。总之，证据正在趋同：发育干扰（遗传或环境）可能使动物在关键时间窗口更容易受到应激的有害影响，在此期间不受控制的应激可能导致日后出现精神病。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应激影响，其快速放电小白蛋白中间神经元独特的成熟特征可能在很大程度上是这种易感性的基础。在这篇综述中，通过讨论临床和基础科学研究中出现的数据，我们提出发育应激易感性是精神分裂症病理生理学中早期易感性与环境触发事件之间的新联系。这一有前景的研究方向不仅可能为病因学提供见解，还可能为疾病预防提供一个“路线图”。
