Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland.
Prog Neurobiol. 2010 Mar;90(3):285-326. doi: 10.1016/j.pneurobio.2009.10.018. Epub 2009 Oct 24.
Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, but they also offer important new avenues for the elucidation of neurobiological, neuroendocrine and neuroimmunological mechanisms involved in the etiopathogenesis of schizophrenia and related disorders.
人类流行病学研究提供了令人信服的证据，表明产前和/或围产期暴露于各种环境应激原，包括母体应激、感染和/或免疫激活、营养缺乏和产科并发症，会显著增加精神分裂症的发病风险。基于这些关联，人们对建立基于产前和/或围产期暴露于此类环境刺激的神经发育动物模型产生了浓厚的兴趣。在本综述中，我们描述了与精神分裂症的病因、神经生物学和精神药理学相关的这种相对新颖的基于流行病学的动物模型。由此，我们讨论了这些模型的一般设计和实际实施，并对源自不同基于流行病学模型的实验结果进行了综合总结，包括母体暴露于心理应激、糖皮质激素治疗、病毒感染、免疫激活剂、蛋白质缺乏、维生素 D 缺乏以及剖宫产和围产期/产后缺氧形式的产科并发症的模型。我们强调，动物产前暴露于这些环境挑战的长期后果成功地捕获了与精神分裂症相关的广泛结构和功能脑异常，其中一些可以通过急性和/或慢性抗精神病药物治疗来正常化。因此，我们得出结论，基于流行病学的精神分裂症神经发育模型具有高的表面效度、结构效度和预测效度，包括与该疾病的内在病因学意义。它们还满足神经发育理论的预期，即产前环境应激的影响通常仅在青春期后才出现。基于流行病学的动物模型不仅为测试人类流行病学关联中因果关系的假设提供了不可或缺的实验工具，而且为阐明精神分裂症及相关障碍的发病机制中的神经生物学、神经内分泌和神经免疫机制提供了重要的新途径。
