Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Mental Health Center, Sankt Hans Hospital, Mental Health Services, Roskilde; Institute of Biological Psychiatry, Mental Health Center, Sankt Hans Hospital, Mental Health Services, Roskilde; Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Mental Health Center, Sankt Hans Hospital, Mental Health Services, Roskilde.
Biol Psychiatry. 2019 Jan 1;85(1):13-24. doi: 10.1016/j.biopsych.2018.07.004. Epub 2018 Jul 12.
The diagnosis of schizophrenia rests on clinical criteria that cannot be assessed in animal models. Together with absence of a clear underlying pathology and understanding of what causes schizophrenia, this has hindered development of informative animal models. However, recent large-scale genomic studies have identified copy number variants (CNVs) that confer high risk of schizophrenia and have opened a new avenue for generation of relevant animal models. Eight recurrent CNVs have reproducibly been shown to increase the risk of schizophrenia by severalfold: 22q11.2(del), 15q13.3(del), 1q21(del), 1q21(dup), NRXN1(del), 3q29(del), 7q11.23(dup), and 16p11.2(dup). Five of these CNVs have been modeled in animals, mainly mice, but also rats, flies, and zebrafish, and have been shown to recapitulate behavioral and electrophysiological aspects of schizophrenia. Here, we provide an overview of the schizophrenia-related phenotypes found in animal models of schizophrenia high-risk CNVs. We also discuss strengths and limitations of the CNV models, and how they can advance our biological understanding of mechanisms that can lead to schizophrenia and can be used to develop new and better treatments for schizophrenia.
精神分裂症的诊断依赖于临床标准，但这些标准无法在动物模型中进行评估。再加上缺乏明确的潜在病理和对导致精神分裂症的原因的理解，这阻碍了信息丰富的动物模型的发展。然而，最近的大规模基因组研究已经确定了一些可增加精神分裂症高风险的拷贝数变异 (CNVs)，为相关动物模型的生成开辟了新途径。有 8 个重现性的 CNVs 已被证明可使精神分裂症的风险增加数倍：22q11.2(del)、15q13.3(del)、1q21(del)、1q21(dup)、NRXN1(del)、3q29(del)、7q11.23(dup)和 16p11.2(dup)。其中 5 个 CNVs 已在动物模型中进行了建模，主要是在老鼠中，也有在大鼠、果蝇和斑马鱼中进行建模，这些模型已经重现了精神分裂症的行为和电生理方面的特征。在这里，我们提供了一个关于精神分裂症高风险 CNVs 动物模型中发现的精神分裂症相关表型的概述。我们还讨论了 CNV 模型的优缺点，以及它们如何促进我们对导致精神分裂症的机制的生物学理解，并可用于开发治疗精神分裂症的新方法和更好的方法。
