Critical reappraisal of mechanistic links of copy number variants to dimensional constructs of neuropsychiatric disorders in mouse models.
Critical reappraisal of mechanistic links of copy number variants to dimensional constructs of neuropsychiatric disorders in mouse models.
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DOI：
10.1111/pcn.12641
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发表时间：
2018-05
影响因子：
11.9
通讯作者：
Hiroi N
中科院分区：
文献类型：
--
作者：
Hiroi N
拷贝数变异是几千到几百万个碱基对的缺失和重复，与极高水平的自闭症谱系障碍、精神分裂症、智力残疾或注意力缺陷/多动障碍有关。拷贝数变异的强大和可重复性的前所未有的水平使它们成为深入研究许多精神障碍的机制基础的最有希望和可靠的切入点之一。然而，由于每个拷贝数变体中编码的许多基因和不同的相关表型特征，这些关联的精确机制基础在人类中仍然难以捉摸。基因工程小鼠提供了一种技术手段，以确定精确的遗传机制之间的关联拷贝数变异和精神疾病的维度方面。分子、细胞和神经元表型可以作为精神疾病的各种行为结构的潜在机制底物被检测到。然而，鼠标模型有许多技术缺陷。遗传背景在许多小鼠模型中没有得到很好的控制，导致相当明显的解释问题。许多拷贝数变体和拷贝数变体内的单个基因的剂量改变导致一些分子、细胞和神经元表型，而没有行为表型或具有与在人类中观察到的相反的行为表型。在这篇综述中，我讨论了技术和解释陷阱的拷贝数变异的小鼠模型，并强调良好的对照研究，提出潜在的神经元机制的精神疾病的维度方面。拷贝数变异的小鼠模型代表了更好地理解神经精神疾病维度的机制基础的立足点，从而为人类开发基于机制的治疗方案提供了立足点。
Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability or attention-deficit/hyperactivity disorder. The unprecedented levels of robust and reproducible penetrance of copy number variants make them one of the most promising and reliable entry points to delve into the mechanistic bases of many mental disorders. However, the precise mechanistic bases of these associations still remain elusive in humans due to the many genes encoded in each copy number variant and the diverse associated phenotypic features. Genetically engineered mice have provided a technical means to ascertain precise genetic mechanisms of association between copy number variants and dimensional aspects of mental illnesses. Molecular, cellular and neuronal phenotypes can be detected as potential mechanistic substrates for various behavioral constructs of mental illnesses. However, mouse models come with many technical pitfalls. Genetic background is not well controlled in many mouse models leading to rather obvious interpretative issues. Dose alterations of many copy number variants and single genes within copy number variants result in some molecular, cellular and neuronal phenotypes without a behavioral phenotype or with a behavioral phenotype opposite to what is seen in humans. In this review, I discuss technical and interpretative pitfalls of mouse models of copy number variants and highlight well-controlled studies to suggest potential neuronal mechanisms of dimensional aspects of mental illnesses. Mouse models of copy number variants represent toeholds to achieve a better understanding of the mechanistic bases of dimensions of neuropsychiatric disorders and thus for development of mechanism-based therapeutic options in humans.
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