Gainetdinov Raul R
Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy.
Atten Defic Hyperact Disord. 2010 Mar;2(1):21-30. doi: 10.1007/s12402-010-0021-3. Epub 2010 Mar 6.
The cause and pathophysiology of attention-deficit hyperactivity disorder (ADHD) are unknown, but compelling evidence suggests an involvement of genetic factors. While dopamine is believed to play a major role in ADHD, the role for norepinephrine and serotonin systems has also been indicated. Mutant mice are valuable tools to dissect the contribution of specific neurotransmitter systems to brain dysfunction and particularly useful to decode complex multi-transmitter interaction that is critical to the pathophysiology of ADHD. Genetically altered mice provided also an opportunity to test experimentally the role of novel candidate genes for this disorder identified in genetic clinical studies. While it is clear that no rodent model would be able to recapitulate fully the complex nature of ADHD, certain endophenotypes could be reasonably well mimicked in these models. Multiple studies have reported associations between polymorphisms in dopamine transporter (DAT) gene and ADHD. Although the functional consequences of these associations are still unclear, it is believed that alterations in DAT-mediated processes might contribute to the pathogenesis of ADHD. Mice lacking the dopamine transporter have elevated dopaminergic tone and represent a genetic animal model in which certain endophenotypes of ADHD can be recapitulated. These mutants as well as other mouse models of DAT dysfunction provided an opportunity to investigate the neuronal circuitry and molecular mechanisms involved in the inhibitory action of psychostimulants on hyperactivity. Several additional knockout and transgenic mouse models have been proposed to model ADHD. Strengths and limitations of currently available genetic mouse models of ADHD are discussed.
注意缺陷多动障碍（ADHD）的病因和病理生理学尚不清楚，但有力证据表明遗传因素与之相关。虽然多巴胺被认为在ADHD中起主要作用，但去甲肾上腺素和血清素系统的作用也已得到证实。突变小鼠是剖析特定神经递质系统对脑功能障碍作用的宝贵工具，对于解读对ADHD病理生理学至关重要的复杂多递质相互作用尤其有用。基因改造小鼠还为实验性测试在基因临床研究中鉴定出的该疾病新候选基因的作用提供了机会。虽然很明显没有啮齿动物模型能够完全重现ADHD的复杂本质，但某些内表型在这些模型中可以得到较好的模拟。多项研究报告了多巴胺转运体（DAT）基因多态性与ADHD之间的关联。尽管这些关联的功能后果仍不清楚，但人们认为DAT介导过程的改变可能有助于ADHD的发病机制。缺乏多巴胺转运体的小鼠多巴胺能张力升高，代表了一种可以重现ADHD某些内表型的遗传动物模型。这些突变体以及其他DAT功能障碍的小鼠模型为研究精神兴奋剂对多动抑制作用所涉及的神经回路和分子机制提供了机会。已经提出了几种额外的基因敲除和转基因小鼠模型来模拟ADHD。本文讨论了目前可用的ADHD遗传小鼠模型的优缺点。
