Akil Mayada, Kolachana Bhaskar S, Rothmond Debora A, Hyde Thomas M, Weinberger Daniel R, Kleinman Joel E
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2003 Mar 15;23(6):2008-13. doi: 10.1523/JNEUROSCI.23-06-02008.2003.
A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. The COMT valine allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis.
儿茶酚-O-甲基转移酶（COMT）基因中的一个功能性多态性已被证明会影响人类的执行认知和前额叶皮质的生理功能，这可能是通过影响前额叶多巴胺信号传导来实现的。与相对较差的前额叶功能相关的COMT缬氨酸等位基因，也是一个可能增加精神分裂症风险的基因。尽管执行认知任务表现不佳和前额叶功能异常是精神分裂症的特征，但精神病也是如此，它与纹状体中突触前多巴胺活动过度有关。动物研究表明，前额叶多巴胺神经传递减少会导致纹状体多巴胺活动上调。我们测量了人类大脑中脑多巴胺神经元中的酪氨酸羟化酶（TH）mRNA，发现COMT缬氨酸等位基因也与TH基因表达增加有关，特别是在投射到纹状体的神经元群体中。这表明COMT基因型是多巴胺调节的一个可遗传方面，它进一步阐明了COMT缬氨酸等位基因增加精神病易感性的机制。
