Department of Psychiatry, Columbia University, New York, New York 10032, USA.
Learn Mem. 2014 Mar 17;21(4):205-14. doi: 10.1101/lm.032094.113.
A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val(158) allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val(158) allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val(158) allele, stimulus-response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans.
一种常见的遗传多态性导致多巴胺调节酶 COMT（COMT Val(158)等位基因）活性增加，已被发现与认知表现较差和更容易患上精神疾病有关。人们普遍认为，这种 COMT 活性的增加通过增加皮质突触中的多巴胺周转率来影响认知功能和精神疾病风险，尽管这在人类中无法直接测量。在这里，我们探索了一种新型的 COMT 活性增加的转基因小鼠模型，其活性增加相当于人类 COMT Val(158)等位基因观察到的相对增加。通过进行广泛的行为测试，我们发现 COMT 过表达小鼠（COMT-OE 小鼠）在受 COMT Val(158)等位基因影响的认知领域表现出认知缺陷，即刺激-反应学习和工作记忆，这在功能上验证了我们的 COMT 活性增加模型。尽管我们没有发现多巴胺合成和多巴胺转运的标志物水平有任何变化，但我们发现 COMT-OE 小鼠在纹状体中显示出多巴胺释放能力的增加。这一结果表明，COMT 活性的增加不仅可能通过增强皮质中的突触清除来影响多巴胺信号，还可能导致纹状体中多巴胺功能的变化。这些变化可能是导致小鼠出现行为缺陷的原因，也可能在与 COMT 活性遗传变异相关的人类认知缺陷和精神疾病风险中发挥作用。
