Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.
Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.
复制标题
DOI：
10.1038/npp.2016.119
复制
发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
儿茶酚氧位甲基转移酶(COMT)调节前额叶皮质中的多巴胺水平。人类基因包含一个多态(Val158Met)，它改变酶活性并影响PFC功能。它还与认知和焦虑有关，但研究结果喜忧参半。因此，我们开发了一种新的COMT活性改变的小鼠模型。将人Met等位基因导入小鼠COMT基因，培育出COMT-Met小鼠，并与野生型小鼠进行比较。该模型被证明具有高度的特异性：与野生型小鼠相比，COMT-Met小鼠的COMT丰度和活性明显降低，其他基因的表达没有发生非靶标变化。尽管多巴胺代谢发生了强烈的变化，但我们发现在基线条件下，某些认知任务只有细微的变化(例如，COMT-Met小鼠与野生型小鼠相比，空间新颖性偏好增加)。然而，在服用COMT抑制剂Tolcapone后，出现了基因差异：在服用Tolcapone后，野生型小鼠的表现有所改善，但COMT-Met小鼠在5个选择的系列反应时间任务中的表现没有改善。在我们使用的测试中，与焦虑相关的行为没有变化。我们的发现与人类对Val158Met多态的研究相一致，并表明当多巴胺系统受到挑战时，COMT的影响最为突出。最后，他们证明了在检查COMT抑制剂的治疗潜力时考虑COMT基因的重要性。
Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val158Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the Val158Met polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors.
登录
查看更多内容
DOI：
10.1073/pnas.111134598
发表时间：
2001-06-05
影响因子：
11.1
作者：
Egan, MF;Goldberg, TE;Weinberger, DR
通讯作者：
Weinberger, DR
影响因子：
2.7
作者：
Hertel, P;Mathe, JM;Svensson, TH
通讯作者：
Svensson, TH
影响因子：
2.5
作者：
Baumann, C.;Klauke, B.;Reif, A.
通讯作者：
Reif, A.
影响因子：
11
作者：
Farrell, M. S.;Werge, T.;Sklar, P.;Owen, M. J.;Ophoff, R. A.;O'Donovan, M. C.;Corvin, A.;Cichon, S.;Sullivan, P. F.
通讯作者：
Sullivan, P. F.
影响因子：
0.9
作者：
Lee LO;Prescott CA
通讯作者：
Prescott CA