Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice.
Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice.
复制标题
儿茶酚-O-甲基转移酶在小鼠认知和应激反应性中的作用的遗传解剖。
DOI：
10.1523/jneurosci.2077-08.2008
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发表时间：
2008-08-27
影响因子：
5.3
通讯作者：
Chen, Jingshan
中科院分区：
文献类型：
--
作者：
Papaleo, Francesco;Crawley, Jacqueline N.;Song, Jian;Lipska, Barbara K.;Pickel, Jim;Weinberger, Daniel R.;Chen, Jingshan
COMT（儿茶酚-O-甲基转移酶）基因与一系列人类表型有关，包括认知、焦虑、疼痛敏感性和精神病。然而，由于人类COMT多态性和临床变异性的复杂性，对其临床影响存在疑问。我们产生过表达人COMT-Val多态性（Val-tg）的转基因小鼠，并将其与含有无效COMT突变的小鼠进行比较。Val-tg小鼠中COMT酶活性增加导致注意力转移能力中断，工作和识别记忆受损，但压力反应和疼痛敏感性减弱。相反，COMT中断改善了工作记忆，但增加了压力反应和疼痛敏感性。安非他明改善了COMT-Val-tg小鼠的识别记忆缺陷，但在野生型中破坏了它，说明了认知和多巴胺之间的倒U型关系的COMT调制。COMT-Val-tg小鼠显示前额叶皮质（PFC）钙/钙调素依赖性蛋白激酶II（CaMKII）水平升高，而COMT缺乏降低PFC CaMKII，但增加PFC CaMKKβ和CaMKIV水平，表明PFC CaMK通路参与COMT调节的认知功能和适应性应激反应。我们的数据表明，COMT基因在认知和情感功能之间明显的进化权衡中起着关键作用。
The COMT (catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation. Increased COMT enzyme activity in Val-tg mice resulted in disrupted attentional set-shifting abilities, and impaired working and recognition memory, but blunted stress responses and pain sensitivity. Conversely, COMT disruption improved working memory, but increased stress responses and pain sensitivity. Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKKβ and CaMKIV levels, suggesting the involvement of PFC CaMK pathways in COMT-regulated cognitive function and adaptive stress responses. Our data indicate a critical role for the COMT gene in an apparent evolutionary trade-off between cognitive and affective functions.