Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum.
Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum.
复制标题
DOI：
10.1101/lm.032094.113
复制
发表时间：
2014-03-17
期刊：
影响因子：
--
通讯作者：
Kandel ER
中科院分区：
文献类型：
--
作者：
Simpson EH;Morud J;Winiger V;Biezonski D;Zhu JP;Bach ME;Malleret G;Polan HJ;Ng-Evans S;Phillips PE;Kellendonk C;Kandel ER
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，已被发现与认知能力较差和患精神疾病的易感性增加有关。一般认为COMT活性的增加通过增加皮质突触中的多巴胺周转来影响认知功能和精神疾病风险，尽管这在人类中不能直接测量。在这里，我们探索了一种新的转基因小鼠模型，增加COMT活性，相当于与人类COMT Val 158等位基因观察到的活性的相对增加。通过进行一系列广泛的行为测试，我们发现COMT过表达小鼠（COMT-OE小鼠）在受COMT Val 158等位基因、刺激-反应学习和工作记忆影响的领域选择性地表现出认知缺陷，这在功能上验证了我们的COMT活性增加模型。虽然我们没有检测到多巴胺合成和多巴胺转运标志物水平的变化，但我们发现COMT-OE小鼠显示纹状体多巴胺释放能力增加。这一结果表明，COMT活性的增加不仅可以通过增强皮层中的突触清除来影响多巴胺信号传导，而且还可以引起纹状体中突触前多巴胺功能的变化。这些变化可能是在小鼠中观察到的行为缺陷的基础，也可能在认知缺陷和与人类COMT活性遗传变异相关的精神疾病风险增加中发挥作用。
A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 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 Val158 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 Val158 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.
登录
查看更多内容
通过基础神经节电路的光遗传控制对帕金森运动行为的调节。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
10.6
作者：
Bruder, GE;Keilp, JG;Gilliam, TC
通讯作者：
Gilliam, TC
影响因子：
4.7
作者：
Myohanen, Timo T.;Schendzielorz, Nadia;Mannisto, Pekka T.
通讯作者：
Mannisto, Pekka T.
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。
影响因子：
5.3
作者：
Papaleo, Francesco;Crawley, Jacqueline N.;Song, Jian;Lipska, Barbara K.;Pickel, Jim;Weinberger, Daniel R.;Chen, Jingshan
通讯作者：
Chen, Jingshan
影响因子：
5
作者：
MILLAR, J;STAMFORD, JA;WIGHTMAN, RM
通讯作者：
WIGHTMAN, RM