Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.
Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.
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DOI：
10.1523/jneurosci.4858-08.2009
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发表时间：
2009-01-28
期刊：
影响因子：
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通讯作者：
Sadee W
中科院分区：
文献类型：
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作者：
Bertolino A;Fazio L;Di Giorgio A;Blasi G;Romano R;Taurisano P;Caforio G;Sinibaldi L;Ursini G;Popolizio T;Tirotta E;Papp A;Dallapiccola B;Borrelli E;Sadee W
在记忆任务中，多巴胺对神经元活动的调制识别出一种非线性的倒U形功能。多巴胺转运体(DAT)和多巴胺D2受体(由DRD2编码)在记忆过程中都对纹状体和前额叶皮质中的多巴胺信号进行关键调节。此外，体外研究表明，DAT和D2蛋白在突触前相互调节。因此，我们评估了导致突触前D2受体表达减少的DRD2多态(Rs1076560)和影响DAT表达的DAT 3‘-VNTR变体(影响DAT表达)之间的遗传交互作用。结果表明，在工作记忆和再认记忆编码过程中，前额叶皮质和纹状体BOLD活动存在显著的DRD2/DAT交互作用。DAT变异体对BOLD活性的不同影响主要表现在与突触前低表达相关的DRD2等位基因的背景下。尾状核灰质体积也有类似的结果。这些相互作用描述了复合基因型和脑活动或灰质体积之间的非线性关系。来自野生型和D2基因敲除动物的纹状体蛋白提取物(D2R−/−)的互补数据表明，DAT和D2蛋白在体内相互作用。综上所述，我们的结果表明，DRD2和DAT基因变体之间的相互作用在记忆加工过程中关键地调节了多巴胺和神经元活动之间的非线性关系。
Dopamine modulation of neuronal activity during memory tasks identifies a non-linear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2 receptors (encoded by DRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D2 proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD2 polymorphism (rs1076560) causing reduced presynaptic D2 receptor expression and the DAT 3’-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing BOLD - fMRI during memory tasks and structural MRI. Results indicated a significant DRD2/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD2 allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a non-linear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2 knock-out animals (D2R−/−) indicate that DAT and D2 proteins interact in vivo. Taken together, our results demonstrate that the interaction between genetic variants in DRD2 and DAT critically modulates the non-linear relationship between dopamine and neuronal activity during memory processing.