Sambataro Fabio, Podell Jamie E, Murty Vishnu P, Das Saumitra, Kolachana Bhaskar, Goldberg Terry E, Weinberger Daniel R, Mattay Venkata S
pRED, NORD DTA, Hoffmann-La Roche, Basel, Switzerland.
Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Eur J Neurosci. 2015 Aug;42(3):1912-8. doi: 10.1111/ejn.12956. Epub 2015 Jun 24.
Dopamine modulation of striatal function is critical for executive functions such as working memory (WM) updating. The dopamine transporter (DAT) regulates striatal dopamine signaling via synaptic reuptake. A variable number of tandem repeats in the 3'-untranslated region of SLC6A3 (DAT1-3'-UTR-VNTR) is associated with DAT expression, such that 9-repeat allele carriers tend to express lower levels (associated with higher extracellular dopamine concentrations) than 10-repeat homozygotes. Aging is also associated with decline of the dopamine system. The goal of the present study was to investigate the effects of aging and DAT1-3'-UTR-VNTR on the neural activity and functional connectivity of the striatum during WM updating. Our results showed both an age-related decrease in striatal activity and an effect of DAT1-3'-UTR-VNTR. Ten-repeat homozygotes showed reduced striatal activity and increased striatal-hippocampal connectivity during WM updating relative to the 9-repeat carriers. There was no age by DAT1-3'-UTR-VNTR interaction. These results suggest that, whereas striatal function during WM updating is modulated by both age and genetically determined DAT levels, the rate of the age-related decline in striatal function is similar across both DAT1-3'-UTR-VNTR genotype groups. They further suggest that, because of the baseline difference in striatal function based on DAT1-3'-UTR-VNTR polymorphism, 10-repeat homozygotes, who have lower levels of striatal function throughout the adult life span, may reach a threshold of decreased striatal function and manifest impairments in cognitive processes mediated by the striatum earlier in life than the 9-repeat carriers. Our data suggest that age and DAT1-3'-UTR-VNTR polymorphism independently modulate striatal function.
多巴胺对纹状体功能的调节对于诸如工作记忆（WM）更新等执行功能至关重要。多巴胺转运体（DAT）通过突触再摄取调节纹状体多巴胺信号。溶质载体家族6成员3（SLC6A3）的3'非翻译区中的可变串联重复序列（DAT1 - 3'-UTR-VNTR）与DAT表达相关，使得9重复等位基因携带者往往比10重复纯合子表达更低水平（与更高的细胞外多巴胺浓度相关）。衰老也与多巴胺系统的衰退有关。本研究的目的是调查衰老和DAT1 - 3'-UTR-VNTR对WM更新过程中纹状体神经活动和功能连接性的影响。我们的结果显示纹状体活动存在与年龄相关的下降以及DAT1 - 3'-UTR-VNTR的影响。相对于9重复携带者，10重复纯合子在WM更新过程中显示出纹状体活动减少以及纹状体 - 海马连接性增加。不存在衰老与DAT1 - 3'-UTR-VNTR的相互作用。这些结果表明，虽然WM更新过程中的纹状体功能受到年龄和基因决定的DAT水平的调节，但纹状体功能与年龄相关的衰退速率在两个DAT1 - 3'-UTR-VNTR基因型组中相似。它们进一步表明，由于基于DAT1 - 3'-UTR-VNTR多态性的纹状体功能基线差异，在整个成年寿命期间纹状体功能水平较低的10重复纯合子可能比9重复携带者更早达到纹状体功能下降的阈值，并在生命早期表现出由纹状体介导的认知过程受损。我们的数据表明年龄和DAT1 - 3'-UTR-VNTR多态性独立调节纹状体功能。
