A variable number of tandem repeats in the 3 '-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span
Eur J Neurosci
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.
School of Medicine