title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.affiliation: Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Podell
authors.affiliation: Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Vishnu P
authors.initials: VP
authors.lastname: Murty
authors.affiliation: Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Saumitra
authors.initials: S
authors.lastname: Das
authors.affiliation: Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.affiliation: Litwin Zucker Alzheimer's Disease Research Center, Feinstein Institute, Manhasset, NY, USA.
authors.forename: Terry E
authors.initials: TE
authors.lastname: Goldberg
authors.affiliation: Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.|Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Baltimore, MD, 21205, USA.|Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.|Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Baltimore, MD, 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D001931:Brain Mapping; D003342:Corpus Striatum / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D020080:Tandem Repeat Sequences; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D050483:Dopamine Plasma Membrane Transport Proteins
keywords: SLC6A3; aging; dopamine; functional magnetic resonance imaging; working memory