文章基本信息

标题：The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants
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作者：Marc A. Mergy ; Raajaram Gowrishankar ; Paul J. Gresch 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：E4779-E4788
DOI：10.1073/pnas.1417294111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDopamine (DA) signaling provides important, modulatory control of movement, at tention, and reward. Disorders linked to changes in DA signaling include Parkinson's disease, attention-deficit hyperactivity disorder, schizophrenia, autism spectrum disorder, and addiction. We identified multiple, functional polymorphisms in the human DA transporter (DAT) gene and showed that one of these variants, which produces the amino acid substitution Val559 (wild-type DATs express Ala559), exhibits normal DA uptake accompanied by a spontaneous outward efflux of the neurotransmitter, reminiscent of the actions of the psychostimulant amphetamine. Here, we identify multiple biochemical, physiological, and behavioral perturbations that arise from DAT Val559 expression in vivo, supporting spontaneous DA efflux as a heretofore-unrecognized mechanism that may underlie multiple DA-linked neurobehavioral disorders. Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.
关键词：dopamine ; transporter ; transgenic ; mouse ; polymorphism