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The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants
Journal article   Open access   Peer reviewed

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Marc A Mergy, Raajaram Gowrishankar, Paul J Gresch, Stephanie C Gantz, John Williams, Gwynne L Davis, C Austin Wheeler, Gregg D Stanwood, Maureen K Hahn and Randy D Blakely
Proceedings of the National Academy of Sciences - PNAS, Vol.111(44), pp.E4779-E4788
11/04/2014
DOI: 10.1073/pnas.1417294111
PMCID: PMC4226116
PMID: 25331903
url
https://doi.org/10.1073/pnas.1417294111View
Published (Version of record) Open Access

Abstract

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.
 Dopamine Plasma Membrane Transport Proteins - metabolism Mental Disorders - pathology Central Nervous System Stimulants - pharmacology Dopaminergic Neurons - pathology Humans Mental Disorders - metabolism Amphetamine - pharmacology Dopamine - genetics Male Mutation, Missense Receptors, Dopamine D2 - metabolism Dopamine Plasma Membrane Transport Proteins - genetics Receptors, Dopamine D2 - genetics Mental Disorders - genetics Animals Dopaminergic Neurons - metabolism Behavior, Animal - drug effects Female Mice Dopamine - metabolism Amino Acid Substitution

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