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

Mergy MA, Gowrishankar R, Gresch PJ, Gantz SC, Williams J, Davis GL, Wheeler CA, Stanwood GD, Hahn MK, Blakely RD
Proc Natl Acad Sci U S A. 2014 111 (44): E4779-88

PMID: 25331903 · PMCID: PMC4226116 · DOI:10.1073/pnas.1417294111

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.

MeSH Terms (15)

Amino Acid Substitution Amphetamine Animals Behavior, Animal Central Nervous System Stimulants Dopamine Dopamine Plasma Membrane Transport Proteins Dopaminergic Neurons Female Humans Male Mental Disorders Mice Mutation, Missense Receptors, Dopamine D2

Connections (3)

This publication is referenced by other Labnodes entities:

Links