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, Ry D. Blakely

Research output: Contribution to journalArticle

30 Scopus citations

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 AMPHevoked DA release, and disruptions in basal and psychostimu-lantevoked 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.

Original languageEnglish (US)
Pages (from-to)E4779-E4788
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number44
DOIs
StatePublished - Nov 4 2014

Keywords

  • Dopamine
  • Mouse
  • Polymorphism
  • Transgenic
  • Transporter

ASJC Scopus subject areas

  • General

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