title: The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.
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.
authors.affiliation: Departments of Pharmacology.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Mergy
authors.affiliation: Departments of Pharmacology.
authors.forename: Raajaram
authors.initials: R
authors.lastname: Gowrishankar
authors.affiliation: Departments of Pharmacology, Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37232-8548; and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gresch
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Gantz
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, OR 97239.
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.affiliation: Departments of Pharmacology.
authors.forename: Gwynne L
authors.initials: GL
authors.lastname: Davis
authors.affiliation: Departments of Pharmacology.
authors.forename: C Austin
authors.initials: CA
authors.lastname: Wheeler
authors.affiliation: Departments of Pharmacology, Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37232-8548; and.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Stanwood
authors.affiliation: Departments of Pharmacology, Medicine, and.
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Hahn
authors.affiliation: Departments of Pharmacology, Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37232-8548; and Psychiatry, and randy.blakely@vanderbilt.edu.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
mesh_terms: D019943:Amino Acid Substitution; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020125:Mutation, Missense; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493214:SLC6A3 protein, human; C493215:Slc6a3 protein, mouse; D000661:Amphetamine; D004298:Dopamine
keywords: dopamine; mouse; polymorphism; transgenic; transporter