Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors
Gabriella E. DiCarlo, … , Mark T. Wallace, Aurelio Galli
Gabriella E. DiCarlo, … , Mark T. Wallace, Aurelio Galli
Published May 16, 2019
Citation Information: J Clin Invest. 2019;129(8):3407-3419. https://doi.org/10.1172/JCI127411.
View: Text | PDF
Research Article Neuroscience

Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors

  • Text
  • PDF
Abstract

The precise regulation of synaptic dopamine (DA) content by the DA transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, autism spectrum disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine-to-methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e., anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous DA efflux. Here, we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation displayed impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

Authors

Gabriella E. DiCarlo, Jenny I. Aguilar, Heinrich J.G. Matthies, Fiona E. Harrison, Kyle E. Bundschuh, Alyssa West, Parastoo Hashemi, Freja Herborg, Mattias Rickhag, Hao Chen, Ulrik Gether, Mark T. Wallace, Aurelio Galli

×

Figure 1

The DAT T356M mutation impairs striatal DA reuptake while maintaining normal DAT expression.

Options: View larger image (or click on image) Download as PowerPoint
The DAT T356M mutation impairs striatal DA reuptake while maintaining no...
(A) Stimulated dopaminergic current recorded (using carbon fiber amperometry) from acute striatal slices of WT (black) and DAT T356M+/+ (red) mice. (B) Peak dopaminergic current recorded from acute striatal slices of WT (black) and DAT T356M+/+ (red) mice. There was no significant difference in the peak DA released between WT and DAT T356M+/+ mice at baseline (–cocaine [–COC]: WT = 1.921 ± 0.17 μM; DAT T356M+/+ = 1.526 ± 0.18 μM; n = 17; P = 0.1908, 2-way ANOVA). With addition of cocaine, peak DA released decreased significantly in DAT T356M+/+ striatum, but not WT striatum (+COC: WT = 1.766 ± 0.19 μM; DAT T356M+/+ = 0.916 ± 0.13 μM; n = 17; P = 0.23 and P = < 0.001, respectively, 2-way ANOVA). ****P < 0.0001; **P = 0.0013 (C) Decay time (t80–t20) of the dopaminergic signal recorded in acute striatal slices of WT (black) and DAT T356M+/+ (red) mice. The decay time was significantly longer at baseline in DAT T356M+/+ striatum when compared with WT striatum (–COC: WT = 121.5 ± 12.39 ms; DAT T356M+/+ = 244.9 ± 19.83; n = 17; P = 0.001, 2-way ANOVA). Addition of cocaine increased decay time of the dopaminergic signal in both WT and DAT T356M+/+ mice (+COC: WT = 334.1 ± 25.82 ms; DAT T356M+/+ = 384.9 ± 32.21 ms; n = 17; P = <0.001 P = and 0.006, respectively, 2-way ANOVA followed by Šidák’s multiple comparisons test), as expected, and confirming the identity of the current as dopaminergic. ***P = 0.001; ****P < 0.0001 (D) Immunoblotting for DAT showed no difference in DAT expression in the striatum between WT and DAT T356M+/+ mice (n = 6; P = 0.877, 2-tailed t test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts