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J Clin Invest. 2019 May 16;129(8):3407-3419. doi: 10.1172/JCI127411.

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

Author information

1
Vanderbilt University Brain Institute, Nashville, Tennessee, USA.
2
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
3
Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
4
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, USA.
6
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
7
DRI Biosciences Corp., Frederick, Maryland, USA.
8
Department of Hearing and Speech Sciences, Vanderbilt University, Nashville, Tennessee, USA.

Abstract

The precise regulation of synaptic dopamine (DA) content by the dopamine 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 dopamine 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 display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

KEYWORDS:

Molecular biology; Neuroscience; Psychiatric diseases; Transport

PMID:
31094705
PMCID:
PMC6668686
[Available on 2019-11-01]
DOI:
10.1172/JCI127411
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