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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.
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Research Article Neuroscience

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

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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

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Figure 5

DAT T356M+/+ mice exhibit spontaneous, persistent hyperlocomotion, repetitive rearing behavior, and altered social behaviors.

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DAT T356M+/+ mice exhibit spontaneous, persistent hyperlocomotion, repet...
(A) DAT T356M+/+ mice traveled significantly further than WT mice during a 60-minute test period (WT = 3648 ± 312.4 cm; DAT T356M+/+ = 20571 ± 1062 cm; n = 15 WT, 16 DAT T356M+/+; ****P < 0.0001, Student’s 2-tailed t test). (B) DAT T356M+/+ mice exhibited hyperlocomotor activity across all 10-minute intervals of the 60-minute test (for all intervals, ****P < 0.0001 by 2-way ANOVA followed by Šidák’s multiple comparison test). (C) DAT T356M+/+ mice exhibited repetitive rearing behavior (WT = 71 ± 5; DAT T356M+/+ = 123 ± 9; n = 15 WT, n = 16 DAT T356M+/+; ****P < 0.0001, 2-way ANOVA followed by Šidák’s multiple comparisons test). (D) WT animals displayed a statistically significant preference for the social target, while DAT T356M+/+ mice exhibited no preference for either target (WT = 115.41 ± 11.06 s with social target, 66.07 ± 8.12 s with empty chamber; n = 15; P = 0.001, 2-way ANOVA followed by Šidák’s multiple comparisons test; DAT T356M+/+ = 72.51 ± 5.91 s with social target, 66.125 ± 5.97 s with empty chamber; n = 16; P = 0.81, 2-way ANOVA followed by Šidák’s multiple comparisons test). **P = 0.0012. (E) DAT T356M+/+ mice won significantly fewer bouts against both familiar and novel mice than would be expected by chance (dashed line indicates chance-level performance; n = 24 bouts from 12 pairs of mice; *P < 0.05, **P < 0.01 by χ2).
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