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

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

doi:10.1172/jci127411

Cited by 122 publications

(124 citation statements)

References 68 publications

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“…This enables the important process of fine-tuning dopamine signaling, which is essential in reward processing and behavioral learning [ 92 ]. Changes in DAT expression are associated with neurological and psychiatric disorders such as ADHD, autism, and Parkinson's disease (PD) [ 93 ]. In line with our findings, previous studies in PD patients (who were characterized by an altered striatal DAT expression due to nigrostriatal dopaminergic degeneration) have shown altered fecal P. copri levels compared to controls [ 94 ], underscoring the role of the gut-brain axis and more specific the enteric nervous system in human disease [ 95 , 96 ].…”

Section: Discussionmentioning

confidence: 99%

Infusion of donor feces affects the gut–brain axis in humans with metabolic syndrome

Hartstra

Schüppel

Imangaliyev

et al. 2020

Molecular Metabolism

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Objective Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown. Methods We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on ( 123 I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points. Results We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S -adenosylmethionine cycle) were also associated with altered striatal DAT expression. Conclusions Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated. NTR registration 4488.

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Section: Discussionmentioning

confidence: 99%

Infusion of donor feces affects the gut–brain axis in humans with metabolic syndrome

Hartstra

Schüppel

Imangaliyev

et al. 2020

Molecular Metabolism

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“…The changes in Drd2 mRNA levels suggest that control of GABAergic indirect pathway projection neurons is affected in ASD, however, a functional change in the striatum is undetermined and there may instead be an impact on D2R in the globus pallidus. A recent study has shown that a DAT mutation identified in an individual with ASD alters dopaminergic transmission in the striatum of a mouse model, an effect paralleled by hyperactive and repetitive behaviors as well as social deficits (DiCarlo et al, 2019 ). In this context, it would also be important to determine if changes in dopaminergic activity are a developmental feature of ASD.…”

Section: Discussionmentioning

confidence: 99%

Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry

Brandenburg

Soghomonian

Zhang

et al. 2020

Front. Cell. Neurosci.

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“…The identification of this patient adds to several reports on heterozygous carriers of coding variants in SLC6A3 that have been diagnosed with neuropsychiatric disease including bipolar disorder, ADHD, and autism spectrum disorder (ASD) (Bowton et al, 2014;Campbell et al, 2019;Cartier et al, 2015;Grunhage et al, 2000;Hamilton et al, 2013;Mazei-Robison et al, 2005;Sakrikar et al, 2012). Most of these DAT variants show deficits in DAT properties and/or trafficking, and several cause behavioral changes in vivo, at least when homozygously expressed (Campbell et al, 2019;Cartier et al, 2015;DiCarlo et al, 2019;Hamilton et al, 2013;Hansen et al, 2014;Herborg et al, 2018; Mazei- Robison et al, 2005;Mergy et al, 2014;Sakrikar et al, 2012;Wu et al, 2015).…”

Section: Introductionmentioning

confidence: 73%

“…Rather, it reflects the absence of common risk variants. Several rare coding DAT variants with functional deficits both in vitro and in vivo have been identified in patients with psychiatric disorders (Bowton et al, 2014;Campbell et al, 2019;Cartier et al, 2015;Davis et al, 2018;DiCarlo et al, 2019;Gowrishankar et al, 2018;Grunhage et al, 2000;Hamilton et al, 2013;Hansen et al, 2014;Herborg et al, 2018;Mazei-Robison et al, 2005;Sakrikar et al, 2012;Stewart et al, 2019;Wu et al, 2015) but the causal link between these putative risk alleles and disease is still elusive as the family trees and cohort sizes have been too small for meaningful linkage or association analysis. We have, to the best or our knowledge, carried out the first association analysis of a coding DAT variant using large-scale exome data, and demonstrate a nominally significant association to bipolar disease.…”

Section: Discussionmentioning

confidence: 99%

A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

Herborg

Jensen

Tolstoy

et al. 2020

Preprint

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Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine transporter (DAT) is essential for the regulation of extracellular dopamine but the genetic and mechanistic link between DAT function and dopamine-related pathologies remains elusive. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here we identify a novel coding DAT variant, DAT-K619N, in a patient with early-onset parkinsonism and comorbid neuropsychiatric disease and in 22 individuals from exome-sequenced samples of neuropsychiatric patients. The variant localizes to the critical C-terminal PDZ-binding motif of DAT and causes reduced uptake capacity, decreased surface expression, and accelerated turnover of DAT in vitro. In vivo, we demonstrate that expression of DAT-K619N in mice and dropsophila imposes impairments in dopamine transmission with accompanying changes in dopamine-directed behaviors. Importantly, both cellular studies and viral overexpression of DAT-K619N in mice show that DAT-K619N has a dominant-negative effect which collectively implies that a single dominant-negative genetic DAT variant can confer risk for neuropsychiatric disease and neurodegenerative early-onset parkinsonism.

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

Cited by 122 publications

References 68 publications

Infusion of donor feces affects the gut–brain axis in humans with metabolic syndrome

Infusion of donor feces affects the gut–brain axis in humans with metabolic syndrome

Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry

A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

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