Summary: Researchers introduced a de novo mutation found in a child with autism into mice. The mutation affects the dopamine transporter (DAT). Mice carrying two copies of the DAT T356M mutation developed social deficits, reduced social dominance and increased hyperactivity, along with impaired striatal dopamine signaling and slower dopamine clearance.
Source: UAB
A new mouse model links a human autism-associated mutation in the dopamine transporter to autism-like and ADHD-like behaviors.
Scientists have recreated in mice a rare, spontaneously occurring mutation discovered in a child diagnosed with autism spectrum disorder (ASD). The mutation alters the DAT protein, which controls dopamine reuptake in the brain. Introducing this change into the mouse genome caused pronounced behavioral and physiological effects that mirror aspects of ASD and attention deficit hyperactivity disorder (ADHD), suggesting a direct mechanistic connection between this specific mutation and altered dopamine signaling.
The study, led by Aurelio Galli, Ph.D., of the University of Alabama at Birmingham, and Mark Wallace, Ph.D., of Vanderbilt University, examines the functional consequences of a threonine-to-methionine substitution at position 356 of the dopamine transporter, referred to as DAT T356M. DAT normally removes dopamine from the synaptic cleft, terminating neurotransmission. Alterations in DAT function can therefore disrupt dopamine-dependent processes such as motor control, motivation, attention and reward learning.
Previous cell and fruit fly experiments showed that DAT T356M can cause abnormal dopamine efflux — effectively pumping dopamine out of neurons — and drives hyperactivity and altered social behaviors in flies. Building on that work, this study is the first to characterize DAT T356M in a mammalian brain and to correlate molecular dysfunction with complex behaviors relevant to human neuropsychiatric conditions.
Mice homozygous for the DAT T356M mutation (carrying two copies) displayed several robust behavioral changes. These animals showed significantly reduced social interaction and a loss of social dominance compared with normal mice. Innate investigative behaviors such as marble burying were diminished. The mutant mice also exhibited repetitive rearing and improved performance on a rotating rod task, consistent with a tendency toward repetitive, perseverative actions. In addition, spontaneous locomotor activity was elevated, indicating hyperactivity — a common comorbidity in people with ASD and a hallmark symptom of ADHD.
Notably, mice heterozygous for the mutation (carrying a single copy) did not show measurable differences from wild-type animals, indicating a dose-dependent effect of the mutation on behavior and physiology.
Pharmacological experiments further support the central role of DAT dysfunction in the observed hyperactivity. Treating DAT T356M mice with two different pharmacological agents that block DAT reduced their excessive locomotor activity. These findings point to DAT as a potential therapeutic target and suggest that DAT blockade deserves further study to determine whether it can also reverse or alleviate social and repetitive behavioral deficits in this model.
At the physiological level, the research team documented impaired striatal dopamine neurotransmission and reduced dopamine clearance in DAT T356M mice. These alterations in dopaminergic signaling map onto the behavioral phenotype: disrupted dopamine dynamics in the striatum can affect motor activity, attention, reward processing and social behavior. The study therefore provides convergent behavioral and neurochemical evidence linking the DAT T356M mutation to functional changes consistent with elements of ASD and ADHD.
The work was led by Galli and Wallace, with significant contributions from M.D./Ph.D. student Gabriella DiCarlo. Co-authors include Gabriella E. DiCarlo, Fiona E. Harrison and Kyle E. Bundschuh of Vanderbilt University; Jenny I. Aguilar and Heinrich J. G. Matthies of the Department of Surgery at UAB School of Medicine; Alyssa West and Parastoo Hashemi of the University of South Carolina; Freja Herborg, Mattias Rickhag and Ulrik Gether of the University of Copenhagen; and Hao Chen of DRI Biosciences Corporation.
Funding: This research was supported by National Institutes of Health grants DA038058, DA35263, MH115535, MH114316, MH106563 and GM007347.
Source:
UAB
Media Contacts:
Jeff Hansen – UAB
Image source:
The image is in the public domain.
Original Research: Open access. Title: “Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors”. Authors include Faurelio Galli et al. Published in the Journal of Clinical Investigation.
Abstract
Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors
Precise control of synaptic dopamine by the dopamine transporter (DAT) is essential for the phasic dopamine signal that underlies reward prediction, motivation, attention and learning. Disruption of the dopamine system contributes to several neuropsychiatric disorders, including ADHD and, increasingly recognized, ASD. An ASD-associated de novo mutation in SLC6A3 producing a threonine-to-methionine substitution at residue 356 (DAT T356M) has been shown previously to drive anomalous dopamine efflux in cells and hyperlocomotion in Drosophila. A related mutation in a DAT-homologous transporter favors an outward-facing transporter conformation that may underlie this anomalous efflux. In this study, mice homozygous for DAT T356M display impaired striatal dopamine neurotransmission and altered dopamine-dependent behaviors that correspond with behavioral phenotypes observed in ASD.