Brain protein mutation from child with autism causes autism-like behavioral change in mice

Summary: Researchers implanted a genetic mutation that encodes the DAT protein from a child with ASD into mice. The mice began to exhibit autism-like behavioral deficits. Mice with the DAT T356M mutation had reduced social interaction and a loss in social dominance. The mice also demonstrated an increase in hyperactivity. At the physiological level, the researchers found impaired striatal dopamine transmission and clearance.

Source: UAB

A de novo gene mutation that encodes a brain protein in a child with autism has been placed into the brains of mice. These mice then showed severe alterations of specific behaviors that closely resemble those seen in human autism spectrum disorder, or ASD.

This major finding from a study published in the Journal of Clinical Investigation “presents the exciting possibility of a potential mechanistic underpinning — in at least a subset of patients — for some of the altered behaviors observed in ASD and attention deficit hyperactivity disorder, or ADHD,” said Aurelio Galli, Ph.D., professor of surgery at the University of Alabama at Birmingham.

The research was led by corresponding authors Galli and Mark Wallace, Ph.D., a neurobiologist and dean at Vanderbilt University.

The brain protein studied is the dopamine transporter or DAT. Certain brain neurons release the neurotransmitter dopamine from the ends of their axons. The dopamine crosses the junction, or synapse, between that axon and a neighboring neuron, triggering a response in that receiving neuron. DAT — which sits in the membrane of the transmitting neuron — has the job of dopamine reuptake, pumping released dopamine back into the transmitting neuron from the synapse, thereby terminating the response of the receiving neuron.

Brain activity involving the dopamine system in the region of the brain called the striatum is a critical regulator of motor activity, motivation, attention and reward processing. Given the integral role of the dopamine system in critical brain functions, it is no surprise that dysregulation of this neurotransmitter system has been implicated in neuropsychiatric disorders that include Parkinson’s disease; substance abuse with heroin, cocaine, speed, nicotine and other drugs; bipolar disorder; ADHD; and recently ASD.

Galli, Wallace, and colleagues studied a mutation in the gene for human DAT that was found in a child with ASD. This mutation generates a substitution at amino acid 356 of DAT, a change from threonine to methionine, so the mutant DAT is called DAT T356M.

A previous study led by Galli and Eric Gouaux, Ph.D., a professor at the Oregon Health & Science University, introduced the mutation into fruit fly DAT; in the flies, the DAT T356M produced abnormal behaviors of increased locomotor activity, fear, repetitive activity and altered social interaction, reminiscent of autism impairments. Bacterial studies suggested that DAT T356M is flipped inside-out compared with normal DAT, so that DAT T356M anomalously pumps dopamine out of a cell rather than into the cell.

Now Galli, Wallace, and M.D./Ph.D. student Gabriella DiCarlo have reported the first study of DAT T356M in a mammalian brain.

Mice that were homozygous with two copies of the DAT T356M gene mutation showed severe changes in behavior that resemble human ASD and ADHD behaviors and significant alterations in brain physiology. ADHD is a common comorbidity of ASD. In contrast, no changes were seen in mice that had only one copy of the DAT T356M gene mutation, as compared with normal mice.

The mice with DAT T356M showed a loss in social interactions, a loss of social dominance and diminished marble burying, an innate behavior of lab mice that are motivated by their desire to investigate. The mice with DAT T356M showed repetitive rearing behavior and enhanced learning of how to keep balance on a rotating rod, which is linked to the propensity toward repetitive behavior.

The DAT T356M mice also showed hyperactivity, as measured by increased spontaneous locomotor activity. Significantly, when the mice were treated with two different compounds that block DAT activity, their hyperactive behavior decreased. “Future work should aim to determine whether blockade of the DAT may eliminate or alleviate the more complex behavioral changes observed in DAT T356M animals,” Galli said.

This shows a child looking at a DNA double helix

Galli, Wallace and colleagues studied a mutation in the gene for human DAT that was found in a child with ASD. The image is in the public domain.

The altered social behavior and the hyperactivity were linked to altered dopamine neurotransmitter signaling activity in the brains of DAT T356M mice. At the physiological level, the researchers found impaired striatal dopamine neurotransmission and clearance.

Co-authors with Galli and Wallace in the study, “Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors,” were Gabriella E. DiCarlo, Fiona E. Harrison and Kyle E. Bundschuh, Vanderbilt University; Jenny I. Aguilar and Heinrich J. G. Matthies, Department of Surgery, UAB School of Medicine; Alyssa West and Parastoo Hashemi, University of South Carolina; Freja Herborg, Mattias Rickhag and Ulrik Gether, University of Copenhagen, Denmark; and Hao Chen, DRI Biosciences Corporation, Frederick, Maryland.

Funding:Support came from National Institutes of Health grants DA038058, DA35263, MH115535, MH114316, MH106563 and GM007347.

About this neuroscience research article

Source:
UAB
Media Contacts:
Jeff Hansen – UAB
Image Source:
The image is in the public domain.

Original Research: Open access
“Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors”. FAurelio Galli et al.
Journal of Clinical Investigation. doi:10.1172/JCI127411

Abstract

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

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.

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