Nav: Home

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

July 23, 2019

BIRMINGHAM, Ala. - 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 is 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.

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.
-end-
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.

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

University of Alabama at Birmingham

Related Autism Articles:

Autism risk estimated at 3 to 5% for children whose parents have a sibling with autism
Roughly 3 to 5% of children with an aunt or uncle with autism spectrum disorder (ASD) can also be expected to have ASD, compared to about 1.5% of children in the general population, according to a study funded by the National Institutes of Health.
Adulthood with autism
The independence that comes with growing up can be scary for any teenager, but for young adults with autism spectrum disorder and their caregivers, the transition from adolescence to adulthood can seem particularly daunting.
Brain protein mutation from child with autism causes autism-like behavioral change in mice
A de novo gene mutation that encodes a brain protein in a child with autism has been placed into the brains of mice.
Autism and theory of mind
Theory of mind, or the ability to represent other people's minds as distinct from one's own, can be difficult for people with autism.
Potential biomarker for autism
A study of young children with autism spectrum disorder published in JNeurosci reveals altered brain waves compared to typically developing children during a motor control task.
Autism often associated with multiple new mutations
Most autism cases are in families with no previous history of the disorder.
State laws requiring autism coverage by private insurers led to increases in autism care
A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health has found that the enactment of state laws mandating coverage of autism spectrum disorder (ASD) was followed by sizable increases in insurer-covered ASD care and associated spending.
Autism's gender patterns
Having one child with autism is a well-known risk factor for having another one with the same disorder, but whether and how a sibling's gender influences this risk has remained largely unknown.
Pinpointing the origins of autism
The origins of autism remain mysterious. What areas of the brain are involved, and when do the first signs appear?
Genes, ozone, and autism
Exposure to ozone in the environment puts individuals with high levels of genetic variation at an even higher risk for developing autism than would be expected just by adding the two risk factors together, a new analysis shows.
More Autism News and Autism Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Meditations on Loneliness
Original broadcast date: April 24, 2020. We're a social species now living in isolation. But loneliness was a problem well before this era of social distancing. This hour, TED speakers explore how we can live and make peace with loneliness. Guests on the show include author and illustrator Jonny Sun, psychologist Susan Pinker, architect Grace Kim, and writer Suleika Jaouad.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.