This is a potential mechanistic underpinning — at least in a subset of patients — for the altered behaviors observed in autism — ScienceDaily

The brains of mice were implanted with a de novo mutation that encodes a brain-protein in a child diagnosed with autism. These mice showed severe behavioral changes that closely resembled those in autism spectrum disorder (or ASD) in humans.

This is the major finding of a study published in Journal of Clinical Investigation“This exciting possibility of a possible mechanistic underpinning — at minimum a subset of patients – for some of the altered behavior observed in ASD, attention deficit hyperactivity disorder or ADHD,” stated Aurelio Gali, Ph.D., professor of Surgery at the University of Alabama at Birmingham.

Galli and Mark Wallace, Ph.D., a neurobiologist, and dean at Vanderbilt University, led the research.

The DAT, or dopamine transporter in brain, is the brain protein being studied. Certain brain neurons release the neurotransmitter, dopamine, from the ends their axons. Dopamine crosses the synapse or junction between the axon and a neighboring nerve, activating a response in the receiving neuron. DAT, which is found in the membrane the transmitting neurons, is responsible for dopamine recovery. This involves pumping dopamine out of the synapse to the transmitting neuraln and thereby ending the receiving neuron’s response.

The brain activity that involves the dopamine system, located in the region of our brain called the striatum, is crucial for motor activity, motivation and reward processing. It is not surprising that neuropsychiatric disorders such as Parkinson’s, substance abuse with heroin, cocaine and speed, and nicotine addiction, and bipolar disorder, have been linked to dysregulation of the dopamine systems in brain functions.

Galli, Wallace, and their colleagues discovered a mutation in human DAT gene that was present in a child suffering from ASD. This mutation causes a substitution at amino Acid 356 of DAT. The change from threonine and methionine results in 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 have shown that DAT T356M is flipped inwards compared to normal DAT. DAT T356M anomalously pumps the dopamine out of cells rather than into them.

Now Galli and Wallace have published their M.D./Ph.D. Gabriella DiCarlo, student, has published the first study on DAT T356M within a mammalian brain.

Mice homozygous for two copies of DAT T356M gene mutation in both their genes showed significant behavioral changes that were very similar to human ASD and ADHD. They also experienced significant brain physiology changes. ADHD is a common comorbidity for ASD. However, there were no changes in mice with one copy of DAT T356M gene mutation compared to normal mice.

DAT T356M caused mice to experience a decrease in social interaction, social dominance, and reduced marble burying. This is a natural behavior of lab mice, which is motivated by the desire to explore. The DAT T356M mice showed repetitive rearing behavior, enhanced learning of how balance is maintained on a rotating rod, which is related to the propensity towards repetitive behavior.

DAT T356M mice also displayed hyperactivity as measured by an increase in spontaneous locomotor activity. Two compounds that block DAT activity significantly reduced hyperactivity in the mice. Galli said that future work should examine whether blocking DAT activity may be able to eliminate or mitigate the more complex behavior changes observed in DAT-T356M animals.

The altered social behavior, and hyperactivity in DAT T356M mice were linked to decreased dopamine neurotransmitter-signaling activity. Researchers found impaired striatal Dopamine neurotransmission and clearance at the physiological level.

Galli and Wallace were coauthors in the study, “Autismlinked dopamine Transporter Mutation Alters Strital Dopamine Neurotransmission and Dopamine-dependent Behaviors.”

National Institutes of Health grants DA038058 to MH115535, MH114316 to MH106563, GM007347 and MH115535, MH115535, MH115316 to MH114316 provided support.

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