The mutation of a brain protein in an autistic child causes a behavioral change similar to that of autism in mice

BIRMINGHAM, Alabama – A de novo gene mutation encoding a brain protein in an autistic child has been placed in the mouse brain. These mice then exhibited severe behavioral changes that closely resembled those seen in the human autism spectrum disorder, or ASD.

This major discovery of a study published in the Journal of Clinical Investigation "presents the exciting possibility of a mechanistic support potential – in at least one subgroup of patients – for some of the impaired behaviors seen in ASD and attention-deficit hyperactivity disorder." , or ADHD, "said Aurelio Galli, Ph.D., professor. of Surgery at the University of Alabama in Birmingham.

The research was conducted by the corresponding authors Galli and Mark Wallace, Ph.D., neurobiologist and dean of Vanderbilt University.

The brain protein studied is the dopamine transporter, or DAT. Some brain neurons release the neurotransmitter dopamine from the ends of their axons. Dopamine crosses the junction, or synapse, between this axon and a neighboring neuron, triggering a response in this receptor neuron. DAT – which is in the emitting neuron's membrane – has the task of reabsorbing dopamine, by pumping the dopamine released into the emitting neuron from the synapse, thus ending the receptor neuron's response.

The brain activity involving the dopamine system in the region of the brain called the striatum is an essential regulator of motor activity, motivation, attention and reward treatment. Given the essential role of the dopaminergic system in essential brain functions, it is not surprising that dysregulation of this neurotransmitter system has been implicated in neuropsychiatric disorders such as Parkinson's disease; addiction with heroin, cocaine, speed, nicotine and other drugs; bipolar disorder; ADHD; and recently ASD.

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

An earlier study led by Galli and Eric Gouaux, Ph.D., professor at Oregon Health & Science University, introduced the mutation into the fruit fly DAT; in flies, the DAT T356M has caused abnormal behaviors: increased locomotor activity, fear, repetitive activity and impaired social interaction, recalling the deficiencies of autism. Bacterial studies have suggested that the T356M DAT is reversed from normal DAT, so the DAT T356M abnormally pumps dopamine out of a cell rather than into the cell.

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

Mice that were homozygous with two copies of the DAT T356M gene mutation exhibited severe behavioral changes that resemble the human behaviors of ADD and ADHD as well as significant alterations in cerebral physiology. ADHD is a common comorbidity of ASD. In contrast, no changes were observed in mice that possessed only one copy of the DAT T356M gene mutation compared to normal mice.

Mice carrying the DAT T356M showed a loss of social interaction, a loss of social dominance and a decrease in marble burial, an innate behavior of laboratory mice motivated by their willingness to investigate. Mice carrying the DAT T356M showed repetitive breeding behavior and better learning how to maintain balance on a rotating stem, which is related to the propensity for repetitive behavior.

DAT T356M mice also exhibited hyperactivity, as measured by an increase in spontaneous locomotor activity. Significantly, when the mice were treated with two different compounds that block the activity of DAT, their hyperactive behavior decreased. "Future work should focus on whether blocking DAT could eliminate or lessen the more complex behavioral changes seen in DAT T356M animals," said Galli.

Altered social behavior and hyperactivity were related to the signaling activity of dopaminergic neurotransmitters altered in the brain of DAT T356M mice. At the physiological level, the researchers found an alteration of neurotransmission and striatal dopamine clearance.

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Galli and Wallace's coauthors in the study, "A mutation in the dopamine transporter linked to autism alters the striatal neurotransmission of dopamine and dopamine-dependent behaviors": Gabriella E. DiCarlo, Fiona E Harrison and Kyle E. Bundschuh of 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 grants DA038058, DA35263, MH115535, MH114316, MH106563 and GM007347 from the National Institutes of Health.