A mutation in the brain proteins of an autistic child causes a behavioural change similar to that of autism in mice

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A mutation in the brain proteins of an autistic child causes a behavioural change similar to that of autism in mice

This is a potential mechanistic basis - at least in a subset of patients - for the modified behaviours observed in autistic people

A de novo gene mutation that codes for a brain protein in a child with autism has been placed in the mouse brain. These mice then showed severe changes in specific behaviours that are very similar to those observed in human autism spectrum disorder, or ASD.

This major discovery from a study published in the Journal of Clinical Investigation "presents an exciting opportunity for potential mechanistic support - in at least a subset of patients - for some of the modified behaviours observed in ASD and Attention Deficit Hyperactivity Disorder, or ADHD," said Aurelio Galli, PhD, Professor of Surgery at the University of Alabama, Birmingham.

The research was conducted by corresponding authors Galli and Mark Wallace, PhD, neurobiologist and Dean of Vanderbilt University.

The brain protein studied is the dopamine transporter, or DAT. Some neurons in the brain release the neurotransmitter dopamine at the end of their axons. Dopamine crosses the junction, or synapse, between this axon and a neighbouring neuron, triggering a response in this receptor neuron. The DAT -- which is located in the membrane of the emitting neuron -- has the function of recapturing the dopamine, pumping the dopamine released into the emitting neuron from the synapse, thus stopping the response of the receiving neuron.

Brain activity involving the dopaminergic system in the region of the brain called striatum is a critical regulator of motor activity, motivation, attention and reward treatment. Given the integral role of the dopamine system in critical brain functions, it is not surprising 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 disorders, ADHD and recently ASD.

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

A previous study by Galli and Eric Gouaux, PhD, Professor at Oregon Health & Science University, introduced DAT mutation in fruit flies; in flies, DAT T356M produced abnormal behaviours of increased locomotor activity, fear, repetitive activity and modified social interaction, suggesting autistic disorders. Bacteriological studies have suggested that DAT T356M is turned upside down compared to normal DAT, so that DAT T356M abnormally pumps dopamine out of a cell rather than into the cell.

Now, Galli, Wallace and Gabriella DiCarlo, medical and doctoral students, have reported the first study of DAT T356M in a mammalian brain.

Homozygous mice carrying two copies of the DAT T356M gene mutation have shown severe behavioural changes that resemble human behaviour at ASD and ADHD and significant changes in brain physiology. ADHD is a common comorbidity of ASDs. However, no changes were observed in mice that had only one copy of the DAT T356M gene mutation compared to normal mice.

Mice with the DAT T356M showed a loss of social interactions, a loss of social dominance and a decrease in marble burial, an innate behaviour of laboratory mice that is motivated by their desire to investigate. Mice with the DAT T356M showed repetitive rearing behaviour and better learning how to maintain balance on a rotating rod, which is related to the propensity for repetitive behaviour.

DAT T356M mice also showed hyperactivity, measured by an increase in spontaneous locomotor activity. Significantly, when mice were treated with two different compounds that block DAT activity, their hyperactive behaviour decreased. "Future work should focus on determining whether DAT blocking can eliminate or mitigate the more complex behavioural changes observed in animals of DAT T356M," said Galli.

Altered social behaviour and hyperactivity have been linked to altered signaling activity of the dopaminergic neurotransmitter in the brains of DAT T356M mice. On the physiological level, the researchers discovered an alteration in the neurotransmission and clearance of striatal dopamine.