darting' mice may hold clues to adhd, autism, bipolar disorder

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November 10, 2014

Vanderbilt University Medical Center

A darting mouse may hold an important clue in the development ofAttention Deficit Hyperactivity Disorder (ADHD), autism and bipolardisorder, according to a study. The transgenic mouse, into which wasinserted a rare human genetic variation in the dopamine transporter(DAT), could lead to improvements in the diagnosis and treatment ofthese all-too-common brain disorders, said the report's senior author.

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Mice inserted with a rare human genetic variation in the dopamine transportercould lead to improvements in the diagnosis and treatment of brain disorders.

darting mouse may hold an important clue in the development ofAttention Deficit Hyperactivity Disorder (ADHD), autism and bipolardisorder, according to a study by a Vanderbilt University-led research

team recently published in the Proceedings of the National Academy ofSciences.

The transgenic mouse, into which was inserted a rarehuman genetic variation in the dopamine transporter(DAT), could lead to improvements in the diagnosis andtreatment of these all-too-common brain disorders, saidRandy Blakely, Ph.D., the report's senior author.

The mutation, which has been found in people withADHD, autism and bipolar disorder, affects the functionof DAT, a protein that regulates the brain's supply ofthe neurotransmitter by removing excess dopaminefrom the synapse, or the space between nerve cells.

The DAT mutation causes the transporter to become"leaky" and spew out dopamine like "a vacuum cleaner

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in reverse," said Blakely, Allan D. Bass Professor ofPharmacology.

While mice with leaky DAT proteins have too much dopamine hanging around theirsynapses, surprisingly they aren't particularly hyperactive, possibly because DAT canstill remove some of the dopamine.

But the mice exhibit an unusual "darting behavior." While their wild-type littermates aredocile and quite unresponsive when researchers pick them up, those with the mutation"take off."

"Early on," Blakely said, "we could tell which ones carried the mutation by observingthis response." Heightened anxiety does not appear to be the cause.

Blakely and his colleagues wonder whether this behavior is a form of "impulsivity."Rather than acting on their memories of being picked up a lot, the mice are opting foran inappropriate escape strategy.

Normal mice also stand up a lot to explore their cage. This "rearing" behavior isexacerbated by stimulant drugs. But not in these mice.

"We wonder whether this may be a sign that their behavior is driven less by searchingfor clues to appropriate behavior versus acting on innate impulses," Blakely said.

Other, better tests of impulsivity that evaluate premature decision-making can beapplied in rodents and humans. "These tests are next on our docket," he said.

The actions of amphetamine and methylphenidate (Ritalin) are also affected by themutation. In normal animals and people without ADHD, the stimulants flood thesynapse with dopamine, eliciting hyperactivity.

But when given to the mutant animals, the drug demonstrates a "blunted" effect onboth dopamine release and on locomotor activation compared to normal animals.

Blakely wonders whether stimulants like Adderall and Ritalin quell hyperactive andimpulsive behaviors in some children with ADHD by reducing inappropriate dopamineleak. "These mice may give us much better clues as to how these drugs are acting,"he said.

To that end, Blakely recently received a five-year, $2-million grant from the NationalInstitutes of Health (NIH grant number MH109054) to pursue explorations of thesemice.

"Dopamine has classically been implicated in reward and the ability to detect noveltyand to respond to pleasure and to engage in effective social interactions," hecontinued. The darting mice thus might shed light on a much broader spectrum ofbehaviors.

"We've got a lot to do," he said, "a lot of needy people (to help)."

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The above story is based on materials provided by Vanderbilt University MedicalCenter. The original article was written by Bill Snyder. Note: Materials may be editedfor content and length.

Journal Reference:

1. M. A. Mergy, R. Gowrishankar, P. J. Gresch, S. C. Gantz, J. Williams, G. L. Davis,C. A. Wheeler, G. D. Stanwood, M. K. Hahn, R. D. Blakely. The rare DAT codingvariant Val559 perturbs DA neuron function, changes behavior, and alters invivo responses to psychostimulants. Proceedings of the National Academy ofSciences, 2014; 111 (44): E4779 DOI: 10.1073/pnas.1417294111

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darting' mice may hold clues to adhd, autism, bipolar disorder

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