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'Darting' mice may hold clues to ADHD, autism, bipolar disorder

Date: November 10, 2014

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Source: Vanderbilt University Medical Center

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

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Related Topics
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Attention Deficit Disorder
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Mice inserted with a rare human genetic variation in the dopamine transporter
could lead to improvements in the diagnosis and treatment of brain disorders.
Credit: Image courtesy of Vanderbilt University
Medical Center

[Click to enlarge image]

darting mouse may hold an important clue in the development of

Attention Deficit Hyperactivity Disorder (ADHD), autism and bipolar
disorder, according to a study by a Vanderbilt University-led research
team recently published in the Proceedings of the National Academy of
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The transgenic mouse, into which was inserted a rare

human genetic variation in the dopamine transporter
(DAT), could lead to improvements in the diagnosis and
treatment of these all-too-common brain disorders, said
Randy Blakely, Ph.D., the report's senior author.

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Attention-deficit
hyperactivity disorder

The mutation, which has been found in people with

ADHD, autism and bipolar disorder, affects the function
of DAT, a protein that regulates the brain's supply of
the neurotransmitter by removing excess dopamine
from the synapse, or the space between nerve cells.

Mar. 1, 2011 Researchers have generated

important new insight into ADHD and how the
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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 of

Pharmacology.
While mice with leaky DAT proteins have too much dopamine hanging around their
synapses, surprisingly they aren't particularly hyperactive, possibly because DAT can
still remove some of the dopamine.
But the mice exhibit an unusual "darting behavior." While their wild-type littermates are
docile 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 observing
this 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 for
an inappropriate escape strategy.

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Normal mice also stand up a lot to explore their cage. This "rearing" behavior is
exacerbated by stimulant drugs. But not in these mice.
"We wonder whether this may be a sign that their behavior is driven less by searching
for clues to appropriate behavior versus acting on innate impulses," Blakely said.
Other, better tests of impulsivity that evaluate premature decision-making can be
applied in rodents and humans. "These tests are next on our docket," he said.
The actions of amphetamine and methylphenidate (Ritalin) are also affected by the
mutation. In normal animals and people without ADHD, the stimulants flood the
synapse with dopamine, eliciting hyperactivity.

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

Images of a Nearly Invisible Mouse

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

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To that end, Blakely recently received a five-year, $2-million grant from the National
Institutes of Health (NIH grant number MH109054) to pursue explorations of these
mice.
"Dopamine has classically been implicated in reward and the ability to detect novelty
and to respond to pleasure and to engage in effective social interactions," he
continued. The darting mice thus might shed light on a much broader spectrum of
behaviors.

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

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Story Source:

Insight

The above story is based on materials provided by Vanderbilt University Medical

Center. The original article was written by Bill Snyder. Note: Materials may be edited
for content and length.

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 coding
variant Val559 perturbs DA neuron function, changes behavior, and alters in
vivo responses to psychostimulants. Proceedings of the National Academy of
Sciences, 2014; 111 (44): E4779 DOI: 10.1073/pnas.1417294111
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... from NewsDaily.com

Science News

Vanderbilt University Medical Center. "'Darting' mice may hold clues to ADHD,
autism, bipolar disorder." ScienceDaily. ScienceDaily, 10 November 2014.
<www.sciencedaily.com/releases/2014/11/141110110726.htm>.

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