A trio of drugs eases repetitive behaviors in mice by activating neurons in a brain region involved in motor control.

Researchers presented the unpublished findings today at the 2017 Society for Neuroscience annual meeting in Washington, D.C.

Repetitive behaviors, such as spinning or hand flapping, are a core feature of autism.

“We know they impact quality of life, but we really don’t have any good drug treatments,” says Amber Muehlmann, assistant professor of psychiatry at the University of Florida in Gainesville, who presented the work. “If we can find out what’s going wrong in the brain that mediates a repetitive behavior, then we can find new drug targets.”

Muehlmann and her colleagues studied two strains of mice that naturally have repetitive behaviors: a laboratory strain called C58; and deer mice, which are found in the wild. Both strains show repeated jumping and backwards somersaulting, performing the movements up to 10,000 times throughout the night when they are awake.

Muehlmann and her team found that a brain region called the subthalamic nucleus is underactive in the mice. The lower the level of activity in the region, the more severe the animal’s repetitive behaviors.

“The thinking was that if we could boost the function of that brain region, we could perhaps see a reduction in the repetitive behavior,” Muehlmann says.

Target practice:

Targeting the subthalamic nucleus directly with a drug proved challenging, however, as neurons in the region sport receptors seen throughout the brain. “We couldn’t find a good strategy for turning on the subthalamic nucleus without turning on a lot of other brain regions,” Muehlmann says.

The researchers turned their attention to a cluster of neurons in a nearby brain region, called the striatum. The neurons belong to a circuit that ultimately excites the subthalamic nucleus, and they express a combination of receptors not seen elsewhere in the brain.

The researchers identified three drugs that either activate or block these receptors. One of the drugs blocks a receptor for the neurotransmitter dopamine; the other two activate receptors for adenosine and glutamate.

Each of the drugs has no effect on behavior when administered alone or in combination with one of the other drugs. But the three drugs together reduce the amount of repetitive jumping and somersaulting by up to 90 percent in deer mice and 50 percent in C58 mice after a single injection.

After seven days of twice-daily injections, neurons in the subthalamic nucleus of C58 mice show an increase in the number of signal-receiving branches, called dendrites. They also show increased expression of certain proteins, such as bone-derived neurotrophic factor, which nurtures cells, and transcription factors, which control gene expression.

“We’re turning on those neurons in a way that’s fixing the problem that was contributing to the repetitive behavior,” Muehlmann says.

The drug cocktail has no effect on overall motor activity in the mice, suggesting the effects are specific to repetitive movements. The researchers hope to identify a single molecule that can target the striatal neurons even more specifically than the triple-drug cocktail.

For more reports from the 2017 Society for Neuroscience annual meeting, please click here.

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