Rare Mutation Study Points to New Targets for Treating Brain Disorders
For decades, a neuroscience team led by Randy D. Blakely, Ph.D., has searched for rare genetic alterations that can change how dopamine works in the brain.
Dopamine is a powerful neurotransmitter implicated in brain functions including movement, mood and reward. Genetic mutations that affect this system are rare, but they give neuroscientists a tool to explore conditions in the brain where dopamine isn’t working like it should.
“From there, you can connect the dots to more common occurrences linked to dopamine disruptions, including disorders displaying attention deficits, impulsivity or repetitive behaviors,” said Blakely, the David J. S. Nicholson Distinguished Professor in Neuroscience, professor of biomedical science in Florida Atlantic’s Charles E. Schmidt College of Medicine, and executive director of the Stiles-Nicholson Brain Institute.
In a recent example, the team reexamined a rare genetic mutation they discovered a decade ago. The variation was carried by a few individuals with diagnoses of attention-deficit/ hyperactivity disorder (ADHD), autism spectrum disorder or bipolar disorder. The mutation, called DAT Val 559, affects dopamine transporters. These are proteins that bind to dopamine and effectively remove it from the synapse, limiting its effects on the brain. But this genetic hiccup leads the transporters to “run backwards,” ejecting dopamine back into the synapse.
“It’s part of a hunt that we’ve been on for some time,” Blakely said. “And we’ve learned our craft. We learned how to find these mutations, and how to convert our findings into testable hypotheses about how they ultimately affect behavior.”
This craft often involves genetically engineering mice to carry the same mutations the team discovers in humans or other organisms. As predicted, mice engineered to produce DAT Val 559 are impulsive and hyperactive when approached.
Then the goal became a challenge for the team to normalize the altered behaviors of the mice by targeting a key mechanism that neurons use to regulate dopamine transporters. The team targeted a receptor that, when activated by a particular opioid, is known to make more dopamine transporters available. That’s a problem in this case, as the transporters are known to leak dopamine.
In their experiment, the team gave the mice a drug that blocks this type of opioid receptor. The results, published recently in the journal Molecular Psychiatry, showed that the drug reduced the availability of the damaged transporters and corrected deficits in learning and memory.
The finding — that a drug blocking an opioid receptor can normalize altered behaviors seen in DAT Val 559 mice — might at first be useful only for the small number of people with the mutation. But the results raise the possibility that this opioid receptor may be an important target for new treatments for much more common dopamine-related disorders.
“We think it has much broader significance. Dopamine signaling can be modified in so many different ways that there are many more common changes that the findings relate to,” Blakely said. “It’s a target that has drawn increasing attention in the field of addiction, and here we make a case that it applies as well to other things that dopamine does.”