Mutant Mouse Gene Quells Fear

Harvard affiliates and other scientists have identified a gene in mice that could lead to new treatments for anxiety disorders in humans.

According to a study published in last week’s issue of the scientific journal “Cell,” a mutation in a single gene that controls production of the protein stathmin can embolden mice to make them more willing to explore and less likely to fear painful or dangerous stimuli.

Vadim Y. Bolshakov—director of McLean Hospital’s Cellular Neurobiology Laboratory and associate professor of psychiatry at Harvard Medical School (HMS)—said that the study’s findings could serve as a launching point for research in psychiatric medicine.

“Stathmin is a protein that is also found in human beings,” said Bolshakov, who worked on the study.

The protein was identified by the same group in an earlier study as playing a key role in the amygdala—a part of the brain that is associated with fear and is important for memory.

Stathmin’s apparent role in both learned and innate fear suggests that a drug can be created to reduce stathmin activity in the amygdala of humans. According to Bolshakov, creating such a drug would be “the next step.”

“Our work has some interesting possibilities for people with anxiety disorders such as post-traumatic stress disorder. If you could regulate this gene expression in humans, you probably could treat anxiety disorders,” Bolshakov said.

The genetic mutation made it impossible for the mice to produce stathmin. The brain activity of the mutant mice showed that they had difficulties strengthening connections between their nerve cells, raising questions about their ability to properly learn fear.

To test this ability, researchers exposed mutant mice and the control group to a small shock immediately after hearing a loud noise. When hearing the same noise 24 hours later, the “knockout” mice froze in place only about 60 percent as long as normal mice. Other tests were conducted to see if the mice had abnormal hearing or pain sensitivities, but this did not appear to be the case.

When normal and mutant mice were placed in a new environment, the mutant mice spent twice as long exploring their new territory as their genetically normal counterparts. The results of this “open field” test suggest that the knockout mice also had less innate fear than the control group.

Mark H. Pollack, director of the Center for Anxiety and Traumatic Stress Disorders at Massachusetts General Hospital and associate professor of psychiatry at HMS, said that the study could help doctors understand anxiety better.

“If you can identify genes that may be relevant for anxiety disorders, like social anxiety and post-traumatic stress disorder, you may be able to design treatments that react in the systems that these genes control,” he said.

But such a treatment would be far from a cure-all.

“It’s unlikely that there’s going to be one gene that’s the answer or that works for everybody,” Pollack said.