According to some estimates, up to one in three people around the world may experience severe anxiety in their lifetime. In a study described today in  Cell Reports , researchers at the Weizmann Institute of Science have revealed a previously unknown mechanism underlying anxiety. Targeting this biochemical pathway may help develop new therapies for alleviating the symptoms of anxiety disorders.

The lab of Prof. Mike Fainzilber in the Institute's Biomolecular Sciences Department has studied the neuronal roles of proteins called importing. These proteins, found in all cells, shuttle molecules into the nucleus. The lab's previous work focused on the nervous system (all nerve tissue in the body except the brain and spinal cord). Postdoctoral fellow Dr. Nicolas Panayotis, who joined the group in 2012, decided to find out if any of the importins also play a role in the central nervous system, that is, the brain and spinal cord.

No alpha-5, no stress

Panayotis and colleagues studied five lines of mice, genetically engineered by Prof. Michael Bader's laboratory in the Max Delbrück Center for Molecular Medicine in Berlin, to lack genes from the alpha subfamily of importing.

The researchers exposed these mice to a battery of behavioral tests and found that one line of mice-those lacks importin alpha-5-stood out in a unique manner: They showed in stressful situations, for example, when they were placed in large, exposed areas or on a highly elevated, open platform. The researchers then checked how these "calmer" mice differed from regular ones regarding gene expression in specific brain regions involved in controlling anxiety.

Computational analyzes pointed to MeCP2, a regulatory gene known to affect anxiety behaviors. It turned out that importin alpha-5 was critical for enabling the entry of MeCP2 into the nuclei of neurons. Changes in the levels of MeCP2 in the core, in turn, affected the standards of an enzyme involved in the production of a signaling molecule called S1P.

In mice lacking importin alpha-5, MeCP2 failed to enter the nuclei of anxiety-controlling neurons, reducing S1P signaling and lowering anxiety.
After performing additional experiments to confirm that they had indeed discovered a new anxiety-regulating mechanism in the brain, the researchers searched for molecules that could modify this mechanism.

They realized that drugs that modulate S1P signaling already existed; one such drug, fingolimod, is used to treat multiple sclerosis. When the patients tested the effects of fingolimod on regular mice, these mice showed reduced anxiety, similarly to the genetically engineered mice lacking the importin alpha-5 gene.

New directions in anxiety research

"Our findings have opened a new direction for research into the mechanisms of anxiety," Panayotis says. "If we understand exactly how the circuitry that we have discovered controls, this may help develop new drugs, or direct the use of existing ones, to alleviate its symptoms."

The study's findings also show that there are no genetic disorders in the MeCP2 gene: Rett syndrome and MeCP2 duplication syndrome. Both these disorders are characterized by anxiety, among other symptoms. Identifying the precise mechanisms responsible for the entry of MeCP2 into neurons' nuclei may, in the future, help develop therapies for these two disorders.