Israeli researchers recently made a discovery that could help develop new therapies for anxiety disorders. With up to one in three people around the world at the risk of experiencing severe anxiety, this is big news.

At the heart of the discovery, published in Cell Reports, is a previously unknown biochemical pathway underlying anxiety.

Researchers from the Weizmann Institute of Science biomolecular sciences department studied the role of proteins called importins in the central nervous system (the brain and spinal cord). Importins are found in all cells. Their job is to shuttle molecules into the nucleus.

Dr. Nicolas Panayotis (Credit: Weizmann Institute of Science)

Postdoctoral fellow Nicolas Panayotis and his colleagues studied five lines of mice genetically engineered to lack genes from the alpha sub-family of importins. They subjected the mice to a series of behavioral tests and found that one line of mice – those lacking importin alpha-5 – showed no anxiety in stressful situations.

The researchers then examined how the “calmer” mice differed from regular ones in terms of gene expression in brain regions involved in controlling anxiety. Computational analyses pointed to MeCP2, a regulatory gene known to affect anxiety behaviors. The researchers discovered 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 nucleus, in turn, affected the levels 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.

The researchers discovered that there are already drugs that modulate S1P signaling, including a drug called fingolimod that is used to treat multiple sclerosis. The researchers administered fingolimod to regular mice, which showed reduced anxiety in a similar manner to the genetically engineered mice lacking the importin alpha-5 gene.

New direction for anxiety research

The Weizmann researchers’ new discovery can explain why a clinical trial of fingolimod showed the drug had a calming effect on patients with multiple sclerosis.

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

Prof. Mike Fainzilber, in whose Weizmann lab the research was carried out, noted that “current drugs for anxiety are limited in their efficacy or have undesirable side effects, which also limit their usefulness. Our findings may help overcome these limitations. In follow-up research, we have already identified a number of drug candidates that target the newly discovered pathway.”

The study’s findings also shed new light on Rett syndrome and MeCP2 duplication syndrome, two rare genetic disorders characterized by mutations in the MeCP2 gene in which patients suffer from anxiety, among other symptoms.

Identifying the mechanisms responsible for the entry of MeCP2 into the neurons’ nuclei could help develop therapies for these disorders.

The study also included researchers from Tel Aviv University and Ariel University in Israel, and the Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin, both in Berlin.