Molecular Discovery Could Provide Good Reason to Fear

Although fear is known to be processed in the amygdala, an almond-shaped structure deep within the brain, as well as in some other brain areas, very little has been known about the molecular mechanisms of learned and innate fear. Specifically, glutamate receptors and major protein kinases have been implicated, but they are important for other types of memories and behaviors besides fear.

Now a fear molecule has been identified, a protein called stathmin. The identification of stathmin as a fear molecule constitutes a notable advance in understanding the molecular basis of fear, both the major investigator and senior investigator of the study told Psychiatric News. The major investigator was Gleb Shumyatsky, Ph.D., an assistant professor of genetics at Rutgers University. The senior investigator was Eric Kandel, M.D., a professor of psychiatry at Columbia University and a winner of the 2000 Nobel Prize in Medicine or Physiology (Psychiatric News, November 3, 2000).

As Shumyatsky, Kandel, and their colleagues reported in the November 18, 2005, Cell, they first found that the amygdala and certain other brain areas crucial to regulating fear are very rich in stathmin. Then they found that mice without the stathmin gene showed less anxiety when they heard a tone that had previously been associated with a shock than did mice with the stathmin gene. The mice without the gene were also more prone than the controls to explore novel open spaces and maze environments. Furthermore, the mice without the stathmin gene did not show deficits in a spatial task dependent on the hippocampus, where stathmin is not normally present.

“Stathmin is involved in fear function, but not in some other types of memory,” Shumyatsky said. As the scientists concluded in their study report, stathmin is “essential in regulating both innate and learned fear.”

Also, Shumyatsky pointed out, “because stathmin is an inhibitor of microtubule formation, our study for the first time links microtubule function to memory for fear, or, for that matter, any kind of memory.” Microtubules, located in the cytoplasm of cells, are involved in cell structure and cell movement.

A challenge now is to determine whether stathmin also plays a role in fear in humans. “One has to see first if stathmin is expressed in the [human] amygdala in a way similar to that in mice,” Shumyatsky explained.“ Then we can look for possible genomic mutations in the stathmin gene sequences in human patients with a history of genetic predisposition to anxiety disorders.”

If stathmin indeed turns out to be involved in fear processing in humans, it could well lead to the discovery of new types of antianxiety drugs, both Shumyatsky and Kandel believe. For example, various compounds could be tested in mice without the stathmin gene.

Shumyatsky, Kandel, and their team are planning to delineate the intricacies of stathmin function in fear and how it interacts with other proteins involved in fear behavior.

The research was funded primarily by the National Institutes of Health and the National Alliance for Research on Schizophrenia and Depression.

An abstract of “Stathmin, a Gene Enriched in the Amygdala, Controls Both Learned and Innate Fear” is posted at<www.cell.com/content/article/abstract?uid=PIIS0092867405008755>.▪