Mouse Model May Reveal Anxiety Gene, Marker for Antidepressant Failure
• Science Update
Provides valuable tool for exploring basis of human anxiety and response to SSRIs.
Studies of a new mouse model suggest that a specific gene variation plays a role in the development of anxiety disorders and in resistance to common medications for anxiety and depression.
With further research, the findings could eventually help explain part of the genetic underpinnings of anxiety disorders, which affect 40 million American adults, and lead to biological markers that predict whether or not selective serotonin reuptake inhibitors will be effective for a given patient. Finding the right medication for each person is often a lengthy process in treatment of anxiety and depression, during which illness may worsen; biological markers could help narrow the search on an individualized basis.
The study was funded by NIMH and the National Institute of Neurological Disorders and Stroke. Results were reported in the October 6 issue of Science by Francis Lee, Zhe-Yu Chen, and colleagues from Weill Medical College of Cornell University, Shandong University (China), and The Rockefeller University.
The scientists created mice with a variation in the BDNF gene, which produces a protein crucial to growth and maintenance of brain cells. The mice exhibited increased anxiety-like behaviors and some resistance to the SSRI fluoxetine only if the variant was present in both copies of the gene. (Each gene has two copies, one from each parent.)
From 20 to 30 percent of Caucasians have the variation in one of their copies of the gene, and it appears in other populations, as well. About 4 percent of Caucasians and 15.9 percent of Japanese people — substantial numbers, in genetic terms — have the variation in both copies.
In humans, past studies had linked this gene variation to memory loss and reduced size of a brain area called the hippocampus, which plays a role in memory. Both characteristics have been linked to some mental disorders, including depression. Having succeeded in inducing memory loss and smaller hippocampi in the mice by adding the variation to the gene, the scientists then probed the same mice to find out if the variation also caused them to have other characteristics of interest.
Their probing revealed that the variation also was linked to increased anxiety-like behaviors that were resistant to SSRIs. The results of the mouse experiments suggest that the variation may contribute to anxiety disorders and SSRI resistance in people.
The scientists also found that mice with the variant had defective brain-cell secretion of the BDNF protein and changes in shape of the brain cells that produce it. These alterations in function and shape may form part of the basis of BDNF's role in anxiety, SSRI resistance, and depression.
The new mouse model appears to be the first report of researchers successfully adding a specific variation to a gene in animals to purposely induce characteristics similar to those caused by the variation in humans.
Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL, and Lee FS. Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior . Science 6 October 2006 314: 140-143.