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Disrupting Brain Protein Produces Antidepressant Effect in Mice

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(Great Neck, N.Y. - May 26, 2009) — A brain protein involved in fear behavior and anxiety may represent a new target for depression therapies, according to a report in the April 29th Journal of Neuroscience about research by NARSAD Investigator John Wemmie, M.D., Ph.D., and colleagues.

Dr. Wemmie’s team at the University of Iowa and the Iowa City Veterans Affairs Medical Center, along with collaborators from the University of Memphis and the University of Utah, found that disrupting ASIC1a, an ion channel protein in the brain, produced an antidepressant-like effect in mice similar to that produced by currently available antidepressant drugs. Importantly, the study also showed that ASIC1a's effect arose through a new and different biological mechanism.

"The mechanism issue is important because if a patient doesn't respond to one drug, the chances of them responding to another drug that works through the same mechanism are low," said Dr. Wemmie, who received NARSAD Young Investigator awards in 2004 and 2007. "We need antidepressants with new mechanisms of action to help those people who don't respond to what is currently available."

The results suggest that ASIC1a inhibition represents a new approach to antidepressant therapy. The channel can be blocked pharmacologically. In addition, manipulating brain pH (a measure of acidity) might be used to inhibit this ion channel, which is activated by acid (low pH). The study also pointed to the potential efficacy of using antidepressant drugs and inhibiting ASIC1a simultaneously.

The researchers focused on ASIC1a because recent studies have pointed to a role for this ion channel in depression. In particular, previous animal studies from Dr. Wemmie's lab showed that ASIC1a plays an important role in fear responses (panic) and anxiety, conditions that often accompany depression. Other research has suggested a strong relationship between anxiety, depression and the brain's fear circuitry, including the amygdala, where ASIC1a is abundant.

In their latest study, Dr. Wemmie's team used experiments targeting the amygdala to show that this brain region is a key site of action for ASIC1a's antidepressant effect. The results support the idea that depression may be caused, at least in part, by abnormal amygdala activity.

"Because the ASIC1a protein is especially abundant in areas of the brain that regulate emotion, it is possible that interventions targeting ASIC1a could treat depression, while having fewer effects on other brain areas and thus fewer side effects than available treatments. But much more work is needed to determine if this approach can be used therapeutically," said Matthew Coryell, Ph.D., lead study author.

The researchers also found that ASIC1a function might underlie the connection between stress and depression. Stress can precipitate depression, and research from other labs has suggested this might be because stress lowers levels of protective brain hormones called neurotrophic factors. The Wemmie team found that removing ASIC1a prevented stress from reducing levels of one neurotrophic factor called BDNF in mice. The findings might mean that inhibiting ASIC1a could increase the brain's ability to resist the negative effects of stress and perhaps reduce a person's likelihood of developing depression.

(This article was adapted with permission from the University of Iowa.)

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We value and respect our HERWriters' experiences, but everyone is different. Many of our writers are speaking from personal experience, and what's worked for them may not work for you. Their articles are not a substitute for medical advice, although we hope you can gain knowledge from their insight.

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