Acid-Sensing Ion Channel-1a in the Amygdala, a Novel Therapeutic Target in Depression-Related Behavior
- Matthew W. Coryell 1 ,
- Amanda M. Wunsch 2 ,
- Jill M. Haenfler 2 , 6 ,
- Jason E. Allen 2 , 6 ,
- Mikael Schnizler 4 ,
- Adam E. Ziemann 4 ,
- Melloni N. Cook 7 ,
- Jonathan P. Dunning 7 ,
- Margaret P. Price 5 ,
- Jon D. Rainier 8 ,
- Zhuqing Liu 8 ,
- Alan R. Light 9 , 10 ,
- Douglas R. Langbehn 2 , and
- John A. Wemmie 1 , 2 , 3 , 6
- 1Neuroscience Program, and
- Departments of 2Psychiatry,
- 3Neurosurgery,
- 4Physiology, and
- 5Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, and
- 6Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242,
- 7Psychology Department, The University of Memphis, Memphis, Tennessee 38152, and
- Departments of 8Chemistry,
- 9Anesthesiology, and
- 10Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84132
- Correspondence should be addressed to Dr. John A. Wemmie, Department of Psychiatry, University of Iowa College of Medicine, 3139 Medical Laboratories, Iowa City, IA 52242. john-wemmie{at}uiowa.edu
Abstract
No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a−/− mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression.
- Copyright © 2009 Society for Neuroscience 0270-6474/09/295381-08$15.00/0
