Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior.
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.
Coryell
Matthew W
MW
Neuroscience Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Wunsch
Amanda M
AM
Haenfler
Jill M
JM
Allen
Jason E
JE
Schnizler
Mikael
M
Ziemann
Adam E
AE
Cook
Melloni N
MN
Dunning
Jonathan P
JP
Price
Margaret P
MP
Rainier
Jon D
JD
Liu
Zhuqing
Z
Light
Alan R
AR
Langbehn
Douglas R
DR
Wemmie
John A
JA
D062565:Acid Sensing Ion Channels; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000523:psychology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D007546:Isoquinolines / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009281:Naphthalenes / Q000008:administration & dosage; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D015222:Sodium Channels / Q000172:deficiency / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology
C506640:A-317567; C568266:ASIC1 protein, human; C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D000928:Antidepressive Agents; D007546:Isoquinolines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D015222:Sodium Channels