Breathe too much carbon dioxide (CO2), and you'll suffocate. That's why people begin to panic if they breathe air enriched with the gas. One reason this happens, according to a new study in mice, is because breathing CO2 triggers chemical sensors in a crucial part of the brain's fear circuitry. The findings could point the way to new treatments for anxiety disorders.
Neuroscientist John Wemmie and colleagues at the University of Iowa in Iowa City focused on a protein found in particular abundance in the amygdala, the brain's fear center. They'd shown previously that mice lacking the gene for this protein, known as acid-sensing ion channel-1a (ASIC1a), have impaired fear behavior. In their new study, reported today in Cell, the researchers show that mice lacking this gene don't freeze in place--a commonly used indicator of rodent fear--to the extent that normal mice do when the team pumped CO2 into their enclosure. But when Wemmie and colleagues injected a virus containing the ASIC1a gene into the amygdala of the mice, they acted like normal mice, freezing up when exposed to elevated CO2.
In additional experiments, the team found that breathing CO2 slightly lowers the pH in the amygdala, meaning that the tissue becomes more acidic. Exposing cultured mouse amygdala neurons to a similar dip in pH elicited an electrical current, but not in neurons from mice lacking ASIC1a. When the researchers injected normal mice with bicarbonate--a buffer that prevents the pH dip--in the amygdala, the mice froze less in response to CO2. Taken together, the findings point to the following scenario, Wemmie says: Inhaling CO2 raises the acid level in the amygdala, thereby activating ASIC1a and altering the electrical signaling of amygdala neurons to produce a fear response. CO2 also increases the breathing rate in mice and humans, and the findings don't rule out the possibility that this change also contributes to fear responses as some researchers have proposed, Wemmie says.
"The evidence is now pretty compelling that these acid-sensing ion channels have a role in fear," says Richard Maddock, a psychiatrist and neuroscientist at the University of California, Davis. If it's possible to develop drugs that target these channels, they might be attractive candidates for treating panic disorder and related conditions, Maddock says.
Stephen Dager, who studies anxiety disorders at the University of Washington, Seattle, is also enthusiastic about the study, but he notes that other researchers have looked for--and so far not found--a link between related human genes and anxiety disorders. That suggests that defects in these channels aren't a major cause of anxiety disorders in people. But, Dager says, but it doesn't rule out the possibility that treatments that target these proteins will prove useful for blunting panic attacks.