The anesthesia medication ketamine has shown promise in treating depression, but its exact effects on the brain are unclear. Now, researchers have discovered that the drug changes the firing patterns of cells in a pea-size structure hidden away in the center of the brain. This could explain why ketamine is able to relieve symptoms of depression so quickly—and may provide a fresh target for scientists developing new antidepressants.
“It’s a spectacular study,” says Roberto Malinow, a neuroscientist at the University of California, San Diego, who was not involved in the work. “It will make a lot of people think.”
In clinical trials, ketamine appears to act much faster than existing antidepressants, improving symptoms within hours rather than weeks. “People have tried really hard to figure out why it’s working so fast, because understanding this could perhaps lead us to the core mechanism of depression,” says Hailan Hu, a neuroscientist at Zhejiang University School of Medicine in Hangzhou, China, and a senior author on the new study.
Hu suspected the drug might target a tiny region in the middle of the brain called the lateral habenula, the so-called “anti–reward center.” This region inhibits nearby reward areas, which can be useful in learning; for example, if a monkey pulls a lever expecting a treat but never receives it, the lateral habenula will reduce the activity of reward areas, and the monkey will be less likely to pull the lever in the future. But research over the past decade has suggested that the area may be overactive in depression, dampening down those reward centers too much.
In a series of experiments using mouse and rat models of depression reported today in Nature, Hu and her colleagues found that ketamine did affect the lateral habenula—but it was the pattern of firing, rather than the overall amount of activity, that proved crucial. A small proportion of the neurons in the lateral habenula fire several times in quick bursts, rather than firing once at regular intervals; the team found that “depressed” rodents had a lot more of these quick burst cells. In brain slices from normal rats, only about 7% of cells were the bursting type, but in rats bred to display depressionlike behavior, the number was 23%.
Direct recordings from the neurons of live mice showed the same pattern: Animals that had gone through a stressful procedure had more bursting cells in the lateral habenula. And, importantly, this bursting behavior appeared to cause depressionlike states. When researchers used optogenetics—a technique that allows cells to be switched on and off with light—to increase the amount of bursting in the lateral habenula, mice behaved in a more “depressed” way, remaining motionless when forced to swim in a container of water, for example. This kind of despair is thought to be similar to the feelings of hopelessness experienced in depression.
When “depressed” mice and rats were given ketamine, the number of bursting cells was much lower, similar to the number in normal animals, Hu’s team found. And even when the researchers forced the neurons to fire in bursts, animals that had been given ketamine no longer showed depressionlike behaviors.
Hu says that neurons firing several times in quick succession produce a more powerful signal. This means that bursting cells may be sending particularly strong messages to dampen down activity in reward areas, which could lead to depression. “Bursting has a special kind of signaling power,” Malinow says. “You get more bang for your buck.”
The findings could also explain why ketamine acts so quickly. By immediately blocking bursts in the lateral habenula, the drug releases the reward areas from those strong signals. This suggests that other drugs that reduce burst firing could also alleviate depression, whether they act on the same receptors or different ones. “Anything that can block the bursting … should be a potential target based on our model,” Hu says. In an accompanying paper, her team reports that a protein found on astrocytes, another type of brain cell that interacts closely with neurons, could be one of these targets.
Panos Zanos, a neuropharmacologist at the University of Maryland in Baltimore, says the immediate effects of the drug in the lateral habenula were interesting. “I’m very excited … to see whether this [also] applies to the long-lasting antidepressant effects of ketamine,” he says. “This is a great study that adds to the literature on how ketamine might work.”