A group of proteins called 4E-BP, involved in memory formation, is the key to deciphering ketamine’s antidepressant effects on the brain.
Ketamine is a powerful antidepressant that can cure symptoms of depression within minutes. Its mechanism of action was not well understood. Canadian researchers at McGill University discovered that a protein (4E-BP), which is involved in memory formation, is the key to deciphering ketamine’s antidepressant effects in the brain. A discovery that could lead to safer treatments for some patients with major depression. They presented their findings on Dec. 16 in the journal Nature.
The proteins that act as switches
About one in three patients is resistant to selective serotonin reuptake inhibitors, the most commonly prescribed antidepressant. To make up for this lack of treatment options, which primarily affects major depressive disorder, scientists have turned to ketamine, which was originally used for anesthesia and pain relief. Unlike conventional antidepressants, which can take several weeks to take effect, ketamine works within a few hours. But until now, little was known about the molecular mechanism that triggers ketamine’s antidepressant effects in the brain.
In the new study, researchers examined the effect of ketamine on the behavior and neuronal activity of mice. Using genetic tools to remove proteins from specific brain cells, the team found that ketamine cannot exert its antidepressant effects when 4E-BP proteins are not present in the brain, particularly in neurons. 4E-BP proteins act as a switch to activate or deactivate the process of protein synthesis, an essential component of memory formation.
Tailored therapeutic approaches
The researchers investigated the role of 4E-BP in the effects of ketamine on two main types of neurons: excitatory neurons, which make up the majority of neurons in certain parts of the brain, and inhibitory neurons, which control excitatory neurons and have important effects on behavior. “We had expected 4E-BP to be important only in excitatory cells, but surprisingly, removing 4E-BP from inhibitory cells was enough to block the effects of ketamine,” said Jean-Claude Lacaille, professor of neuroscience at McGill University and co-author of the study.
“Our discovery has the potential to bring us closer to finding a safer alternative to ketamine and, ultimately, a personalized medical approach in which medical treatments are tailored to each patient’s individual characteristics,” said study co-author Aguilar-Valles.