A group of proteins called 4E-BPs, involved in memory formation, is the key to unlocking the antidepressant effect of ketamine in the brain, according to researchers from three Canadian universities. The scientists believe their discovery could lead to better and safer treatments for certain patients suffering from major depression.
More than 30% of patients are resistant to selective serotonin reuptake inhibitors (SSRI), the most commonly-prescribed antidepressants, so finding an effective treatment for major depressive disorder is challenging.
Initially, ketamine was approved for anesthesia and pain relief. Since its discovery, researchers have been studying new uses for this drug, and ketamine was approved last year for patients with major depression who are treatment-resistant. Unlike standard antidepressants, which can take several weeks to have an effect, ketamine works within hours. Until now, little was known about the molecular mechanism that triggers the antidepressant effect of ketamine on the brain.
In the study “Antidepressant actions of ketamine engage cell-specific translation via eIF4E” published in Nature, researchers from McGill University, Université de Montréal, and Carleton University investigated the effect of ketamine on behavior and neuronal activity in mice. Using genetic tools to remove proteins from specific brain cells, the team found that when 4E-BPs are absent in the brain, specifically in neurons, ketamine cannot produce its antidepressant effect. 4E-BPs act as a switch to turn on or off the process of protein synthesis, an essential component of memory formation.
“Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, provide rapid and long-lasting antidepressant effects in these patients, but the molecular mechanism of these effects remains unclear. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK),” write the investigators.
“The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase. mTORC1 controls various neuronal functions, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs).”
“Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1–4E-BP signaling in pyramidal excitatory cells of the cortex.”
“To test this hypothesis, we studied the behavioral response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission.”
“Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.”
“This is yet another prime example of how basic research, in this case the control of protein synthesis, leads to major discoveries in understanding disease, and the hope of curing it,” says co-author Nahum Sonenberg, PhD, a professor at the department of biochemistry at McGill University.
The researchers examined the role of 4E-BPs on ketamine’s effect in two major types of neurons: excitatory neurons, which make up most of the neurons in certain parts of the brain, and inhibitory neurons, which control excitatory neurons and have important effects on behavior.
“We were expecting that 4E-BPs would only be important in excitatory cells, but surprisingly, removing 4E-BPs from inhibitory cells was sufficient to block the effect of ketamine,” notes co-author Jean-Claude Lacaille, a professor at the department of neurosciences at Université de Montréal.
The discovery and approval of ketamine for treatment-resistant patients was considered a major advance in modern psychiatry. Despite its promise, ketamine remains a less-than-perfect therapy because it can be addictive. The researchers hope that their findings will pave the way for better and safer antidepressant therapies for patients with major depressive disorder.
“Too many decisions continue to be made by a trial-and-error approach that can prolong the suffering of patients and affect their quality of life,” says co-author Aguilar-Valles, PhD, a former research associate at McGill University and now an assistant professor at Carleton University. “Our discovery has the potential to bring us closer to find a safer alternative to ketamine, and ultimately to a personalized medicine approach, where medical treatments are tailored to the individual characteristics of each patient.”
The researchers will next examine whether males and females have different responses to ketamine. This could have important implications for treatment for people with depressive disorders, among which women are significantly overrepresented.