A new study has revealed how ketamine works, which scientists say paves the way toward the development of safe, effective treatments for depression.
Ketamine has been gaining increasing attention as a rapid-acting antidepressant as it can work within hours. However, it has so far been unclear how ketamine works this way.
A new study has now discovered that ketamine exerts its lasting antidepressant effect by enhancing the Kcnq2 potassium channels in a certain subtype of glutamate-sensitive neurons.
Kcnq2 encodes a potassium channel which opens up in the cell membrane, enabling the passage of potassium ions. Potassium channels play a central role in the life of neurons, maintaining their stability and preventing their excessive firing.
The study has been carried out at the Weizmann Institute of Science in Rehovot, Israel, and at the Max Planck Institute of Psychiatry in Munich, Germany, in collaboration with the Helmholtz Zentrum, Munich, and published in Neuron.
Uncovering how ketamine works
Previously when scientists tried to clarify ketamine’s mechanism of action, they examined its impact on gene expression in brain tissues, but not in individual brain cells. For this study, the team, led by Dr Juan Pablo Lopez, mapped out gene expression in thousands of individual neurons – which belong to networks that convey their signals by means of the neurotransmitter glutamate – in the brains of mice that had been given a dose of ketamine.
Ketamine had been known since the 1990s to produce its effects by acting on such neurons – this is in contrast to older antidepressants, which mainly affect neurons influenced by serotonin. However, as ketamine’s effect persists long after it leaves the body, its action could not be explained by mere blockage of glutamate receptors on the surfaces of neurons.
Lopez commented: “We wanted to clarify the molecular cascade that is triggered by ketamine, leading to its sustained antidepressant effects. In the past, other researchers used whole tissue samples, which are composed of different cell types, so ketamine’s effects on specific cell types were averaged out.”
The scientists focused on the ventral hippocampus, a brain region that in previous studies had been associated with the antidepressant effects of ketamine.
After mapping out gene expression in cells from this area of the mouse brain, the researchers identified a subpopulation of neurons with a characteristic genetic signature, finding that ketamine had increased these neurons’ expression of Kcnq2.
The researchers tested ketamine’s effects in combination with an epilepsy drug, retigabine, known to activate potassium channels in the brain. When the drugs were given together, ketamine’s antidepressant effects were significantly enhanced.
“A single dose of retigabine was enough to amplify and prolong ketamine’s antidepressant action in mice,” said Lopez.
“Not only that, ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects.”
Both drugs already have FDA approval, opening a path toward testing their combined action in humans.
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