How Ketamine Works for Depression
Ketamine restored synapses in neurons of the brain of mice
Ekaterina Rusakova, N+1
Neuroscientists have uncovered the mechanism of action of ketamine as an antidepressant, reported in Science (Moda-Sava et al., Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation). It turns out that ketamine promotes the growth of dendritic spikes on neurons of the medial prefrontal cortex of the brain, which disappear during prolonged stress.
Ketamine is a synthetic substance obtained in the 1960s, which until recently was used as an anesthetic and a means for anesthesia. In addition, it is a psychoactive substance and causes disturbances in the work of consciousness. At the same time, clinical studies have shown that ketamine quickly (in a few hours) relieves symptoms in patients with clinical depression, while other antidepressants begin to act much more slowly. In March, the FDA approved esketamine, an enantiomer of ketamine, as a drug for the treatment of resistant depression, which acts in the same way as ketamine, but less often causes side effects. However, the mechanism of action of these substances as antidepressants is unknown. Since ketamine acts quickly, it can be used to study the mechanism of remission in depression.
One of the causes of depression is stress, which alters the plasticity of neurons in the brain. It has been shown that in rats, during repetitive stress, the density of synapses in the medial prefrontal cortex (MPC) of the brain decreases. This area, among other things, is involved in the processes of learning, planning and switching attention. It is also involved in the generation of phases of slow-wave sleep. It was assumed that ketamine acts as an antidepressant due to the fact that it increases the number of synaptic connections in the MPC. Perhaps it accelerates the recovery of synapses. However, until recently it was difficult to verify exactly how ketamine acts on brain neurons, and how the restoration of synaptic connections is associated with the treatment of depression. Now, with the development of optogenetics methods, such an opportunity has appeared.
American and Japanese researchers led by Conor Liston from Cornell University tested the hypothesis that ketamine accelerates remission in depression due to the fact that it promotes the appearance of new synapses in the medial prefrontal cortex. In the experiments, they used genetically modified mice in which yellow fluorescent protein was expressed in sensory and motor neurons of the brain. Animals were implanted with microprisms in the MPC, which allowed researchers to take photos of neurons using a two-photon laser microscope. Mice from the experimental group (six animals) were given water with corticosterone, the main stress hormone of mice and rats, for 21 days. Before, during and after the experiment, the researchers took pictures of neurons of the medial prefrontal cortex, in which yellow fluorescent protein was expressed, and thus observed the disappearance and growth of dendritic spines – processes on neurons that receive information from other neurons through synapses.
Corticosterone led to the appearance of anxious and depressive behavior in mice. They began to drink less sweetened water and became motionless when they were suspended by their tails during a standard test to measure stress in rodents. Their dendritic spines began to disappear more often and new ones appeared less often. As the scientists found, 89 percent of dendritic spines that disappeared after 10 days of taking corticosterone did not recover for 21 days, at the end of the experiment. Moreover, the processes did not disappear randomly, but in clusters located on certain areas of neurons. The researchers repeated the stress test using spatial constraints (mice were periodically kept in narrow plastic tubes) and got the same results.
After 21 days of stress, the authors of the article gave ketamine to mice once and after 24 hours took pictures of MPC neurons, as well as monitored changes in animal behavior. The behavior of mice after taking an antidepressant returned to normal within 3-6 hours, and persisted for up to 7 days. But the growth of neurons began later, after 12-24 hours. The growth rate of dendritic spines increased by 17 percent after a day. At the same time, the processes were formed not randomly, but in clusters, in certain places of neurons. At the same time, ketamine did not reduce the rate of disappearance of dendritic spines. The scientists also made sure that ketamine restores part of the dendritic spines: they were formed in the places from where they disappeared under stress. Moreover, ketamine contributed to the emergence of synapses on the appendages.
Scheme and results of the experiment. Above: a diagram of a mouse brain with an implanted microprism. In the center: a time-line experiment. The gray arrows show the days when scientists took pictures of neurons, the blue one shows the day when mice were given ketamine. Below: dendritic spines that disappeared and grew during the experiment. A drawing from an article in Science.
Since several hours passed between the change in the behavior of mice and the beginning of the growth of dendritic spines, the scientists decided to make sure whether the appearance of new spines was really necessary for remission or at least correlated with it. To do this, the researchers first gave ketamine to stressed mice, and then, a day after taking it, destroyed the grown dendritic spines with the help of an optically activated protein that regulates their contraction and disappearance. The destruction of the grown spikes partially blocked the effect of ketamine: the mice stopped taking the stress test, but did not lose interest in sweetened water.
"Human studies have also shown that patients with depression have reduced synapses," says neuroscientist Ronald S. Duman from Yale University, who was not involved in the study. The results of the new work serve as another proof of this, showing that the destruction of newly formed synapses can block the effect of ketamine.
A few years ago, researchers discovered that one of the metabolites of ketamine works as an antidepressant when tested on mice, but it does not cause the side effects characteristic of ketamine. Hydroxynorketamine did not cause side effects even at concentrations 40 times higher than the standard dosage of ketamine.
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