Summary: Ketamine’s rapid action as an antidepressant is a result of increasing the activity of a small number of newborn neurons, which are part of ongoing neurogenesis in the brain.
Source: Northwestern University
Ketamine is the speedster of antidepressants, working within hours compared to more common antidepressants that can take several weeks. But ketamine can only be given for a limited amount of time because of its many side effects.
Now, a new Northwestern Medicine study identifies for the first time exactly how ketamine works so quickly, and how it might be adapted for use as a drug without the side effects.
The study in mice shows ketamine works as a rapid antidepressant by increasing the activity of the very small number of newborn neurons, which are part of an ongoing neurogenesis in the brain.
New neurons are always being made at a slow rate. It’s been known that increasing the number of neurons leads to behavioral changes. Other antidepressants work by increasing the rate of neurogenesis, in other words, increasing the number of neurons. But this takes weeks to happen.
By contrast, ketamine produces behavioral changes simply by increasing the activity of the existing new neurons. This can happen immediately when the cells are activated by ketamine.
“We narrowed down the population of cells to a small window that is involved,” said lead study author Dr. John Kessler, a professor of neurology at Northwestern University Feinberg School of Medicine and the Ken and Ruth Davee Professor of Stem Cell Biology.
“That’s important because when you give ketamine to patients now, it affects multiple regions of the brain and causes a lot of adverse side effects. But since we now know exactly which cells we want to target, we can design drugs to focus only on those cells.”
The side effects of ketamine include blurred or double vision, nausea, vomiting, insomnia, drowsiness and addiction.
The study was published recently in Nature Communications.
Goal to develop faster-working antidepressant
“The goal is to develop an antidepressant that doesn’t take three to four weeks to work because people don’t do well during that period of time,” Kessler said. “If you are badly depressed and start taking your drug and nothing is happening, that is depressing in itself. To have something that works right away would make a huge difference.”
Newborn neurons act like a match to ignite activity in neurons
“We prove neurogenesis is responsible for the behavioral effects of ketamine,” Kessler said. “The reason is these newborn neurons form synapses (connections) that activate the other cells in the hippocampus. This small population of cells acts like a match, starting a fire that ignites a bunch of activity in a lot of other cells that produce the behavioral effects.”
“However, it has not been understood that the same behavioral changes can be accomplished by increasing the activity of the new neurons without increasing the rate at which they are born,” Kessler said. “This obviously is a much more rapid effect.”
For the study, Northwestern scientists created a mouse in which only the very small population of newborn neurons had a receptor that allowed these cells to be silenced or activated by a drug that did not affect any other cells in the brain.
Scientists showed if they silenced the activity of these cells, ketamine didn’t work anymore. But if they used the drug to activate this population of cells, the results mirrored those of ketamine. This showed conclusively that it is the activity of these cells that is responsible for the effects of ketamine, Kessler said.
Funding: This work was supported by grants F30MH124269, K99MH125016 and R01 MH114923 from the National Institute of Mental Health and T32GM008152 from the National Institute of General Medicine, all of the National Institutes of Health, and the Davee Foundation.
Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice
Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear.
Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine.
Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice.
Chemogenetic inhibition of ABIN activity blocks the antidepressant effects of ketamine, indicating that this activity is necessary for the behavioral effects.
Conversely, chemogenetic activation of ABINs without any change in neuron numbers mimics both the cellular and the behavioral effects of ketamine, indicating that increased activity of ABINs is sufficient for rapid antidepressant effects.
These findings thus identify a specific cell population that mediates the antidepressant actions of ketamine, indicating that ABINs can potentially be targeted to limit ketamine’s side effects while preserving its therapeutic efficacy.