Ketamine works as a rapid antidepressant by increasing the activity of the very small number of newborn neurons


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.

Although ketamine can exert a rapid antidepressant effect, symptoms reemerge as the effects of a single dose diminish, and repeated administration of even low doses can have addictive and deleterious effects 8–10. To circumvent the limitations of ketamine use, there has been great interest in investigating other drugs and targets to elicit a similar rapid antidepressant response with fewer risks. However, thus far few other drugs have produced effects comparable to the speed and magnitude of ketamine’s 74,75.

Identification of a single cell population in one area of the brain that can be targeted to mimic the antidepressant activity of ketamine can potentially help with the development of drugs that do not produce as many side effects as ketamine, which exerts effects in multiple areas of the brain.

In this study, we selectively modulated the activity of adult-born immature granule neurons (ABINs) in the mouse DG to determine the nature of ABINs’ contribution to the rapid behavioral effects of ketamine. The use of DREADDs (hM4Di and hM3Dq) provided a means to specifically regulate the activity of ABINs while avoiding the potential confounding effects of altering neurogenesis, changing the number of ABINs, compensation in developmental models, or damage to the neurogenic niche.

Loss of ABIN activity in the DG blocked ketamine-induced behavioral changes, indicating that ABIN activation is necessary for these changes. Conversely, activation of ABINs was sufficient to induce behavioral effects of the same quality and magnitude as ketamine, indicating that ABIN activity is, by itself, sufficient to produce the behavioral changes seen after ketamine treatment.

We also observed that ABIN activity is reduced by NBQX, a known inhibitor of ketamine’s antidepressant effects that acts via blockade of AMPARs 23,24,73, indicating that AMPAR activity is an upstream signal that activates ABINs. Taken together, these data demonstrate that activation of ABINs in the DG of the hippocampus is both necessary and sufficient for the rapid behavioral effects of ketamine.

In mammals, adult neurogenesis occurs in the hippocampal dentate gyrus and in the subventricular zone, and substantial evidence links dysfunction of the hippocampal neurogenic niche to major depressive disorder (MDD). Hippocampal neurogenesis decreases with MDD and increases with antidepressant treatment 32–34,76. Increasing neurogenesis can rescue the effects of chronic stress while inhibiting neurogenesis blocks the ameliorative effects of antidepressants 32,35–37.

Ketamine induces numerous effects on the hippocampus, both rapidly (e.g., increased dendritic spines 77 and reduction of synaptic inhibitory input78) and after a delay (e.g., increased neurogenesis 79). Studies in vitro have shown that direct application of ketamine to hippocampal slices induces synaptic potentiation 20,26,74,80–83 or pyramidal cell activation 78, acting directly on hippocampal NMDA receptors.

However, in vivo, ketamine’s behavioral effects require alterations in numerous brain regions, suggesting that circuitry beyond the hippocampus is necessary for ketamine’s ultimate behavioral effect. Our work bridges these observations by suggesting how numerous signals may converge on the hippocampus and produce an antidepressant effect.

ABINs regulate the circuitry of the DG, specifically by regulating the activity of mature granule neurons according to their presynaptic partners 84. As reviewed by Doan et al. 2019, ABINs establish glutamatergic synapses onto hilar GABAergic interneurons to inhibit mature granule cells, while weakening inhibitory synaptic currents through a different mechanism85. In this manner, alterations in ABIN activity can modulate existing DG circuits to provoke downstream effects.

Recent work demonstrates that signaling at hippocampal CA3-CA1 synapses, downstream of the DG, are essential for ketamine-induced long-term potentiation78,83, providing another event in this cascade that supports the role of hippocampal circuitry in rapid antidepressant effects. Future work is warranted to examine whether increased ABIN activity leads to changes in CA3-CA1 signaling after ketamine treatment.

The dorsal and ventral hippocampus regulate different behaviors and neuronal circuitry 86–92. Our work suggests that low-dose ketamine acts predominantly on the ventral hippocampus. This is consistent with the observation that patients given a single administration of low-dose ketamine show some initial negative cognitive effects, but after 24 h, only the affective antidepressant changes persist71. Given the association between the dorsal hippocampus and cognition and ventral hippocampus and mood, our results provide a possible explanation for ketamine’s predominantly mood-related effects.

The hippocampus also plays a role in the sustained antidepressant effects of ketamine. After a single dose of ketamine, patients continue to experience antidepressant effects long after the drug has been metabolized and excreted 93, implicating processes that outlast the presence of the drug. In rodents, NMDAR antagonism increases neurogenesis 94, and the sustained behavioral effects of ketamine are blocked by ablation of the neurogenic niche95, suggesting that the DG contributes to both the acute and the sustained mechanisms of ketamine action.

Our data corroborate prior work demonstrating that neurogenesis does not have to be altered for the acute effect of ketamine to be realized, as neural progenitor cells, which have not yet become immature neurons at the time of ketamine treatment, do not contribute to acute effects41. Our work demonstrates that altering the activity, but not the number, of ABINs mediates the rapid effects of ketamine. However, the longer-term effects of ketamine may be influenced by changes in neurogenesis.

Our use of the drug NBQX highlights that the ketamine-induced increase in ABIN activity is dependent on AMPAR activity. AMPAR potentiation and positive allosteric modulation also have antidepressant effects, but they do not have the same duration or magnitude as ketamine96,97.

Additional work is needed to determine the critical site(s) of AMPAR receptor effects-whether upstream of the hippocampus, or even on ABINs themselves. AMPAR activity in different brain regions (e.g., medial prefrontal cortex, mPFC) is necessary for acute ketamine effects and may provide important input to the DG circuitry 20,24,73. However, ABINs themselves express both NMDARs and AMPARs 53,98,99, so it is possible that AMPARs in the hippocampus or DG itself are directly mediating some of the effects of ketamine. Retrograde neuronal tracing studies paired with conditional, specific knockouts of the AMPAR may be required to determine which cell populations are responsible for the AMPAR activity that stimulates ABINs.

Activating ABINs using hM3Dq recapitulated ketamine effects on the variety of behaviors tested here. However, behavior and cognition have many facets, and it is possible that there are behavioral or downstream signaling differences between hM3Dq activation and ketamine treatment that we did not see in the assortment of tests that we used. While our testing paradigm was informed by numerous previously published studies and included DG-dependent depression-like behavior tests and anxiety-like behavior tests, which in sum assessed spatial, social, and memory-related behaviors, future work may include a detailed assessment of possible differences in adverse (e.g., addictive and hedonistic) effects between ketamine treatment and ABIN activation, especially because a key risk of ketamine use is addiction potential.

Different signaling pathways appear to be involved in ketamine-induced antidepressant behaviors compared to its addictive ones100, and tracing studies could also help identify whether cell activation differentially regulates the balance of activity and modification of neuronal circuitry.

Prior reports have shown that ketamine alters circuitry between the mPFC and other areas of the brain101,102, and in fact, that the activity of a ventral hippocampus to the mPFC pathway underlies ketamine’s acute antidepressant effect102. These studies strongly support our conclusions and inform our hypothesis that the increased activity of immature neurons regulates this circuitry by inhibiting mature neurons, which in turn provide altered signals to downstream pathways and areas of signaling.

Taken together, these results establish the necessity of ABIN activity for ketamine’s antidepressant effects and the sufficiency of this activity to induce these effects on the same time scale and magnitude as ketamine, providing a strong basis for future studies focused on targeting ABINs and the pathways that regulate them.

reference link :

More information: Radhika Rawat et al, Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice, Nature Communications (2022). DOI: 10.1038/s41467-022-30386-5


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