Ketamine’s rapid antidepressant effects traced to overlooked brain cells

A new study has uncovered a surprising player in ketamine’s rapid antidepressant effects: astrocytes, the star-shaped support cells of the brain. By studying larval zebrafish, researchers found that ketamine reduces behavioral passivity by altering astrocytic activity in response to futile conditions. Their findings have been published in the journal Neuron.

Ketamine is a medication traditionally used as an anesthetic, but in recent years, it has gained attention for its rapid and long-lasting antidepressant effects at low doses. Unlike conventional antidepressants, which often take weeks to produce noticeable results, ketamine can alleviate symptoms of depression within hours.

This fast-acting property makes it especially promising for conditions like treatment-resistant depression. However, the exact mechanisms behind ketamine’s antidepressant effects remain only partially understood, particularly its influence on non-neuronal brain cells such as astrocytes.

Researchers were interested in larval zebrafish as a model for studying ketamine because of the fish’s unique biological characteristics. Zebrafish are small, transparent, and genetically modifiable, allowing scientists to observe brain-wide activity in real-time.

“We were originally studying a behavior in which larval zebrafish ‘gave up’ in response to their actions becoming futile and thought that this behavior had some similarities to rodent assays (e.g., forced swim task or tail suspension task) commonly used to test antidepressants,” said study author Alex B. Chen, a neuroscience graduate student at Harvard University and graduate research fellow at the Howard Hughes Medical Institute Janelia Research Campus.

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“Because the larval zebrafish has unique advantages—it is transparent and small enough that the activity of all of its brain’s neurons can be simultaneously recorded during behavior—we sought to determine whether we could use it to investigate ketamine’s behavioral effects.”

The researchers used larval zebrafish aged 5 to 8 days post-fertilization. These fish were genetically modified to express calcium indicators in neurons or astrocytes, allowing researchers to monitor their activity during experiments. They also employed optogenetic and chemogenetic tools to manipulate specific brain regions and cell types, further investigating the mechanisms underlying observed behavioral changes.

The researchers exposed zebrafish to a transient dose of the drug (200 micrograms per milliliter). The experimental setup involved a custom-designed virtual reality environment in which visual stimuli simulated forward movement when the fish swam. However, during the “open loop” phase, swimming no longer resulted in any apparent progress, creating a condition of futility.

Ketamine-treated zebrafish exhibited a marked reduction in passivity during the open loop phase compared to untreated controls. This effect was dose-dependent and persisted long after the drug had cleared from their systems. Importantly, ketamine did not affect the fish’s baseline locomotion during normal swimming conditions, suggesting that its influence was specific to behaviors related to futility.

Further analysis focused on the activity of astrocytes, star-shaped glial cells in the brain that support neurons, regulate neurotransmitter levels, and play a role in brain signaling and homeostasis. During futile swimming, astrocytes in the hindbrain typically show elevated calcium activity, integrating signals from neurons to suppress swimming. However, after ketamine exposure, astrocytes displayed reduced calcium responses during the open loop phase, indicating diminished engagement in the behavioral suppression process. This reduced activity in astrocytes correlated with the observed decrease in passivity, suggesting that ketamine might exert its effects by altering the astrocytic response to futility.

“Ketamine has gained popularity in recent years as a rapid-acting antidepressant, but the mechanisms through which it works remain poorly understood,” Chen told PsyPost. “We show that at least some of its antidepressant effects might occur due to its actions on a population of non-neuronal cells called astrocytes. Astrocytes have traditionally been seen as passive support cells in the brain, but more recently, they have been shown to play active roles in brain computations. We show that ketamine decreases astroglial responsiveness to futility, leading to increased resilience.”

This finding was particularly surprising, Chen said, because “previous studies have largely focused on ketamine’s effects on neurons, so we did not expect that it would affect astrocytes so much.”

The researchers found that the effects of ketamine on passivity and astrocytic activity were not unique to zebrafish. In complementary experiments using mice, they observed similar behavioral and cellular changes. In rodents subjected to the tail suspension test—a mammalian analog of futility-induced passivity—ketamine treatment reduced immobility. Astrocytes in the retrosplenial cortex of mice displayed a prolonged elevation in calcium activity following ketamine exposure, mirroring patterns observed in zebrafish.

The study also provided insights into how ketamine might trigger these changes. The researchers identified norepinephrine as a critical modulator in the process. Ketamine was shown to elevate norepinephrine levels, which in turn activated astrocytes and induced long-lasting changes in their response to futile signals. This hyperactivation during ketamine exposure appeared to desensitize astrocytes, reducing their responsiveness to future futile conditions and promoting behavioral perseverance.

The use of larval zebrafish in this study presents both significant strengths and notable limitations. As a model organism, zebrafish offer unique advantages due to the ability to monitor brain-wide activity in real-time at a cellular level. Their genetic accessibility also allows for precise manipulation and visualization of specific cell types, such as astrocytes and neurons. These features make zebrafish an excellent model for investigating complex neural and behavioral phenomena.

However, the zebrafish model also has inherent weaknesses that limit the study’s broader applicability. For one, the simplicity of the zebrafish brain, while advantageous for certain types of experiments, may not fully capture the complexity of mammalian or human brain circuits.

“While zebrafish are vertebrates, they are still very different from humans, and it is hard to say whether fish can get depressed,” Chen noted. “Therefore, some of our findings remain to be validated in mammalian models like rodents or in humans themselves.”

Future research could explore the molecular and genetic changes underlying ketamine’s effects on astrocytes and neurons. Studies could also investigate how the observed mechanisms in zebrafish translate to more complex mammalian systems, particularly in brain regions relevant to human depression, such as the prefrontal cortex or hippocampus.

“Our goal is to continue using the larval zebrafish to examine ketamine’s mechanisms of action,” Chen said. “One question of particular interest is what molecular changes are happening in astrocytes to cause the changes in their physiology that we see following ketamine administration. Furthermore, we hope to use larval zebrafish to screen for other compounds that could be antidepressant.”

The study, “Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance,” was authored by Marc Duque, Alex B. Chen, Eric Hsu, Sujatha Narayan, Altyn Rymbek, Shahinoor Begum, Gesine Saher, Adam E. Cohen, David E. Olson, Yulong Li, David A. Prober, Dwight E. Bergles, Mark C. Fishman, Florian Engert, and Misha B. Ahrens.