Health
How does ketamine function? Recent research provides clarity.
Marc Duque Ramírez in the laboratory.
Photos by Grace DuVal
An emerging anesthetic recognized as a revolutionary treatment for severe, treatment-resistant depression
The anesthetic ketamine has gained prominence as a remedy for individuals experiencing severe depression unresponsive to traditional treatments. Numerous studies have recorded the drug’s transformative effects, but researchers have been unclear about its precise mechanisms of action. Now, a diminutive, semi-transparent fish appears to offer significant new revelations.
Zebrafish, belonging to the minnow family and widely used as a model organism in neuroscience studies and home aquariums, do not experience depression in the typical sense. However, when placed in a virtual setting that replicates a lack of movement, they seem to “give up”—that is, they cease swimming.
Scientists have utilized this behavior, which echoes persistent traits seen in human depression, along with the zebrafish’s transparent body to scrutinize how their inclination to surrender shifts with the introduction of ketamine. In research released last month in the journal Neuron, researchers from Harvard and the Howard Hughes Medical Institute Janelia Research Campus traced the drug’s interaction with an unexpected neural collaborator.
Similar to humans, ketamine enhances zebrafish’s “resilience against this sense of futility,” stated Alex Chen, a Ph.D. student in the Engert Lab within Harvard’s Department of Molecular and Cellular Biology and the Ahrens Lab at Janelia, who was a co-author of the study.
Most research efforts have centered on neurons, noted Chen and co-lead author Marc Duque Ramírez, but their team discovered that supportive cells called astroglia were the ones engaged during this fish’s “depression” and its subsequent treatment.
When the fish initially sense they are not moving, activity within the astroglia cells increases, prompting the zebrafish to swim more vigorously. The astroglia ultimately reach a threshold that signals the fish’s neurons to halt swimming. Ketamine, however, seems to overstimulate the astroglia, reducing their sensitivity. This overstimulation occurs through its activation of noradrenergic neurons that stimulate astrocytes (similar to astroglia), paradoxically calming the “giving up” reaction and allowing the fish to persist in swimming.
“That was certainly a surprise for us,” remarked Chen. “We understood these cells were contributing to the behavior, and we were curious if administering ketamine to the fish would impact these cells after the drug is eliminated. But we had no inkling that the cells would respond so dramatically to the drug.”
“We anticipated an opposing effect,” added Duque Ramírez, a Ph.D. student in the Griffin Graduate School of Arts and Sciences who is also part of the Engert Lab.
The initial 10 seconds show the larval zebrafish at rest. When the scenario shifts to one simulating immobilization, the ketamine-treated fish struggles initially but does not yield as easily and is less inert than an untreated fish.
Credit: Duque, Chen, Hsu, et al.
Duque Ramírez elaborated that the drug modifies calcium levels in the cells, hindering rises that typically trigger the “giving up” mechanism. “Our hypothesis is that by inducing this hyperactivation of astroglia, it somehow readjusts the system to a new homeostatic baseline where substantially more calcium is necessary to induce surrender.”
While the study enhances comprehension of ketamine’s operation, the illumination it has provided on astroglia’s role is crucial.
However, while this response sheds light on ketamine’s function, the findings do not seem to extend to other pharmaceuticals.
“We also examined several other antidepressants,” remarked Duque Ramírez. “With certain psychedelic compounds, despite observing similar behavioral effects, they did not result in this increase of astroglia calcium. We believe this could indicate that these alternative drugs engage different pathways, potentially converging on the same targets, but that this specific effect was unique to ketamine.”
“Most current research on ketamine and other rapid-acting antidepressants has predominantly concentrated on their impacts on neurons,” mentioned Chen. “It seems plausible that neglecting these other cell types in the brain has posed a challenge in the field’s understanding of how these drugs function.”
This investigation received partial funding from the National Institutes of Health and the National Science Foundation.