Doctors use ketamine as general anesthesia before surgery and prescribe it in low doses for pain management. More recently, it has been used for treatment-resistant depression when other drugs have failed. A new study released on Jul. 31 reveals that ketamine's effects on the brain differ between male and female mice, a finding that could impact how drugs are tested and lead to improved treatments for depression if confirmed in humans.
Researchers at the Institute of Science and Technology Austria, collaborating with scientists at the Allen Institute, found that after a single sedation with ketamine, female mice showed significantly more active microglia than males during recovery. These specialized brain cells extended their branch-like arms to interact with surrounding cells, leading to removal of the extracellular matrix—the proteins and molecules supporting cell structure—and creating space for new synapses to form. This process increased neuroplasticity but was not observed in male mice.
"We didn't expect to see this; it was a surprising finding," said Sandra Siegert, professor at the Institute of Science and Technology Austria and senior author of the study. Microglia serve as immune cells in the brain that clear debris, trigger inflammation for protection, and help maintain optimal function.
The researchers identified a specific pathway behind this effect: during recovery from ketamine anesthesia, corticosterone levels spiked in the blood. This hormone triggered microglia to activate the Fkbp5 gene, producing FKBP51 protein, which then activated microglia interaction with neurons—ultimately increasing neuroplasticity. Scientists at the Allen Institute used single-nucleus RNA sequencing to identify this pathway and determine that only female mice exhibited activation of this gene.
Bosiljka Tasic, Director of Molecular Genetics at the Allen Institute and co-author of the study, said: "Understanding how to balance good plasticity versus maladaptive plasticity is very important for healthy life, healthy aging, and neuropsychiatric diseases." Tasic added: "How can you modify and modulate this plasticity but in a positive way? Many of the major plasticity-inducing drugs have become quite interesting, especially as treatments for depression, but we still don't know how they work."
The findings indicate that FKBP51 protein may be key to regulating neuroplasticity in female brains through ketamine exposure if replicated in humans. Siegert said: "How drug effects differ between males and females is important to know in order to offer the best treatment." She also noted that immune cells often respond differently based on sex—a factor now being explored by scientists studying microglia.
