Ketamine boosts brain plasticity in female mice, not males

A new study from the Institute of Science and Technology Austria and the Allen Institute found ketamine triggered a neuroplasticity pathway in female mice that did not appear in males. If the results hold in humans, they could reshape how depression drugs are tested and tailored by sex.

Why it matters: - Ketamine is already used as anesthesia, for pain management, and for treatment-resistant depression. - The new findings suggest the drug may affect male and female brains differently, which could matter for how depression treatments are evaluated and prescribed. - If the mouse results translate to humans, researchers may need to account for sex differences when testing drugs that change brain plasticity.

What happened: - Researchers at the Institute of Science and Technology Austria worked with scientists at the Allen Institute to study how a single ketamine sedation affected mice. - Female mice showed much stronger microglia activity during recovery than male mice. - Microglia extended branch-like arms, interacted more with nearby brain cells, and helped remove the extracellular matrix around cells. - That process made room for new synapses and increased neuroplasticity in female mice. - The same response was not observed in male mice.

The details: - The team traced the effect to a corticosterone spike in the blood during recovery from ketamine anesthesia. - Corticosterone activated the Fkbp5 gene in microglia. - The Fkbp5 gene produced the FKBP51 protein. - FKBP51 then helped trigger microglia to intermingle with surrounding neurons. - Scientists at the Allen Institute used single-nucleus RNA sequencing to identify the gene activity that appeared in female mice but not in males. - Sandra Siegert, professor at the Institute of Science and Technology Austria and senior author, said the team did not expect the result. - Bosiljka Tasic, director of Molecular Genetics at the Allen Institute and a co-author, said balancing healthy plasticity versus maladaptive plasticity is important for healthy life, healthy aging, and neuropsychiatric disease. - Tasic added that many plasticity-inducing drugs are of interest for depression, but researchers still do not fully understand how they work.

Between the lines: - The study points to FKBP51 as a possible control point for regulating neuroplasticity in female brains. - The findings add to growing evidence that immune-like cells in the brain may respond differently by sex, similar to what is already known in immunology. - The work also suggests that drug studies may miss important biology if they do not separate male and female responses. - Siegert said understanding how drug effects differ between males and females is important for offering the best treatment.

What's next: - The researchers said the key question is whether the same pathway appears in humans. - If replicated, the work could influence future depression drug trials and help identify more targeted treatments. - Siegert said scientists are only now beginning to explore sex differences in microglia.

The bottom line: - Ketamine appears to switch on a neuroplasticity pathway in female mice that male mice do not share, making sex a potentially crucial variable in future brain-drug research.