Ketamine Induces Sex-Specific Neuroplasticity Through Microglial Activation in Female Mice
Key Insights
Researchers discovered that ketamine triggers a female-specific microglial activation pathway during anesthesia recovery, absent in male mice, leading to enhanced neuroplasticity.
The mechanism involves a corticosterone surge that upregulates the Fkbp5 (search) gene in microglia, producing FKBP51 (search) protein that drives extracellular matrix degradation and synaptic remodeling.
Single-nucleus RNA sequencing by the Allen Institute (search) identified the precise transcriptomic changes differentiating male and female microglial responses to ketamine.
Researchers at the Institute of Science and Technology Austria (search) (ISTA), in collaboration with scientists at the Allen Institute (search), have uncovered a sex-specific mechanism through which ketamine induces neuroplasticity in the brain. The study, published in Science Advances, reveals that female mice experience a distinct microglia-mediated remodeling of neural networks following ketamine anesthesia — a pathway entirely absent in male mice.
"We didn't expect to see this; it was a surprising finding," said Sandra Siegert, professor at ISTA and senior author of the study.
The discovery centers on microglia, the brain's resident immune cells that clear debris, trigger inflammation, and maintain optimal brain function. During recovery from a single ketamine sedation, female mice exhibited markedly increased microglial activity compared to their male counterparts. These specialized cells extended their branch-like processes to intermingle with surrounding neurons, ultimately degrading components of the extracellular matrix — the structural scaffold of proteins and molecules that supports and organizes cells. This degradation created space for new synapses to form, thereby remodeling the neural network and increasing neuroplasticity.
The Corticosterone-Fkbp5 (search)-FKBP51 (search) Signaling Cascade
The researchers mapped the precise molecular pathway underlying this phenomenon. During recovery from ketamine anesthesia, circulating corticosterone — a key stress hormone in rodents — spiked in the blood of female mice. This endocrine signal triggered microglia to upregulate the Fkbp5 (search) gene, leading to production of the FKBP51 (search) protein. FKBP51, a stress-responsive co-chaperone, then activated microglia to intermingle with adjacent neurons and strip away extracellular matrix components.
Scientists at the Allen Institute (search) performed single-nucleus RNA sequencing to isolate the precise cellular populations and transcriptomic changes that differentiate male and female microglial responses to ketamine. The sequencing revealed that Fkbp5 (search) was specifically turned on in female microglia but not in males.
To validate the corticosterone-driven mechanism, the researchers removed the primary source of corticosterone through adrenalectomy. This intervention reduced the close microglia-neuron interaction, which was subsequently restored following corticosterone injection, confirming the hormone's central role.
Functional Neuronal Changes
The microglia-neuron interaction induced plastic and functional neuronal changes, as evidenced by increased miniature excitatory postsynaptic current (mEPSC) frequency. Notably, this effect was occluded upon microglia depletion, demonstrating that microglia are essential mediators of the ketamine-induced plasticity.
Implications for Depression Treatment
Ketamine is used clinically as a general anesthetic, in low doses for pain management, and increasingly for treatment-resistant depression where other pharmacological interventions have failed. The drug works by dampening communication between brain cells, yet the mechanisms underlying its antidepressant effects have remained incompletely understood.
"Understanding how to balance good plasticity versus maladaptive plasticity is very important for healthy life, healthy aging, and neuropsychiatric diseases," said Bosiljka Tasic, Director of Molecular Genetics at the Allen Institute (search) and study co-author. "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 position FKBP51 (search) as an inducible lever for controlling structural neuroplasticity in the brain, with ketamine representing one means of engaging this mechanism — at least in female mice.
Sex Differences in Drug Response
The study highlights a broader imperative for considering biological sex in drug development and efficacy testing. "How drug effects differ between males and females is important to know in order to offer the best treatment," said Siegert.
In immunology, it is well established that immune cells respond differently between males and females, contributing to divergent outcomes in infectious diseases. "Microglia, which have capabilities similar to macrophages, are not necessarily excluded from this assumption," Siegert noted. "It is only now that scientists are exploring this topic."
If replicated in humans, these findings could fundamentally alter how the efficacy of ketamine and other plasticity-inducing drugs is evaluated, potentially leading to sex-specific treatment strategies for major depressive disorder (search) and other neuropsychiatric conditions.