Summary: Researchers identified a sex-specific mechanism by which ketamine promotes neuroplasticity in female mice.
During recovery from ketamine anesthesia, female mice show a transient rise in circulating corticosterone that triggers microglia—the brain’s resident immune cells—to increase expression of the Fkbp5 gene and produce the FKBP51 protein. This signaling cascade induces microglia to extend processes that interact with nearby neurons and remove portions of the extracellular matrix. The resulting loosening of structural constraints provides space for synaptic remodeling and network reorganization. This microglial remodeling response was not detected in male mice, revealing a distinct neuroimmune pathway tied to biological sex and pointing to FKBP51 as a potential molecular target to regulate neuroplasticity and refine depression therapies.
Key Facts
- Sex-differentiated microglial activation: During recovery from ketamine anesthesia, microglia in female mice extend processes and intermingle with surrounding neurons; this pattern was not observed in male mice.
- Extracellular matrix remodeling: Activated female microglia degrade components of the extracellular matrix, removing structural barriers and enabling formation of new synaptic connections.
- Endocrine–immune signaling: A surge of circulating corticosterone during recovery activates microglial Fkbp5 expression, which leads to production of FKBP51 and downstream microglial action.
- Single-nucleus transcriptomics: Single-nucleus RNA sequencing helped identify the specific cell populations and the Fkbp5 transcript upregulated in female microglia but not in males.
- Therapeutic implications: FKBP51 represents an inducible lever for controlling structural neuroplasticity, underscoring the importance of accounting for sex differences when evaluating treatments for major depressive disorder and other neuropsychiatric conditions.
Source: Allen Institute
Ketamine is used clinically as a general anesthetic and at lower doses for pain management; more recently, it has been adopted for treatment-resistant depression when other therapies fail. Its primary action involves altering neural communication, but this new study shows that downstream effects differ by sex in mice and may influence therapeutic outcomes.
The study, led by researchers at the Institute of Science and Technology Austria in collaboration with the Allen Institute, found that after a single ketamine sedation episode female mice display markedly increased microglial activity during recovery compared with males. These microglia extend fine processes that reach into nearby neural tissue, interact closely with neurons, and remove parts of the surrounding extracellular matrix.
Removal of extracellular matrix components—the proteins and structural molecules that surround cells—creates physical room for synapse formation and network remodeling, increasing neuroplasticity. The same microglial behavior and extracellular matrix remodeling were not detectable in male mice under the same conditions.
“We did not 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 the brain’s immune sentinels: they clear debris, regulate inflammation, and help maintain healthy neural function. This study ties microglial behavior directly to a hormone-driven stress response during anesthesia recovery.
A pathway to neuroplasticity
The researchers traced the effect to a specific endocrine–immune cascade. During recovery from ketamine anesthesia, blood corticosterone levels rise. Corticosterone, a stress hormone, activates microglial expression of the Fkbp5 gene in females, producing the FKBP51 protein. FKBP51 then promotes microglial process extension, close interaction with neurons, and degradation of extracellular matrix elements, which together enable synaptic remodeling and functional plasticity.
Single-nucleus RNA sequencing performed by the Allen Institute helped pinpoint the cellular populations and the sex-specific transcriptional change—Fkbp5 upregulation—occurring in female microglia. Electrophysiological and imaging measures indicated increased synaptic activity and structural plasticity that were dependent on microglial presence and on the corticosterone-FKBP51 pathway.
Neuroplasticity must be tightly regulated: both excessive and insufficient plasticity are associated with neuropsychiatric disorders. “Understanding how to promote adaptive plasticity while avoiding maladaptive changes is critical for healthy aging and for treating psychiatric disease,” said Bosiljka Tasic, Director of Molecular Genetics at the Allen Institute and a co-author. Identifying the FKBP51-mediated mechanism suggests a route to modulate plasticity therapeutically, potentially improving how drugs like ketamine are used for depression.
The study emphasizes that immune responses in the brain can differ substantially between sexes, echoing broader immunology findings. Microglia, which share many functions with peripheral macrophages, may therefore participate in sex-specific outcomes in brain health and disease. Recognizing these differences is important for designing and evaluating treatments.
Key Questions Answered:
A: Recovery from ketamine anesthesia produces a corticosterone spike that activates Fkbp5 expression in female microglia. FKBP51 production then prompts microglia to invade local neural tissue and remove parts of the extracellular matrix, creating space for new synapses and network reorganization.
A: No. The corticosterone-driven Fkbp5/FKBP51 microglial activation and subsequent extracellular matrix degradation were observed only in female mice, demonstrating a sex-specific neuroimmune reaction to ketamine recovery.
A: Because neuroplasticity is central to ketamine’s antidepressant effects, the FKBP51 pathway offers a potential molecular target to adjust therapeutic plasticity. The findings also underline the need to consider sex differences when developing and testing psychiatric medications to ensure optimal, personalized treatments.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context and clarification were added by staff.
About this neuroscience and neuroplasticity research news
Author: Peter Kim
Source: Allen Institute
Contact: Peter Kim – Allen Institute
Image credit: Neuroscience News
Original Research: Open access. Title: “Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia” by Alessandro Venturino et al., published in Science Advances. DOI: 10.1126/sciadv.adz6517
Abstract
Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia
Anesthesia recovery is essential for restoring normal physiological and neuronal functions, yet the underlying mechanisms are incompletely understood. This study identifies a female-specific corticosterone-driven interaction between microglia and neurons during recovery from ketamine anesthesia that does not occur in males. The interaction produces functional and structural neuronal changes, including increased miniature excitatory postsynaptic current (mEPSC) frequency that depends on microglial presence. The process is driven by upregulation of the stress-responsive co-chaperone Fkbp5 mRNA and its protein FKBP51 in female microglia. Because Fkbp5/FKBP51 mediates corticosteroid responses, these results highlight a critical interface between endocrine signaling and microglial function. Surgical removal of adrenal corticosterone sources reduced the microglia–neuron interaction, which was restored by corticosterone replacement. These findings reveal a sex-specific, microglia-mediated mechanism of neuronal plasticity during anesthesia recovery and expand our understanding of sex differences in brain function.