In female mice, so you'll have to contact your competent? doctor to get human testing going. Make sure you can get protocols for neuroplasticity on demand!
Ketamine Reshapes Neural Networks and Neuroplasticity
Summary: Researchers discovered a sex-specific mechanism through which ketamine induces neuroplasticity in female mice.
During recovery from ketamine anesthesia, female mice experience a spike in circulating corticosterone, triggering microglia, the brain’s resident immune cells, to upregulate the Fkbp5 gene and produce the FKBP51 protein. This pathway activates microglia to extend processes, intermingle with adjacent neurons, and strip away sections of the extracellular matrix.
The degradation of this structural support creates space for synaptic remodeling and network reorganization. This microglial remodeling pathway was entirely absent in male mice, highlighting distinct neuroimmune responses between sexes and providing a novel molecular target for regulating neuroplasticity and optimizing depression treatments.
Key Facts
- Sex-Differentiated Microglial Activation: Microglial processes extend and intermingle with surrounding neurons during ketamine recovery specifically in female mice, a behavior not observed in male counterparts.
- Extracellular Matrix Degradation: Activated female microglia degrade and remove components of the extracellular matrix, breaking down structural barriers to allow the formation of new synaptic connections.
- Endocrine-Immune Signaling Cascade: The underlying pathway relies on a surge of systemic corticosterone during recovery, which activates microglial Fkbp5 gene expression to yield the functional FKBP51 protein.
- Single-Nucleus Transcriptomics: Single-nucleus RNA sequencing conducted by the Allen Institute isolated the precise cellular populations and transcriptomic changes that differentiate male and female microglial responses to ketamine.
- Therapeutic Implications: Demonstrates that FKBP51 acts as an inducible lever for controlling structural neuroplasticity, underscoring the critical need to account for biological sex in drug efficacy testing for major depressive disorder and neuropsychiatric conditions.
Source: Allen Institute
Doctors use ketamine on patients as general anesthesia before surgery. They also prescribe it in low doses for pain management, and more recently, it’s been used for treatment-resistant depression where other drugs have failed. It works by dampening communication between brain cells.
But a new study reveals that its effects on the brain are different in male and female mice. This insight—if reproduced in humans—could change the way we test the efficacy of drugs and unlock better treatments for depression.
Researchers at the Institute of Science and Technology Austria, in collaboration with scientists at the Allen Institute, discovered that when female mice are recovering from a single ketamine sedation, their brains become much more active than their male counterparts, specifically their microglia. These specialized brain cells began reaching out with their branch-like arms to intermingle with surrounding brain cells.
This increased activity led to the removal of the extracellular matrix—the proteins and molecules surrounding, supporting, and giving structure to cells—and created space that allowed new synapses to form and remodel the neural network, thereby increasing neuroplasticity. Researchers didn’t observe this behavior 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 are the brain’s defense system—immune cells that help clear debris, trigger inflammation to protect the brain, and maintain optimal brain function.
A pathway to neuroplasticity
Importantly, scientists uncovered the precise pathway of this increased neuroplasticity: during recovery from ketamine anesthesia, corticosterone spiked in the blood. Corticosterone is an important hormone that helps animals respond to stress. This hormone triggered microglia to turn on the Fkbp5 gene, which then produces the FKBP51 protein.
This protein in turn activated the microglia to start intermingling with surrounding neurons, which eventually led to an increase in neuroplasticity. Scientists at the Allen Institute performed single-nucleus RNA sequencing to help uncover this hidden pathway and reveal the specific gene that was turned on in female mice but not in males.
Neuroplasticity is a delicate balance: too much or too little has both been linked to neuropsychiatric disorders. “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 and one of the study co-authors.
“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 new research reveals that at least in female mice, the FKBP51 protein can be a lever to pull in order to regulate neuroplasticity in the brain, and that ketamine can be one way to pull this lever. The findings, if fully replicated in humans, point to the importance of sex differences when evaluating the effects of drugs and treatments. “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 known that immune cells respond differently between males and females, which can lead to different outcomes in infectious diseases. “Microglia, which have capabilities similar to macrophages, are not necessarily excluded from this assumption,” said Siegert. “It is only now that scientists are exploring this topic.”
Key Questions Answered:
A: Ketamine recovery causes a spike in corticosterone, which activates the Fkbp5 gene in female microglia. The resulting FKBP51 protein prompts microglia to reach into surrounding neural tissue and clear away portions of the extracellular matrix, creating physical space for new synapses to form and reorganize the neural network.
A: No. The corticosterone-driven FKBP51 microglial activation and subsequent degradation of the extracellular matrix were uniquely observed in female mice, demonstrating a distinct sex-specific neuroimmune response to ketamine sedation.
A: Because neuroplasticity is central to ketamine’s antidepressant effects, identifying the FKBP51 pathway reveals a potential molecular target to modulate therapeutic plasticity. It also highlights that psychiatric medications can operate via fundamentally different biological mechanisms in males and females, requiring sex-tailored drug design and evaluation.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience and neuroplasticity research news
Author: Peter Kim
Source: Allen Institute
Contact: Peter Kim – Allen Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia”
by Alessandro Venturino, MohammadAmin Alamalhoda, Thomas Negrello,
Kelly Jin, Cindy T. J. van Velthoven, Ryan John A. Cubero, Jake Yeung,
Peter Koppensteiner, Bosiljka Tasic, Sandra Siegert. Science Advances
DOI:10.1126/sciadv.adz6517
