Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy
- 1Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
- 2Doctoral School of Translational Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland
Abstract
Ketamine has revolutionized psych iatric treatment, challenging monoamine-based paradigms through its capacity for rapid antidepressant action. While N-methyl-D-aspartate receptor (NMDAR) antagonism remains the canonical mechanism, this integrative review proposes a multi-receptor, neuron–glia convergence model to help account for ketamine's therapeutic efficacy. We outline the well-established disinhibition cascade, whereby preferential NMDAR blockade on GABAergic interneurons induces cortical disinhibition, triggering a transient glutamate surge and subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Furthermore, we discuss emerging, albeit indirect reports suggesting that ketamine and its metabolites may interact with the tropomyosin receptor kinase B (TrkB) transmembrane domain and modulate TrkB-related signaling. Beyond neurons, we consider the contributions of glial cells, particularly astrocytes, microglia, and oligodendrocyte lineage cells, as players in ketamine response in antidepressant effects. We further discuss evidence for opioid context-dependent effects that, at present, are insufficient to account for ketamine's broader antidepressant effects. Finally, we highlighted the sigma-1 receptor (S1R) as a chaperone modulator of ketamine-induced sustained neuroplasticity and intercellular neuron-glia communication. Collectively, the available data suggest that ketamine's efficacy likely arises from convergent actions across multiple molecular targets and both neuronal and glial cell types. Importantly, many components of this model remain hypothetical and require rigorous in vivo functional verification. By delineating testable mechanisms and distinguishing putative pro-plasticity effects from dissociative liabilities, this framework may inform precision psychiatry, biomarker-guided patient stratification, and the rational design of safer, next-generation rapid-acting antidepressants.
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BibTeX
@article{sulej2026integrating,
title = {{Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy}},
author = {Zuzanna Sulej and Magdalena Zielińska},
journal = {Frontiers in Molecular Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnmol.2026.1950244},
url = {https://doi.org/10.3389/fnmol.2026.1950244},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy
AU - Zuzanna Sulej
AU - Magdalena Zielińska
PY - 2026
DA - 2026/10/21
JO - Frontiers in Molecular Neuroscience
DO - 10.3389/fnmol.2026.1950244
UR - https://doi.org/10.3389/fnmol.2026.1950244
AB - Ketamine has revolutionized psych iatric treatment, challenging monoamine-based paradigms through its capacity for rapid antidepressant action. While N-methyl-D-aspartate receptor (NMDAR) antagonism remains the canonical mechanism, this integrative review proposes a multi-receptor, neuron–glia convergence model to help account for ketamine's therapeutic efficacy. We outline the well-established disinhibition cascade, whereby preferential NMDAR blockade on GABAergic interneurons induces cortical disinhibition, triggering a transient glutamate surge and subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Furthermore, we discuss emerging, albeit indirect reports suggesting that ketamine and its metabolites may interact with the tropomyosin receptor kinase B (TrkB) transmembrane domain and modulate TrkB-related signaling. Beyond neurons, we consider the contributions of glial cells, particularly astrocytes, microglia, and oligodendrocyte lineage cells, as players in ketamine response in antidepressant effects. We further discuss evidence for opioid context-dependent effects that, at present, are insufficient to account for ketamine's broader antidepressant effects. Finally, we highlighted the sigma-1 receptor (S1R) as a chaperone modulator of ketamine-induced sustained neuroplasticity and intercellular neuron-glia communication. Collectively, the available data suggest that ketamine's efficacy likely arises from convergent actions across multiple molecular targets and both neuronal and glial cell types. Importantly, many components of this model remain hypothetical and require rigorous in vivo functional verification. By delineating testable mechanisms and distinguishing putative pro-plasticity effects from dissociative liabilities, this framework may inform precision psychiatry, biomarker-guided patient stratification, and the rational design of safer, next-generation rapid-acting antidepressants.
SN - 1662-5099
ER -