TrkB/mGluR5 cross-talk underlies a synaptic metaplasticity mechanism of ketamine.
Anisul Arefin, Jihye Kim, Manas Pratim Chakraborty, Silvia Martinelli, Betty Bai, Francis S Lee, Joshua Levitz
Science Advances May 1, 2026 DOI: 10.1126/sciadv.aec1444 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Esketamine Ketamine |
| Citations | 1 |
| Key findings | Ketamine's antidepressant action depends on signaling cross-talk between TrkB and mGluR5 receptors, and an mGluR5 positive allosteric modulator can enhance this interplay and boost ketamine's effects. |
Abstract
A complex ensemble of neuromodulatory receptors orchestrates the many forms of synaptic plasticity that drive behavioral state changes, but an understanding of how such receptors functionally interact is limited. Here, we find that the antidepressant action of ketamine is dependent on both the receptor tyrosine kinase, tropomyosin-related kinase B (TrkB), and the G protein-coupled receptor, metabotropic glutamate receptor 5 (mGluR5). mGluR5 amplifies brain-derived neurotrophic factor (BDNF)-driven signaling of TrkB, enabling synaptic potentiation via "signaling cross-talk," while BDNF activation of TrkB drives mGluR5 endocytosis via "trafficking cross-talk," impairing synaptic depression. These modes of cross-talk are enhanced by ketamine, which increases surface and postsynaptic levels of TrkB. Last, we find that an mGluR5 positive allosteric modulator can enhance both modes of cross-talk and boost the effects of ketamine. Together, these data unravel the intimate relationship between different classes of neuromodulatory receptors, revealing that receptor-receptor interplay can drive therapeutic action.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation Normal human subjects | 2003 | Experimental study | n = 7 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression Patients with treatment-resistant bipolar depression | 2012 | Population pharmacokinetic analysis | n = 9 |