Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice
Shi-Ge Xue, Jin-Gang He, Ling-Li Lu, Shiqian Song, Meijuan Chen, Fang Wang, Jian-Guo Chen
Nature Communications December 2, 2023 DOI: 10.1038/s41467-023-42780-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Stressed male mice |
| Intervention | Ketamine |
| Dose | sub-anesthetic dosage |
| Topics | Esketamine Ketamine |
| Key points | Ketamine rescues depressive-like behaviors and decreased AMPA receptor-mediated neurotransmission by recruiting TARP-γ8 to postsynaptic sites in the ventral hippocampus of stressed male mice. |
Abstract
Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 10
- Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors. Molecular Pharmacology October 17, 2024
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression. European Archives of Psychiatry and Clinical Neuroscience August 29, 2024
- Psychoactive substances for the treatment of neuropsychiatric disorders. Asian Journal of Psychiatry November 1, 2024
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
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Cites 13
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
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