Ketamine induced synaptic plasticity operates independently of long-term potentiation.
Michelle K Piazza, Ege T Kavalali, Lisa M Monteggia
Neuropsychopharmacology October 1, 2024 DOI: 10.1038/s41386-024-01895-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine corticosterone |
| Topics | Ketamine Neuroplasticity Esketamine |
| Keywords | Antidepressants Mental health |
| Citations | 21 |
| Key findings | Ketamine-induced homeostatic plasticity does not impair subsequent Hebbian plasticity (LTP) in hippocampal synapses, even under stress modeled by chronic corticosterone exposure. |
Abstract
Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian plasticity are two such mechanisms by which neuronal synapses can be altered. Although these two processes are mechanistically distinct, they converge on downstream regulation of AMPA receptor activity to modify glutamatergic neurotransmission. However, much remains to be explored regarding how these two prominent forms of plasticity interact. Ketamine, a rapidly acting antidepressant, increases glutamatergic transmission via pharmacologically-induced homeostatic plasticity. Here, we demonstrate that Hebbian plasticity mechanisms are still intact in synapses that have undergone homeostatic scaling by ketamine after either systemic injection or perfusion onto hippocampal brain slices. We also investigated this relationship in the context of stress induced by chronic exposure to corticosterone (CORT) to better model the circumstances under which ketamine may be used as an antidepressant. We found that CORT induced an anhedonia-like behavioral phenotype in mice but did not impair long-term potentiation (LTP) induction. Furthermore, corticosterone exposure does not impact the intersection of homeostatic and Hebbian plasticity mechanisms, as synapses from CORT-exposed mice also demonstrated intact ketamine-induced plasticity and LTP in succession. These results provide a mechanistic explanation for how ketamine used for the treatment of depression does not impair the integrity of learning and memory processes encoded by mechanisms such as LTP.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 10
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
- A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals? Journal of Affective Disorders April 15, 2026
- Synaptic basis of rapid antidepressant action. European Archives of Psychiatry and Clinical Neuroscience September 29, 2024
- Joint administration of sub-threshold doses of the acetylcholinesterase inhibitor donepezil with those of the NMDA receptor antagonist ketamine improved rats' recognition memory abilities. Neuroscience Letters November 20, 2024
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacology February 1, 2026
and 5 more in the library
Cites 11
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
- A Review of the Nonmedical Use of Ketamine: Use, Users and Consequences Journal of Psychoactive Drugs December 1, 2000
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action Cell Reports August 1, 2021
- Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Molecular Brain June 16, 2020
and 6 more in the library