ArticleMolecular brain2020
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression.
Article in Molecular brain, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 83 citations in OpenAlex.
- The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response.Nature communications · 2026Article
- Ketamine and Evolving Neuroplasticity.Clinical drug investigation · 2026Review
- Low Dose Ketamine Preconditions Astrocyte Mitochondria to Achieve Antidepressant Efficacy via Adenosine, Humanin, and Melatonin Upregulation and Efflux.Alpha psychiatry · 2026Article
- Enhancing plasticity to treat depression and other central nervous system diseases using event-driven pharmacology.Journal of psychopharmacology (Oxford, England) · 2026Review
- Intermittent Ketamine and Neuromodulation Treatment Evoke Synergistic Antidepressant-Relevant Action.Biological psychiatry · 2026Article
- Cerebral organoid exosomes reversed behavioral deficits by repressing NLRP3-mediated neuroinflammation in stress models.iScience · 2026Article
- A Time-Sensitive Plasticity Distinguishes the Rapid and Sustained Synaptic Actions of Ketamine from Its (2The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Review
- GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities inScience advances · 2026Article
- Review
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine.Molecular psychiatry · 2025Review
- Article
- Ketamine Reverses Chronic Stress-Induced Behavioral Changes via the Expression of CaFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model.Cell reports · 2025Article
- Depression-like effects induced by chronic unpredictable mild stress in mice are rapidly reversed by a partial negative allosteric modulator of mGluPsychopharmacology · 2025Article
- Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- The curious interpretation of novel object recognition tests.Trends in neurosciences · 2025Review
- Ketamine induced synaptic plasticity operates independently of long-term potentiation.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- Targeting metaplasticity mechanisms to promote sustained antidepressant actions.Molecular psychiatry · 2024Review
- A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression.Neuroscience applied · 2024Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine's effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY rat model, restoring dHPC LTP was not correlated with ketamine's effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to "reset the system".
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.