The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus
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Rapastinel (GLYX-13) is an N-methyl-d-aspartate receptor (NMDAR) modulator that has characteristics of a glycine site partial agonist. Rapastinel is a robust cognitive enhancer and facilitates hippocampal long-term potentiation (LTP) of synaptic transmission in slices. In human clinical trials, rapastinel has been shown to produce marked antidepressant properties that last for at least one week following a single dose. The long-lasting antidepressant effect of a single dose of rapastinel (3mg/kg IV) was assessed in rats using the Porsolt, open field and ultrasonic vocalization assays. Cognitive enhancement was examined using the Morris water maze, positive emotional learning, and contextual fear extinction tests. LTP was assessed in hippocampal slices. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex. Significant antidepressant-like or cognitive enhancing effects were observed that lasted for at least one week in each model. Rapastinel facilitated LTP 1day-2weeks but not 4weeks post-dosing. Biweekly dosing with rapastinel sustained this effect for at least 8weeks. A single dose of rapastinel increased the proportion of whole-cell NMDAR current contributed by NR2B-containing NMDARs in the hippocampus 1week post-dosing, that returned to baseline by 4weeks post-dosing. The NMDAR antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the antidepressant-like effect of rapastinel 1week post dosing. A single injection of rapastinel also increased mature spine density in both brain regions 24h post-dosing. These data demonstrate that rapastinel produces its long-lasting antidepressant effects via triggering NMDAR-dependent processes that lead to increased sensitivity to LTP that persist for up to two weeks. These data also suggest that these processes led to the alterations in dendritic spine morphologies associated with the maintenance of long-term changes in synaptic plasticity associated with learning and memory.
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Preclinical evidence suggests rapastinel may enhance dendritic complexity and long-term potentiation via bidirectional modulation of NMDA signal transduction.
“Preclinical evidence suggests that rapastinel may enhance dendritic complexity and long-term potentiation via bidirectional modulation of NMDA signal transduction [161,162,163].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [162]
Partial agonists at the NMDAR glycineB binding site, including GLYX-13 and D-cycloserine, manifest antidepressant effects in clinical trials and animal tests without sharing ketamine's NMDAR inhibition-mediated side effects.
“Another finding challenging the NMDAR inhibition hypothesis of ketamine’s antidepressant mechanism of action is the fact that partial agonists at the NMDAR glycineB binding site, including GLYX-13 (i.e., rapastinel) and D-cycloserine manifest antidepressant effects in clinical trials 104, 105 and in animal tests 106–109, without sharing ketamine’s NMDAR inhibition-mediated side effects 109.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [107]
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- Burgdorf J Zhang XL Weiss C Matthews E Disterhoft JF Stanton PK Moskal JR The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats Neurobiol Aging 2011c 32 698 706 19446371 PMC3035742
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“Past treatment approaches (such as total sleep deprivation and ECT) and emerging findings with other medications, including scopolamine, (S)-ketamine, and GLYX-13, support the notion that depression can be treated rapidly, provided that the correct receptors, synapses, and/or circuits are targeted.”
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- Authors
- Burgdorf, J., Zhang, X.-L., Weiss, C., Gross, A., Boikess, S. R., Kroes, R. A., Khan, M. A., Burch, R. M., Rex, C. S., Disterhoft, J. F., Stanton, P. K., & Moskal, J. R.
- Affiliations
- Northwestern University (US)
- New York Medical College (US)
- Afraxis (United States) (US)
- Corresponding author
- Moskal, J.R.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 308
- Pages
- 202-211
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC4721228
- OpenAlex
- W1561342581
- Cited by
- 88
- References
- 43
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 5 · 2023: 3 · 2022: 11 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 13 · 2017: 14 · 2016: 9
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH094835, MH094835, MH-47340, R01MH047340, R56MH047340)
- National Institute of Neurological Disorders and Stroke (R01NS059879, NS 044421, R01NS044421, NS059879, R56NS044421)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- antidepressant effects, NMDA receptor modulation, metaplasticity, hippocampal long-term potentiation, medial prefrontal cortex, dendritic spine morphology, cognitive enhancement, fear extinction, synaptic plasticity
- MeSH terms
- Animals, Antidepressive Agents, Depressive Disorder, Disease Models, Animal, Dose-Response Relationship, Drug, Hippocampus, Male, Membrane Potentials, Memory, Neuronal Plasticity, Oligopeptides, Time Factors, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Maze Learning, Tissue Culture Techniques, Dendritic Spines
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