BDNF Release and Signaling Are Required for the Antidepressant Actions of GLYX-13
Open accessAbstract
Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-D-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized. Here we use a combination of neutralizing antibody (nAb), mutant mouse and pharmacological approaches to test the role of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TrkB) signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex (intra-mPFC) infusion of an anti-BDNF nAb or in mice with a knock-in of the BDNF Val66Met allele, which blocks the processing and activity-dependent release of BDNF. We also demonstrate that pharmacological inhibitors of BDNF-TrkB signaling or of L-type voltage-dependent Ca 2+ channels (VDCCs) block the antidepressant behavioral actions of GLYX-13. Finally, we examined the role of the Rho GTPase proteins by injecting a selective inhibitor into the mPFC and found that activation of Rac1 but not RhoA is involved in the antidepressant effects of GLYX-13. Together, these findings indicate that enhanced release of BDNF through exocytosis caused by activation of VDCCs and subsequent TrkB-Rac1 signaling is required for the rapid and sustained antidepressant effects of GLYX-13.
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A single infusion of recombinant BDNF into the mPFC produces rapid and sustained antidepressant effects similar to those observed with ketamine administration.
“a single infusion of recombinant BDNF into the mPFC produces rapid and sustained antidepressant effects similar to those observed with ketamine administration [75,76]”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [76]
The Results section on Rho GTPase signaling reports that BDNF infusion into the mPFC produced a significant antidepressant effect in the forced swim test. It does not establish that this effect was rapid and sustained or directly compare BDNF infusion with ketamine administration. The Methods section mentions BDNF infusion but does not identify it as recombinant BDNF; page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmTORC1 activation is driven by BDNF signaling and might enhance BDNF production, creating a positive feedback loop that sustains neuroplasticity.
“mTORC1 activation appears to be driven by BDNF signaling, and in turn, mTORC1 itself might enhance BDNF production, creating a positive feedback loop that sustains neuroplasticity [75,76].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [76]
The Discussion states that released BDNF activates TrkB signaling, including mTORC1, and links mTORC1 activation to increased spine number, maturation, and function. It does not say that mTORC1 enhances BDNF production or creates a positive feedback loop that sustains neuroplasticity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBlocking BDNF-TrkB signaling completely eliminates the antidepressant effects of GLYX-13.
“Blocking BDNF-TrkB signaling, whether through neutralizing antibodies or genetic models that inhibit BDNF release, has been shown to completely eliminate the antidepressant effects of GLYX-13 [76].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [76]
GLYX-13 exerts antidepressant effects by targeting the glutamatergic system through NMDA receptor modulation.
“Like ketamine and esketamine, GLYX-13 exerts its antidepressant effects by targeting the glutamatergic system, specifically through NMDA receptor modulation [76].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [76]
GLYX-13's antidepressant actions are mediated by activity-dependent release of BDNF, which enhances synaptic plasticity.
“Its antidepressant actions are mediated by the activity-dependent release of BDNF, which plays a crucial role in enhancing synaptic plasticity [76].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [76]
The antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex infusion of an anti-BDNF antibody or in mice with a knock-in of the BDNF Val66Met allele.
“Recent evidence demonstrates that the antidepressant effects of GLYX-13, a novel glutamatergic compound that acts as an NMDA modulator with glycine-like partial agonist properties, are blocked by intra-medial prefrontal cortex infusion of an anti-BDNF antibody or in mice with a knock-in of the BDNF Val66Met allele.”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [227]
Pharmacological inhibition of BDNF-TrkB signaling or L-type voltage-dependent Ca2+ channels blocks the antidepressant behavioral actions of GLYX-13.
“Pharmacological inhibition of BDNF-TrkB signaling or L-type voltage-dependent Ca2+ channels (VDCCs) blocks the antidepressant behavioral actions of GLYX-13 [227].”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [227]
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- Authors
- Kato, T., Fogaça, M. V., Deyama, S., Li, X.-Y., Fukumoto, K., & Duman, R. S.
- Affiliations
- Sumitomo Dainippon Pharma (Japan) (JP)
- Yale University (US)
- Corresponding author
- Duman, R S
- Venue
- Molecular Psychiatry
- Published
- 2017-12-05
- Volume
- 23
- Issue
- 10
- Pages
- 2007-2017
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5988860
- OpenAlex
- W2773429044
- Cited by
- 88
- References
- 51
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 11 · 2021: 8 · 2020: 22 · 2019: 12 · 2018: 18
- FWCI
- 9.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Allergan
- National Institute of Mental Health (R01MH093897, R01MH074354, R37MH045481, R01MH045481, R01MH105910)
- 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 mechanism, brain-derived neurotrophic factor, TrkB signaling, NMDA receptor modulation, rapid antidepressant effects, medial prefrontal cortex, BDNF Val66Met polymorphism, L-type voltage-dependent calcium channels, Rac1, Rho GTPases, depression
- MeSH terms
- Animals, Antidepressive Agents, Depression, Ketamine, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Oligopeptides, Signal Transduction, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Brain-Derived Neurotrophic Factor, Receptor, trkB, Mice, Rats
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