Positive AMPA Receptor Modulation Rapidly Stimulates BDNF Release and Increases Dendritic mRNA Translation
Open accessAbstract
Brain-derived neurotrophic factor (BDNF) stimulates local dendritic mRNA translation and is involved in formation and consolidation of memory. 2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan-10-one (CX614), one of the best-studied positive AMPA receptor modulators (also known as ampakines), increases BDNF mRNA and protein and facilitates long-term potentiation (LTP) induction. Several other ampakines also improve performance in various behavioral and learning tasks. Since local dendritic protein synthesis has been implicated in LTP stabilization and in memory consolidation, this study investigated whether CX614 could influence synaptic plasticity by upregulating dendritic protein translation. CX614 treatment of primary neuronal cultures and acute hippocampal slices rapidly activated the translation machinery and increased local dendritic protein synthesis. CX614-induced activation of translation was blocked by K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], CNQX, APV, and TTX, and was inhibited in the presence of an extracellular BDNF scavenger, TrkB-Fc. The acute effect of CX614 on translation was mediated by increased BDNF release as demonstrated with a BDNF scavenging assay using TrkB-Fc during CX614 treatment of cultured primary neurons and was blocked by nifedipine, ryanodine, and lack of extracellular Ca(2+) in acute hippocampal slices. Finally, CX614, like BDNF, rapidly increased dendritic translation of an exogenous translation reporter. Together, our results demonstrate that positive modulation of AMPA receptors rapidly stimulates dendritic translation, an effect mediated by BDNF secretion and TrkB receptor activation. They also suggest that increased BDNF secretion and stimulation of local protein synthesis contribute to the effects of ampakines on synaptic plasticity.
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Cell culture studies demonstrate that glutamate receptor stimulation of synaptogenesis requires the release of brain-derived neurotrophic factor to stimulate TrkB-mTOR signaling and synaptic protein synthesis.
“These findings are consistent with cell culture studies demonstrating that glutamate receptor stimulation of synaptogenesis requires the release of BDNF to stimulate TrkB-mTOR signaling and synaptic protein synthesis (50).”
From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [50]
The Abstract says that CX614 activates dendritic protein-synthesis machinery and that this requires BDNF release and TrkB–mTOR activation. The Results show that blocking released BDNF prevents CX614-dependent mTOR phosphorylation in cultured neurons. The paper does not demonstrate that BDNF release is required for synaptogenesis itself; the Discussion describes BDNF release as implicated in long-lasting synapse formation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBDNF is a potent activator of mTOR signaling.
“Previous work has shown that BDNF is a potent activator of mTOR signaling (Jourdi et al., 2009; Takei et al., 2004; Slipczuk et al., 2009), and mTOR is a key integrator for many signaling pathways (see Costa-Mattioli and Monteggia, 2013).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Jourdi et al., 2009
Treatment with the antagonist NBQX entirely inhibits the ketamine-induced release of BDNF.
“The necessity of AMPA receptors was validated by studies showing that treatment with the antagonist NBQX entirely inhibits the ketamine-induced release of BDNF [69].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [69]
The Discussion reports that CX614 increases BDNF release, and the Results report that the AMPA receptor blocker CNQX blocks some CX614-dependent signaling effects. Searches for ketamine-induced BDNF release and NBQX found no passage addressing whether NBQX inhibits that release. Page numbers were unavailable in our copy. (LLM, conf=0.77)
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References 53 · Cited by 226
- Authors
- Jourdi, H., Hsu, Y.-T., Zhou, M., Qin, Q., Bi, X., & Baudry, M.
- Affiliations
- University of Southern California (US)
- Western University of Health Sciences (US)
- Corresponding author
- Baudry, M.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-07-08
- Volume
- 29
- Issue
- 27
- Pages
- 8688-8697
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2761758
- OpenAlex
- W1995630439
- Cited by
- 226
- References
- 53
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 9 · 2023: 12 · 2022: 17 · 2021: 19 · 2020: 23 · 2019: 7 · 2018: 13 · 2017: 15 · 2016: 13 · 2015: 16 · 2014: 10 · 2013: 18 · 2012: 8
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P01NS045260, R01NS057128)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- ampakines, BDNF release, local protein synthesis, TrkB receptor, synaptic plasticity, long-term potentiation, hippocampus, calcium signaling, nifedipine, ryanodine, memory consolidation
- MeSH terms
- Animals, Cells, Cultured, Dendrites, Hippocampus, Humans, Neuronal Plasticity, Organ Culture Techniques, Oxazines, RNA, Messenger, Protein Biosynthesis, Rats, Sprague-Dawley, Receptors, AMPA, Brain-Derived Neurotrophic Factor, Rats
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