Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons
Open accessAbstract
Significance: The transfer of lactate, a product of aerobic glycolysis, from astrocytes to neurons was recently shown to be necessary for the establishment of long-term memory and for the maintenance of in vivo long-term potentiation. Here, we report that lactate induces the expression of plasticity genes such as Arc, c-Fos, and Zif268 in neurons. The action of lactate is mediated by the modulation of NMDA receptor activity and the downstream Erk1/2 signaling cascade, through a mechanism associated with changes in the cellular redox state. These observations unveil an unexpected role of lactate as a signaling molecule in addition to its role in energy metabolism and open a previously unidentified research avenue for the study of neuronal plasticity and memory.
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On longer time scales, lactate can alter neuroplasticity via the NMDAR-BDNF pathway.
“On longer time scales, lactate can alter neuroplasticity via the NMDAR-BDNF pathway: lactate entering neurons can induce NMDAR opening and calcium influx, which in turn promotes ERK phosphorylation and BNDF transcription and expression [57].”
From High-intensity interval training or lactate administration combined with aerobic training enhances visceral fat loss while promoting VMH neuroplasticity in female rats (2024) · cites this paper as [57]
The paper reports that lactate potentiates NMDAR-mediated calcium signaling and increases Erk1/2 phosphorylation; it also reports increased BDNF expression at a later time point (Significance; Involvement of NMDARs, page unavailable). Its inhibitor experiments establish NMDAR–Erk1/2 involvement for other plasticity genes, but do not establish that this pathway causes the BDNF increase or demonstrate BDNF-mediated changes in neuroplasticity. (LLM, conf=0.84)
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- Authors
- Yang, J., Ruchti, E., Petit, J.-M., Jourdain, P., Grenningloh, G., Allaman, I., & Magistretti, P. J.
- Affiliations
- Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland;
- Centre Hospitalier Universitaire Vaudois (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-07-28
- Volume
- 111
- Issue
- 33
- Pages
- 12228-12233
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4143009
- OpenAlex
- W2014988592
- Cited by
- 504
- References
- 35
- Citations by year
- 2026: 48 · 2025: 48 · 2024: 50 · 2023: 53 · 2022: 44 · 2021: 46 · 2020: 35 · 2019: 41 · 2018: 36 · 2017: 26 · 2016: 37 · 2015: 37 · 2014: 2
- FWCI
- 15.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (130821)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- L-lactate, synaptic plasticity, NMDA receptor signaling, ERK1/2, Arc, c-fos, Zif268, NADH, intracellular calcium, long-term potentiation, long-term memory, sensorimotor cortex, aerobic glycolysis, neuronal energy metabolism
- MeSH terms
- Animals, Calcium, Cells, Cultured, Neuronal Plasticity, Neurons, Signal Transduction, Gene Expression, N-Methylaspartate, Lactic Acid, Mice
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