Reversal of age‐related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting d‐serine‐dependent NMDA receptor activation
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Summary: Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age‐related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age‐related effects of the reducing agent N‐acetyl‐L‐cysteine (L‐NAC) on the activation of the N‐methyl‐ d‐aspartate receptor (NMDA‐R) by its co‐agonist d‐serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long‐term dietary supplementation with L‐NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA‐R‐mediated synaptic potentials and theta‐burst‐induced long‐term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous d‐serine. Chronic treatment with L‐NAC, but not acute application of the reducing agent, restored potent d‐serine‐dependent NMDA‐R activation and LTP induction in aged rats. In addition, it is also revealed that the age‐related decrease in d‐serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA‐R activation by the amino acid, was rescued by long‐term dietary treatment with L‐NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA‐R activation through the d‐serine‐dependent pathway.
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When neurons and oligodendrocytes sustain age-related damage through altered DNA methylation, mitochondrial dysfunction, and reactive oxygen species, their lack of regenerative capacity renders them more susceptible to irreversible damage compared to other cell types.
“When neurons and oligodendrocytes sustain age-related damage through altered DNA methylation, mitochondrial dysfunction, and reactive oxygen species (ROS), their lack of regenerative capacity renders them more susceptible to irreversible damage compared to other cell types [59,60].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [59]
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- Authors
- Haxaire, C., Turpin, F. R., Potier, B., Kervern, M., Sinet, P., Barbanel, G., Mothet, J., Dutar, P., & Billard, J.
- Affiliations
- Sorbonne Paris Cité (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Billard, Jean‐Marie
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-02
- Volume
- 11
- Issue
- 2
- Pages
- 336-344
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- OpenAlex
- W1853749271
- Cited by
- 88
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 6 · 2013: 7 · 2012: 4
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HAL Portal Artxiker (Hindustan Aeronautics Limited (India)) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- oxidative stress, aging, hippocampus, synaptic plasticity, NMDA receptor, D-serine, N-acetylcysteine, serine racemase, long-term potentiation, cognitive aging, redox state, reactive oxygen species, dietary supplementation, CA1
- MeSH terms
- Acetylcysteine, Aging, Animals, Hippocampus, Lysine, Male, Neuronal Plasticity, Serine, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, Oxidative Stress, Rats
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