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d-Serine as a Neuromodulator: Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors
Open accessAbstract
d-Serine is localized in mammalian brain to a discrete population of glial cells near NMDA receptors, suggesting that d-serine is an endogenous agonist of the receptor-associated glycine site. To explore this possibility, we have compared the immunohistochemical localizations of d-serine, glycine, and NMDA receptors in rat brain. In the telencephalon,d-serine is concentrated in protoplasmic astrocytes, which are abundant in neuropil in close vicinity to NMDA receptor 2A/B subunits. Ultrastructural examination of the CA1 region of hippocampus reveals d-serine in the cytosolic matrix of astrocytes that ensheath neurons and blood vessels, whereas NR2A/B is concentrated in dendritic spines. By contrast, glycine immunoreactivity in telencephalon is the lowest in brain. During postnatal week 2,d-serine levels in cerebellum are comparable to those in adult cerebral cortex but fall to undetectable levels by day 26. During week 2, we observe parallel ontogeny of d-serine in Bergmann glia and NR2A/B in Purkinje cells, suggesting a role for astrocytic d-serine in NMDA receptor-mediated synaptogenesis.d-Serine in the radial processes of Bergmann glia is also well positioned to regulate NMDA receptor-dependent granule cell migration. In the inner granule layer,d-serine is found transiently in protoplasmic astrocytes surrounding glomeruli, where it could regulate development of the mossy fiber/granule cell synapse.d-Serine seems to be the endogenous ligand of glycine sites in the telencephalon and developing cerebellum, whereas glycine predominates in the adult cerebellum, olfactory bulb, and hindbrain.
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“D-serine, expressed in the mammalian brain, acts as a neuromodulator.[18]”
From Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection (2025) · cites this paper as [18]
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Verkhratsky, A., & Nedergaard, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00042.2016 · Cited by 1,678
“The concept of D-serine as a specific astroglial neuromodulator received much popularity in recent years following initial observations claiming the exclusive astrocytic presence of D-serine and its synthesizing enzyme serine racemase (1558, 1559, 1892).”
Astrocyte Control of Synaptic Transmission and Neurovascular Coupling
Haydon, P. G., & Carmignoto, G. (2006) · Physiological Reviews · doi:10.1152/physrev.00049.2005 · Cited by 1,371
“Since this enzyme is only expressed in astrocytes (186, 187, 228), these glial cells are the source of this endogeous ligand for the glycinebinding site of the NMDAR.”
BackgroundD-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor.
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Self-citationGlia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory
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Wolosker, H., Blackshaw, S., & Snyder, S. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.23.13409 · Cited by 811
Self-citation
Metadata
- Authors
- Schell, M. J., Brady Jr., R. O., Molliver, M. E., & Snyder, S. H.
- Affiliations
- Johns Hopkins University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1997-03-01
- Volume
- 17
- Issue
- 5
- Pages
- 1604-1615
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6573391
- OpenAlex
- W1793612468
- Cited by
- 415
- References
- 80
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 8 · 2023: 13 · 2022: 11 · 2021: 14 · 2020: 12 · 2019: 12 · 2018: 12 · 2017: 8 · 2016: 14 · 2015: 12 · 2014: 18 · 2013: 17 · 2012: 15
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da004431-08)
- U.S. Public Health Service
- National Institute of Mental Health (R01MH018501, R37MH018501, MH-18501)
- National Institute on Drug Abuse (DA 00074, 5RO1DA04431, K05DA000074)
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- D-serine, NMDA receptor, glycine site, neuromodulation, astrocytes, Bergmann glia, glycine, cerebellar development, hippocampal CA1, synaptogenesis, granule cell migration, mossy fiber synapses, telencephalon, postnatal development, rat brain
- MeSH terms
- Animals, Brain Chemistry, Cerebellum, Glycine, Hippocampus, Ligands, Models, Neurological, Neuroglia, Olfactory Bulb, Organ Specificity, Rabbits, Rhombencephalon, Serine, Stereoisomerism, Telencephalon, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, Glycine, Neurotransmitter Agents, Rats
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