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 is expressed in the mammalian brain and acts as a neuromodulator.
“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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“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).”
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InfluentialSerine racemase is predominantly localized in neurons in mouse brain
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“Aside from synthesizing and storing D-serine (Schell et al, 1995, 1997; Mothet et al, 2000; Wolosker et al, 1999), perisynaptic astroglial processes express a variety of neurotransmitter receptors and ion channels, and so are well positioned to respond in a graded manner to transmitters and ions…”
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“…and glial exocytosis of D-serine in vivo remain to be clarified; D-serine has been detected in both astrocytes and neurones in the brain (Kartvelishvily et al., 2006; Williams et al., 2006; Miya et al., 2008), with distribution patterns similar to those of the NMDA receptor (Schell et al., 1997).”
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“Like D-serine, SRR is present in both astrocytes and neurons of the brain (Williams et al., 2006b; Wolosker et al., 1999; Yoshikawa et al., 2006; Miya et al., 2008; Kartvelishvily et al., 2006), with a regional distribution that closely resembles that of NMDARs (Schell et al., 1997).”
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“Despite its extensive regulation, it was recently proposed that astrocytic D-serine is not available in sufficient amounts to modulate synaptic activity in vivo , under physiological conditions (296).”
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“D-Serine has subsequently been immunolocalized to populations of astrocyte-like cells in rodent brain (Schell et al., 1995, 1997), and possibly at very low levels in neurons (Yasuda et al., 2001).”
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“There is now considerable evidence, including a regional distribution more closely resembling that of NMDA receptors than is the case with glycine (4) and a stronger affinity than glycine for the glycine binding site on the NR1 subunit of the NMDA receptor (31, 32), indicating that D-serine may be more important in th…”
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“Endogenous synaptic NMDA modulators such asd-serine (Schell et al., 1995, 1997) may also be potential targets.”
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Nishikawa, T. (2011) · Journal of Chromatography B · doi:10.1016/j.jchromb.2011.08.030 · Cited by 145 · see citing works
Metabolism of the neuromodulator d-serine
Pollegioni, L., & Sacchi, S. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0307-9 · Cited by 128 · see citing works
“D-serine is likely the main endogenous ligand for the strychnineinsensitive glycine-binding site (also referred to as the GlyB site) of NR1 subunit of NMDARs: activation of NMDARs requires glutamate and a coagonist and D-serine might be an alternative to glycine for NMDAR activation [5, 6].”
BackgroundDistribution and pharmacology of alanine–serine–cysteine transporter 1 (asc‐1) in rodent brain
Helboe, L., Egebjerg, J., Møller, M., & Thomsen, C. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02966.x · Cited by 117 · see citing works
D-serine in glia and neurons derives from 3-phosphoglycerate dehydrogenase
Ehmsen, J. T., Ma, T. M., Sason, H., Rosenberg, D., Ogo, T., Furuya, S., Snyder, S. H., & Wolosker, H. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4914-12.2013 · Cited by 118 · see citing works
“D-Serine localized to neurons and astrocytes As with Srr, reports of D-serine localizations have varied with descriptions of astrocytic (Schell et al., 1997; Kartvelishvily et al., 2006; Williams et al., 2006) and neuronal (Kartvelishvily et al., 2006) sites.”
BackgroundSelf-citationD-serine as a gliotransmitter and its roles in brain development and disease
Horn, M. R. V., Sild, M., & Ruthazer, E. S. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00039 · Cited by 121 · see citing works
“The dendrites of pyramidal neurons in prefrontal cortex, as well as primary somatosensory cortex, of SR−/− mice are less complex and have a shorter total length (Balu et al., 2012).”
BackgroundInfluentialAdage, T., Trillat, A., Quattropani, A., Perrin, D., Cavarec, L., Shaw, J., Guerassimenko, O., Giachetti, C., Greco, B. M., Chumakov, I. M., et al. (2007) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2007.06.006 · Cited by 119 · see citing works
Contributions of the d-serine pathway to schizophrenia
Labrie, V., Wong, A. H. C., & Roder, J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.030 · Cited by 118 · see citing works
“Furthermore , regional distributions of D-serine in the brain resemble that of NMDARs more closely than glycine (Schell et al., 1997).”
InfluentialD‐Serine as a glial modulator of nerve cells
Miller, R. F. (2004) · Glia · doi:10.1002/glia.20073 · Cited by 116 · see citing works
“In addition, O’Brien et al. (2003) used capillary electrophoresis to identify Dserine in the salamander retina.”
BackgroundInfluentialKatsuki, H., Nonaka, M., Shirakawa, H., Kume, T., & Akaike, A. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.070912 · Cited by 115 · see citing works
d-Serine and Serine Racemase are Localized to Neurons in the Adult Mouse and Human Forebrain
Balu, D. T., Takagi, S., Puhl, M. D., Benneyworth, M. A., & Coyle, J. T. (2014) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-014-0027-z · Cited by 126 · see citing works
“The first studies (Schell et al. 1997; Schell et al. 1995; Wolosker et al. 1999) showing astrocytic”
InfluentialAlmond, S. L., Fradley, R. L., Armstrong, E. J., Heavens, R. B., Rutter, A. R., Newman, R. J., Chiu, C.-S., Konno, R., Hutson, P. H., & Brandon, N. J. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2006.05.003 · Cited by 108 · see citing works
“Available online on ScienceDirect (www.sciencedirect.com). correlated with that of NMDARs (Hashimoto and Oka, 1997; Matsui et al., 1995; Schell et al., 1997).”
BackgroundEnhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury
Perez, E. J., Tapanes, S. A., Loris, Z. B., Balu, D. T., Sick, T. J., Coyle, J. T., & Liebl, D. J. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92300 · Cited by 126 · see citing works
Fukushima, T., Iizuka, H., Yokota, A., Suzuki, T., Ohno, C., Kono, Y., Nishikiori, M., Seki, A., Ichiba, H., Watanabe, Y., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101652 · Cited by 102 · see citing works
“By contrast, we did observe a significant decrease in serum levels of D-serine, a co-agonist of the glycine site of the NMDA receptor [5,42] (Table 2), which is consistent with previous reports [6,10].”
ResultThe N –methyl D–aspartate receptor glycine site and D–serine metabolism: an evolutionary perspective
Schell, M. J. (2004) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2003.1399 · Cited by 98 · see citing works
Self-citationd-Amino acids in brain neurotransmission and synaptic plasticity
Billard, J. (2012) · Amino Acids · doi:10.1007/s00726-012-1346-3 · Cited by 103 · see citing works
“Several interesting results obtained with complementary technical approaches are consistent with this hypothesis: using specific antibodies raised against the amino acid and adequate perfusion of cerebral tissues, D-serine is found to concentrate in the vicinity of N-methyl-D-aspartate receptors (NMDA-R) (Hashimoto et…”
ResultRutter, A. R., Fradley, R. L., Garrett, E., Chapman, K., Lawrence, J., Rosahl, T., & Patel, S. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05446.x · Cited by 99 · see citing works
“enzyme d-amino acid oxidase is tightly regulated during this early stage of development it was important to establish if mechanisms responsible for d-serine uptake in 21-day-old mice were significantly different from those in adult mice (Schell et al., 1997; Wang & Zhu, 2003).”
Backgroundde Koning, T. D., & Klomp, L. (2004) · Current Opinion in Neurology · doi:10.1097/00019052-200404000-00019 · Cited by 99 · see citing works
Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1).
Ma, L., Liu, Y., Ky, B., Shughrue, P., Austin, C., & Morris, J. A. (2002) · Genomics · doi:10.1006/geno.2002.7012 · Cited by 98 · see citing works
Cell-type specific mechanisms of D-serine uptake and release in the brain
Martineau, M., Parpura, V., & Mothet, J. (2014) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2014.00012 · Cited by 108 · see citing works
The Origin and Turnover of D-Serine in Brain
Dunlop, D. S., & Neidle, A. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6724 · Cited by 96 · see citing works
Structure–function relationships in human d-amino acid oxidase
Sacchi, S., Caldinelli, L., Cappelletti, P., Pollegioni, L., & Molla, G. (2012) · Amino Acids · doi:10.1007/s00726-012-1345-4 · Cited by 95 · see citing works
Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in micePreprint
Labrie, V., Duffy, S. N., Wang, W., Barger, S. W., Baker, G. B., & Roder, J. (2008) · Learning & Memory · doi:10.1101/lm.1112209 · Cited by 89 · see citing works
“In the brain, the localization of D-serine closely resembles that of NMDARs (Schell et al. 1997), and D-serine has been”
BackgroundNeurobiology through the looking-glass: d-serine as a new glial-derived transmitter
Wolosker, H., Panizzutti, R., & Miranda, J. D. (2002) · Neurochemistry International · doi:10.1016/s0197-0186(02)00055-4 · Cited by 92 · see citing works
“Animals older than 3 weeks begin to express d-amino acid oxidase in the cerebellum (Horiike et al., 1987), which coincides with a large reduction of d-serine levels in Bergmann glia (Schell et al., 1997b).”
InfluentialTime and space profiling of NMDA receptor co‐agonist functions
Mothet, J., Bail, M. L., & Billard, J. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13204 · Cited by 98 · see citing works
Turpin, F. R., Potier, B., Dulong, J., Sinet, P., Alliot, J., Oliet, S. H. R., Dutar, P., Epelbaum, J., Mothet, J., & Billard, J. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.09.001 · Cited by 95 · see citing works
Panizzutti, R., Miranda, J. D., Ribeiro, C. S., Engelender, S., & Wolosker, H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091002298 · Cited by 83 · see citing works
EphrinBs Regulate d-Serine Synthesis and Release in Astrocytes
Zhuang, Z.-Y., Yang, B., Theus, M. H., Sick, J. T., Bethea, J. R., Sick, T. J., & Liebl, D. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0481-10.2010 · Cited by 77 · see citing works
“D-Serine serves as an endogenous coagonist at strychnine-insensitive glycine sites of NMDA receptors (Schell et al., 1997; Stevens et al., 2003; Yang et al., 2003; Shleper et al., 2005; Panatier et al., 2006b), and is important in regulating long-term potentiation (Henneberger et al.”
BackgroundReviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia
Boks, M. P., Rietkerk, T., van de Beek, M. H., Sommer, I. E., de Koning, T. J., & Kahn, R. S. (2007) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2006.12.003 · Cited by 80 · see citing works
Mouse brain serine racemase catalyzes specific elimination of L‐serine to pyruvate
Stříšovský, K., Jirásková, J., Bařinka, C., Majer, P., Rojas, C., Slusher, B., & Konvalinka, J. (2003) · FEBS Letters · doi:10.1016/s0014-5793(02)03855-3 · Cited by 85
Deep Brain Stimulation: Are Astrocytes a Key Driver Behind the Scene?
Fenoy, A. J., Goetz, L., Chabardès, S., & Xia, Y. (2014) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12223 · Cited by 86 · see citing works
Yang, S., Qiao, H., Wen, L., Zhou, W., & Zhang, Y.-X. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2004.12.033 · Cited by 84
- 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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