Cited by 415Neuroscience and Neuropharmacology ResearchAmino Acid Enzymes and MetabolismNeuroinflammation and Neurodegeneration Mechanisms

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d-Serine as a Neuromodulator: Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors

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Schell, Michael J., Brady Jr., Roscoe O., Molliver, Mark E., Snyder, Solomon H.·1997·The Journal of Neuroscience

DOI 10.1523/jneurosci.17-05-01604.1997PMC PMC6573391

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Abstract

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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Verkhratsky, A., & Rose, C. R. (2019) · Cell Calcium · doi:10.1016/j.ceca.2019.102136 · Cited by 55
“considered to be an epitome “gliotransmitter” [130-133].”
The intrinsic disorder alphabet. III. Dual personality of serine
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To Gate or not to Gate: Are the Delta Subunits in the Glutamate Receptor Family Functional Ion Channels?
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“With regard to the availability of D-serine in sufficiently high concentration, two findings are particularly interesting: First, D-serine concentrations are high in the developing cerebellum and restricted to Bergmann glia cells that ensheath parallel fiber to Purkinje cell synapses [110, 111 ].”
Background
Changes in D‐serine levels and localization during postnatal development of the rat vestibular nuclei
Puyal, J., Martineau, M., Mothet, J., Nicolas, M., & Raymond, J. (2006) · The Journal of comparative neurology · doi:10.1002/cne.21016 · Cited by 48
“Moreover, in the cerebellum the transient emergence of a high level of D-serine in Bergmann glia concomitant with a transient expression of NR2 subunits in Purkinje cells suggested a role for astrocytic D-serine in NMDA receptormediated synapse formation (Schell et al., 1997).”
BackgroundMethodInfluential
Determination of amino acids associated with cerebral ischaemia in rat brain microdialysates using narrowbore liquid chromatography and fluorescence detection.
Hemelrijck, A. V., Sarre, S., Smolders, I., & Michotte, Y. (2005) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.10.013 · Cited by 48
Pharmacology of Ionic Channel Function: Activators and Inhibitors
Endo, M., Kurachi, Y., & Mishina, M. (2000) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-57083-4 · Cited by 48
Development of PET and SPECT Probes for Glutamate Receptors
Fuchigami, T., Nakayama, M., & Yoshida, S. (2015) · The Scientific World JOURNAL · doi:10.1155/2015/716514 · Cited by 53
“Glycine is ubiquitously distributed in the brain, while d-serine is predominantly found in the forebrain [48, 49].”
Background
Bergmann glial GlyT1 mediates glycine uptake and release in mouse cerebellar slices
Huang, H., Barakat, L., Wang, D. D., & Bordey, A. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.067801 · Cited by 50
“It is important to consider that d-serine has been suggested to be the endogenous ligand of the glycineB sites in many CNS regions (Schell et al. 1997; Baranano et al. 2001).”
BackgroundInfluential
Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases
Kölker, S. (2018) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-018-0201-4 · Cited by 57
Chiral Measurement of Aspartate and Glutamate in Single Neurons by Large-Volume Sample Stacking Capillary Electrophoresis
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Active release of glycine or d‐serine saturates the glycine site of NMDA receptors at the cerebellar mossy fibre to granule cell synapse
Billups, D., & Attwell, D. (2003) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2003.02996.x · Cited by 45
Gliotransmission of D-serine promotes thirst-directed behaviors in Drosophila
Park, A., Croset, V., Otto, N., Agarwal, D., Treiber, C. D., Meschi, E., Sims, D., & Waddell, S. (2022) · Current Biology · doi:10.1016/j.cub.2022.07.038 · Cited by 45
Postsynaptic Serine Racemase Regulates NMDA Receptor Function
Wong, J. M., Folorunso, O., Barragan, E. V., Berciu, C., Harvey, T. L., DeChellis-Marks, M., Glausier, J., Macdonald, M. L., Coyle, J., Balu, D., et al. (2020) · Journal of Neuroscience · doi:10.1101/2020.06.16.155572 · Cited by 44
“Early studies suggested that D-serine is exclusively synthesized and released by astrocytes (Schell et al., 1995; Schell et al., 1997; Wolosker et al., 1999) leading to the classification of D-serine as a gliotransmitter (Wolosker et al., 2002; Miller, 2004; Panatier et al., 2006).”
BackgroundInfluential
Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia
de Bartolomeis, A., Manchia, M., Marmo, F., Vellucci, L., Iasevoli, F., & Barone, A. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00369 · Cited by 54
“Immunohistochemical studies comparing D-serine, glycine, and NMDARs pattern of distribution in rat brain, showed that D-serine and NMDARs overlap each other and have the highest concentration in telencephalon and developing cerebellum; conversely, glycine immunoreactivity does not correspond to NMDARs localization (ex…”
Background
D-Serine and Serine Racemase Are Associated with PSD-95 and Glutamatergic Synapse Stability
Lin, H., Jacobi, A. A., Anderson, S. A., & Lynch, D. R. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00034 · Cited by 47
“SR was initially localized to astrocytes, but later found prominently in neurons (Schell et al., 1997; Wolosker et al., 1999, 2008; Kartvelishvily et al., 2006; Martineau et al., 2006, 2014; Panatier et al., 2006; Miya et al., 2008; Benneyworth et al., 2012; Ehmsen et al., 2013; Balu et al., 2014;…”
Background
d -Amino Acid Oxidase Generates Agonists of the Aryl Hydrocarbon Receptor from d -Tryptophan
Nguyen, L. P., Hsu, E. L., Chowdhury, G., Dostálek, M., Guengerich, F. P., & Bradfield, C. A. (2009) · Chemical Research in Toxicology · doi:10.1021/tx900043s · Cited by 40
“Interestingly, the relatively high endogenous levels of D-serine along with its potent activation of the N-methyl-D-Asp receptor (NMDR) have led to the postulation that D-serine is an endogenous ligand of NMDR (32,33).”
Background
Determination of minute amounts of d-leucine in various brain regions of rat and mouse using column-switching high-performance liquid chromatography
Inoue, T. M., Hamase, K., Morikawa, A., & Zaitsu, K. (2000) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)00244-9 · Cited by 51
Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia
Pei, J.-C., Luo, D.-Z., Gau, S.-S., Chang, C., & Lai, W. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.742058 · Cited by 48
Glycine agonism in ionotropic glutamate receptors
Stroebel, D., Mony, L., & Paoletti, P. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108631 · Cited by 51
Functional and immunocytochemical characterization of D‐serine transporters in cortical neuron and astrocyte cultures
Shao, Z., Kamboj, A. K., & Anderson, C. M. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22086 · Cited by 40
“Although glycine may be the dominant coagonist in cerebellum (Schell et al., 1997), strong consensus indicates that D-serine is the major endogenous NMDA receptor coagonist in other brain regions examined (Brugger et al., 1990; Mothet et al., 2000; Billups and Attwell, 2003; Boehning and Snyder,…”
Background
D‐serine signalling as a prominent determinant of neuronal‐glial dialogue in the healthy and diseased brain
Billard, J. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00315.x · Cited by 46
“Because D-serine also concentrates in closed vicinity of these receptors in forebrain regions [28] and that D-[(3)H]serine selectively labels the glycine-binding site of NMDA-R, the amino acid was rapidly regarded as a putative endogenous ligand of the receptors in brain areas particularly involved in cognitive proces…”
Background
Modulation of NMDA receptors in the cerebellum. II. Signaling pathways and physiological modulators regulating NMDA receptor function
Sánchez‐Pérez, A. M., Llansola, M., Cauli, O., & Felipo, V. (2005) · The Cerebellum · doi:10.1080/14734220510008003 · Cited by 37
“Schell et al. ( 34 ) showed that, in cerebellum, D-serine levels during postnatal week 164 A. Sanchez-Perez et al.”
BackgroundInfluential
Spinal N-methyl-D-aspartate receptors and nociception-evoked release of primary afferent substance P.
Nazarian, A., Gu, G., Gracias, N. G., Wilkinson, K., Hua, X., Vasko, M., & Yaksh, T. L. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2007.11.037 · Cited by 41
Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics
de Bartolomeis, A., Vellucci, L., Austin, M. C., Simone, G. D., & Barone, A. (2022) · Biomolecules · doi:10.3390/biom12070909 · Cited by 43
Gliotransmission of D-serine promotes thirst-directed behaviors in Drosophila
Park, A., Croset, V., Otto, N., Agarwal, D., Treiber, C., Meschi, E., Sims, D., & Waddell, S. (2022) · bioRxiv · doi:10.1101/2022.03.07.483255 · Cited by 40
Contribution of endogenous glycine and d-serine to excitotoxic and ischemic cell death in rat cerebrocortical slice cultures.
Katsuki, H., Watanabe, Y., Fujimoto, S., Kume, T., & Akaike, A. (2007) · Life Science · doi:10.1016/j.lfs.2007.07.001 · Cited by 40
Müller Glia in Retinal Development: From Specification to Circuit Integration
Tworig, J. M., & Feller, M. B. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.815923 · Cited by 52
Inhibition of d-Amino-Acid Oxidase Activity Induces Pain Relief in Mice
Zhao, W.-J., Konno, R., Zhou, X.-J., Yin, M., & Wang, Y.-X. (2008) · Cellular and molecular neurobiology · doi:10.1007/s10571-007-9200-y · Cited by 39
“D-Serine, on the other hand, was confined to the forebrain of mammals, with a high concentration in protoplasmic astrocytes, a subtype of glia cells that closely apposed NMDA synapses (Hashimoto et al. 1993b; Schell et al. 1995; Schell et al. 1997 ).”
Background
A role for the protein phosphatase 2B in altered hippocampal synaptic plasticity in the aged rat
Jouvenceau, A., & Dutar, P. (2006) · Journal of Physiology-Paris · doi:10.1016/j.jphysparis.2005.12.009 · Cited by 35
Variations of l- and d-amino acid levels in the brain of wild-type and mutant mice lacking d-amino acid oxidase activity
Du, S., Wang, Y., Weatherly, C. A., Holden, K. I., & Armstrong, D. W. (2018) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-018-0979-9 · Cited by 45
Glycine transport inhibitors as potential antipsychotic drugs
Aubrey, K. R., & Vandenberg, R. J. (2001) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.5.4.507 · Cited by 36
“D-serine is synthesised by serine racemase in glial cells and release may be stimulated by kainate receptor activation [60].”
Background
d-Serine in the aging hippocampus
Billard, J. (2015) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2015.02.013 · Cited by 41
Spinal sigma-1 receptor activation increases the production of d-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain
Moon, J.-Y., Choi, S., Roh, D., Yoon, S. Y., Kwon, S. G., Choi, H., Kang, S.-Y., Han, H. J., Kim, H., Beitz, A. J., et al. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.08.019 · Cited by 38
“of the neuropil known to surround the dendrites and spines of neurons [16,17].”
d-Serine diffusion through the blood–brain barrier: Effect on d-serine compartmentalization and storage
Pernot, P., Maucler, C., Tholance, Y., Vasylieva, N., Debilly, G., Pollegioni, L., Cespuglio, R., & Marinesco, S. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.03.008 · Cited by 40
Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules.
Hopkins, S., Heffernan, M. L. R., Saraswat, L. D., Bowen, C., Melnick, L., Hardy, L., Orsini, M., Allen, M. S., Koch, P., Spear, K. L., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4002583 · Cited by 36
Modulation of NMDA receptor function by inhibition of d-amino acid oxidase in rodent brain
Strick, C. A., Li, C., Scott, L., Harvey, B., Hajós, M., Steyn, S. J., Piotrowski, M. A., James, L. C., Downs, J. T., Rago, B., et al. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.06.029 · Cited by 42
“, 1996), but their different distribution patterns across the brain (Schell et al., 1997) suggest”
Background
D-serine: a new word in the glutamatergic neuro-glial language
Scolari, M., & Acosta, G. B. (2007) · Amino Acids · doi:10.1007/s00726-006-0481-0 · Cited by 36
“In the adult stage, the highest level of this D-aac is in the forebrain, while in neonates it is found in the cerebellum ( Schell et al., 1995, 1997 ).”
BackgroundInfluential
Glutamate Receptor Ion Channels: Activators and Inhibitors
Jane, D. E., Tse, H., Skifter, D. A., Christie, J. M., & Monaghan, D. T. (2000) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-57083-4_17 · Cited by 22
d ‐amino acid oxidase knockout ( Dao −/− ) mice show enhanced short‐term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption
Pritchett, D., Hasan, S., Tam, S. K. E., Engle, S. J., Brandon, N. J., Sharp, T., Foster, F., Harrison, P. J., Bannerman, D. M., & Peirson, S. N. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12880 · Cited by 34
“Hence, DAO is able to influence NMDAR function by regulating the availability of D-serine within synapses (Schell et al., 1997; Mothet et al., 2000; Almond et al., 2006; Panatier et al., 2006).”
Effects of D-cycloserine, a positive modulator of N-methyl-D-aspartate receptors, and ST 587, a putative alpha-1 adrenergic agonist, individually and in combination, on the non-delayed and delayed foraging behaviour of rats assessed in the radial arm maze
Pussinen, R., & Sirviö, J. (1999) · Journal of Psychopharmacology · doi:10.1177/026988119901300210 · Cited by 33
Localization of the brain-specific high-affinity l-proline transporter in cultured hippocampal neurons: molecular heterogeneity of synaptic terminals.
Crump, F. T., Fremeau, R., & Craig, A. M. (1999) · Molecular and cellular neurosciences · doi:10.1006/mcne.1998.0727 · Cited by 35
Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection
Xue, Y., Wang, C., Li, H., Du, S., Zhong, Y., Zhang, Y., Wang, S., Guo, K., Hou, X., Kang, D. D., et al. (2025) · Advanced Materials · doi:10.1002/adma.202417097 · Cited by 34
d -serine and schizophrenia: an update
Nunes, E. A., MacKenzie, E. M., Rossolatos, D., Perez-Parada, J., Baker, G. B., & Dursun, S. M. (2012) · Expert Review of Neurotherapeutics · doi:10.1586/ern.12.65 · Cited by 32
Effect of the intracerebroventricular and systemic administration of L-serine on the concentrations of D- and L-serine in several brain areas and periphery of rat.
Hashimoto, A. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03466-2 · Cited by 34
Decreased levels of free d-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice
Horio, M., Ishima, T., Fujita, Y., Inoue, R., Mori, H., & Hashimoto, K. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.02.015 · Cited by 30
Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: Implications for affective pain
Cao, H., Ren, W.-H., Zhu, M.-Y., Zhao, Z.-Q., & Zhang, Y.-Q. (2012) · Neuroscience Bulletin · doi:10.1007/s12264-012-1060-x · Cited by 33
“[41] Schell MJ, Brady RO Jr, Molliver ME, Snyder SH.”
Background
d-Serine: The right or wrong isoform?
Fuchs, S. A., Berger, R., & de Koning, T. J. (2011) · Brain Research · doi:10.1016/j.brainres.2011.05.039 · Cited by 36
“However, D-serine mimics the anatomical localization of NMDArs more precisely (Hashimoto et al., 1993b; Schell et al., 1997).”
Influential

Authors: Schell, M. J., Brady Jr., R. O., Molliver, M. E., & Snyder, S. H.
Affiliations: Johns Hopkins University (US)
ORCID: Schell, Michael J.
Snyder, Solomon H.
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
DOI: 10.1523/jneurosci.17-05-01604.1997
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: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 184 d)
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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d-Serine as a Neuromodulator: Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors

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