In Vivo Modulation of the <i>N</i>‐Methyl‐D‐Aspartate Receptor Complex by D‐Serine: Potentiation of Ongoing Neuronal Activity as Evidenced by Increased Cerebellar Cyclic GMP

Wood, Paul L.; Emmett, Mark R.; Rao, Tadimeti S.; Mick, Steve J.; Cler, Julie A.; Iyengar, Smriti

doi:10.1111/j.1471-4159.1989.tb11803.x

Cited by 96 publications

(40 citation statements)

References 18 publications

(29 reference statements)

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“…Beginning around P21, these glycine sites are not saturated, because the NMDA-stimulated cGMP response is enhanced by exogenous D-serine. In adult cerebellum, in vivo studies have demonstrated that the glycine site involved in nitric oxide production is not saturated (Wood et al, 1989). We find that D-serine levels in the P7-14 cerebellum are 10 -40 times higher than in adults.…”

Section: Ontogenic Roles Of D-serine In the Cerebellummentioning

confidence: 53%

“…Moreover, D-serine is about three times more potent than glycine at many "glycine sites," so lower levels of D-serine would suffice to saturate the sites. A substantial number of studies suggest that glycine sites are not always saturated, because exogenous D-serine and glycine potentiate responses to NMDA in vivo (Salt, 1989;Wood et al, 1989;Thiels et al, 1992;Schmitt et al, 1995). Moreover, pretreating intact rats with D-serine increases the potency of exogenous NMDA as a convulsant (Larson and Beitz, 1988;Singh et al, 1990).…”

Section: Ontogenic Roles Of D-serine In the Cerebellummentioning

confidence: 99%

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

Schell¹,

Brady²,

Molliver³

et al. 1997

J. Neurosci.

392

349

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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. Key words: D-serine; glycine; NMDA receptor; glia; D-amino acid; cerebellumActivation of NMDA receptor channels requires both glutamate and stimulation of a "glycine site" (Johnson and Ascher, 1987;Reynolds et al., 1987;Kemp and Leeson, 1993). Neurophysiological studies of expressed NMDA receptors indicate that with certain combinations of NR1 and NR2 subunits, D-serine is up to three times more potent than glycine at the glycine site (Matsui et al., 1995;Priestley et al., 1995). Although D-amino acids have long been known to exist in bacteria, worms, and insects (Corrigan, 1969), only very recently have high levels of D-serine been demonstrated in mammalian tissues, especially in the brain (Hashimoto et al., 1992a(Hashimoto et al., , 1993aNagata, 1992;Chouinard et al., 1993;Nagata et al., 1994).We have mapped D-serine immunohistochemically in rat brain and observed a pattern that parallels the localization of D-serine binding sites associated with NMDA receptors in the forebrain (Schell et al., 1995). D-Serine is concentrated in gray matter regions enriched in NMDA receptors and is selectively localized to protoplasmic astrocytes. We have also demonstrated that agonists of non-NMDA receptors enhance the efflux of preloaded D-serine from cultures of cortical type 2 astrocytes. These data suggest that D-serine is an endogenous ligand at the glycine site of many NMDA receptors and that glutamate releases D-serine from glial ...

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Section: Ontogenic Roles Of D-serine In the Cerebellummentioning

confidence: 53%

Section: Ontogenic Roles Of D-serine In the Cerebellummentioning

confidence: 99%

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

Schell¹,

Brady²,

Molliver³

et al. 1997

J. Neurosci.

392

349

View full text Add to dashboard Cite

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“…Furthermore, when D-serine is injected into the brain of live animals, it positively modulates NMDA receptor function (17) and ameliorates stereotypical behavioral alterations and ataxia caused by administration of the NMDA antagonist phencyclidine (18,19). These results suggest that D-serine may mitigate nervous system symptoms related to NMDA receptor hypofunction, including schizophrenia.…”

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confidence: 70%

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Yang

Wada

Yoshida

et al. 2010

Journal of Biological Chemistry

115

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In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D-serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for Dserine synthesis by generating mice with a conditional deletion of D-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L-and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that Lserine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.Glutamate is the principal excitatory neurotransmitter in mammalian brain, acting on ionotropic and metabotropic glutamate receptors. Ionotropic glutamate receptors can be divided into three classes based on their preference for the ligands N-methyl-D-aspartate (NMDA), 3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and kainate. Among these receptors, NMDA receptors have been implicated in synapse refinement, synaptic plasticity, and learning/memory as well as brain pathologies including excitotoxicity and psychiatric diseases (for review, see Refs. 1-3). Two NMDA receptor subunits, NR1 and NR2, form tetramers that comprise the functional receptors. For the NMDA receptor to function as a ligand-gated ion channel, a co-agonist must occupy the glycine modulatory site on NR1 coincident with glutamate binding to the transmitter recognition site on NR2 (4 -6).D-Serine occurs naturally in the adult brain of higher vertebrates and is particularly enriched in forebrain regions (7). This D-amino acid acts as an endogenous co-agonist at the glycine modulatory site of NMDA receptors (for review, see Refs. 8 -11). In the telencephalon, where D-serine is abundant (12), its distribution pattern resembles that of NR2A/B subunits (13). In contrast, immunoreactivity for free glycine is very low in telencephalon and is detected primarily in the hindbrain and hypothalamus, where NR2A/B expression is weaker than in ...

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“…Glycine is often called a "coagonist" with glutamate at the NMDA receptor, since occupation of the glycine site is absolutely required to gate the channel (10,21 NMDA receptors in vivo, indicating that the sites are not normally saturated (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release.

Schell

Molliver

Snyder

1995

Proc. Natl. Acad. Sci. U.S.A.

761

671

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Recently several groups have reported the existence of D-serine in serum (2), urine (3), and brain (4, 5) of mammals, including humans (6). Hashimoto et at (7) showed with biochemical techniques that the distribution of D-serine in rat brain regions parallels the distribution of N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors. This is of interest because stimulation of NMDA receptors by glutamate requires the binding of glycine (8,9), and D-serine mimics glycine at these sites (10).To ascertain whether endogenous D-serine plays a physiologic role in neurotransmission, we have developed polyclonal antibodies that are selective for D-serine. We now report a localization of D-serine throughout rat brain that closely parallels NMDA receptors and is concentrated in gray-matter astrocytes of the telencephalon. We also demonstrate that D-serine is released from type 2 astrocyte cultures stimulated with agonists of non-NMDA glutamate receptors. MATERIALS AND METHODSMaterials. D-[3H]Serine (22 Ci/mmol; 1 Ci = 37 GBq) was provided by Steven Hurt (New England Nuclear). Antibody to glial fibrillary acidic protein (GFAP) was from Dako, and antibody to glutamine synthetase was from Chemicon. Glutaraldehyde was from EM sciences. Gold chloride was from Aldrich. Alkaline phosphatase-coupled anti-rabbit antibody was from The Jackson Laboratories. The peroxidase Elite staining kit was from Vector Laboratories. Glutamate receptor drugs were from Research Biochemicals (Natick, MA). CellThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. culture reagents were from GIBCO/BRL. All other reagents were from Sigma.Preparation of Polyclonal Antiserum to D-Serine. D-Serine was coupled to bovine serum albumin (BSA) with glutaraldehyde and then reduced with NaBH4 (11). After extensive dialysis against water, the conjugate was adsorbed to freshly prepared 45-nm colloidal gold particles (12). A rabbit was immunized intradermally every 3 weeks with the BSA conjugate alone and intravenously with the gold particles. Before use, all D-serine antiserum used in this study was incubated for 2 hr at room temperature with Sepharose beads coupled to glutaraldehyde-treated BSA, to eliminate antibodies not selective for D-serine (13). Liquid-phase conjugates of various amino acids to glutaraldehyde were prepared identically to the original immunogen, except that BSA was omitted and free aldehyde groups were blocked with excess Tris. For dot blot screens, various amino acids were coupled to dialyzed rat brain cytosol with glutaraldehyde as described above for D-serine/ BSA conjugates and then spotted on nitrocellulose. After overnight incubation with the primary antiserum, blots were visualized with an alkaline phosphatase-coupled anti-rabbit secondary antibody. High-affinity stereoselective antibodies appeared after 5 months of immunization.Immunohistochemistry. Anesthetized rats (age, 45-...

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In Vivo Modulation of the N‐Methyl‐D‐Aspartate Receptor Complex by D‐Serine: Potentiation of Ongoing Neuronal Activity as Evidenced by Increased Cerebellar Cyclic GMP

Cited by 96 publications

References 18 publications

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

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

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release.

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