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NMDA Receptor Regulation by D-serine: New Findings and Perspectives

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Abstract

The N-methyl-d-aspartate (NMDA) receptors play key roles in excitatory neurotransmission and are involved in several important processes, including learning, behavior, and synaptic plasticity. The regulation of NMDA receptor neurotransmission has been extensively studied, but many important questions still remain unsolved. One of the most debated aspects of the NMDA receptor regulation relates to the identity, role, and cellular origin of the NMDA coagonist(s). In addition to glutamate, the NMDA receptor activity was believed to be regulated by the coagonist glycine. More recently, d-serine has also been proposed to play a role as a key coagonist for NMDA receptor activity and neurotoxicity. A surprising unique biosynthetic pathway for d-serine has been demonstrated, indicating the conservation of d-amino acid metabolism in mammals. d-Serine was originally shown to be exclusively made in astrocytes, indicating a possible role as a gliotransmitter. Nevertheless, recent data indicate that d-serine has a neuronal origin as well, which raises several new questions on d-serine disposition. In this review, I discuss recent advances in the field and propose a novel model of d-serine signaling that includes a bidirectional flow of d-serine between astrocytes and neurons.

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References

  1. Danysz W, Parsons AC (1998) Glycine and N-methyl-d-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 50:597–664

    PubMed  CAS  Google Scholar 

  2. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531

    PubMed  CAS  Google Scholar 

  3. Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241:835–837

    PubMed  CAS  Google Scholar 

  4. Kessler M, Terramani T, Lynch G, Baudry M (1989) A glycine site associated with N-methyl-d-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 52:1319–1328

    PubMed  CAS  Google Scholar 

  5. Kleckner NW, Dingledine R (1989) Selectivity of quinoxalines and kynurenines as antagonists of the glycine site on N-methyl-d-aspartate receptors. Mol Pharmacol 36:430–436

    PubMed  CAS  Google Scholar 

  6. Salt TE (1989) Modulation of NMDA receptor-mediated responses by glycine and d-serine in the rat thalamus in vivo. Brain Res 481:403–406

    PubMed  CAS  Google Scholar 

  7. Wood PL, Emmett MR, Rao TS, Mick S, Cler J, Iyengar S (1989) 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. J Neurochem 53:979–981

    PubMed  CAS  Google Scholar 

  8. Thiels E, Weisz DJ, Berger TW (1992) In vivo modulation of N-methyl-d-aspartate receptor-dependent long-term potentiation by the glycine modulatory site. Neuroscience 46:501–509

    PubMed  CAS  Google Scholar 

  9. Fadda E, Danysz W, Wroblewski JT, Costa E (1988) Glycine and d-serine increase the affinity of N-methyl-d-aspartate sensitive glutamate binding sites in rat brain synaptic membranes. Neuropharmacology 27:1183–1185

    PubMed  CAS  Google Scholar 

  10. Benveniste M, Clements J, Vyklicky L Jr, Mayer ML (1990) A kinetic analysis of the modulation of N-methyl-d-aspartic acid receptors by glycine in mouse cultured hippocampal neurones. J Physiol 428:333–357

    PubMed  CAS  Google Scholar 

  11. Lerma J, Zukin RS, Bennett MV (1990) Glycine decreases desensitization of N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes and is required for NMDA responses. Proc Natl Acad Sci U S A 87:2354–2358

    PubMed  CAS  Google Scholar 

  12. Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, Salter MW (2003) Glycine binding primes NMDA receptor internalization. Nature 422:302–307

    PubMed  CAS  Google Scholar 

  13. Hashimoto A, Nishikawa T, Hayashi T, Fujii N, Harada K, Oka T, Takahashi K (1992) The presence of free d-serine in rat brain. FEBS Lett 296:33–36

    PubMed  CAS  Google Scholar 

  14. Wolosker H, Blackshaw S, Snyder SH (1999) Serine racemase: a glial enzyme synthesizing d-serine to regulate glutamate-N-methyl-d-aspartate neurotransmission. Proc Natl Acad Sci U S A 96:13409–13414

    PubMed  CAS  Google Scholar 

  15. Snyder SH, Ferris CD (2000) Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry 157:1738–1751

    PubMed  CAS  Google Scholar 

  16. Wolosker H, Panizzutti R, De Miranda J (2002) Neurobiology through the looking-glass: d-serine as a new glial-derived transmitter. Neurochem Int 41:327

    PubMed  CAS  Google Scholar 

  17. Miller RF (2004) d-serine as a glial modulator of nerve cells. Glia 47:275–283

    PubMed  Google Scholar 

  18. Nishikawa T (2005) Metabolism and functional roles of endogenous d-serine in mammalian brains. Biol Pharm Bull 28:1561–1565

    PubMed  CAS  Google Scholar 

  19. Hashimoto A, Nishikawa T, Oka T, Takahashi K, Hayashi T (1992) Determination of free amino acid enantiomers in rat brain and serum by high-performance liquid chromatography after derivatization with N-tert.-butyloxycarbonyl-l-cysteine and o-phthaldialdehyde. J Chromatogr 582:41–48

    PubMed  CAS  Google Scholar 

  20. Hashimoto A, Oka T, Nishikawa T (1995) Extracellular concentration of endogenous free d-serine in the rat brain as revealed by in vivo microdialysis. Neuroscience 66:635–643

    PubMed  CAS  Google Scholar 

  21. Ciriacks CM, Bowser MT (2004) Monitoring d-serine dynamics in the rat brain using online microdialysis-capillary electrophoresis. Anal Chem 76:6582–6587

    PubMed  CAS  Google Scholar 

  22. Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K (1995) Functional comparison of d-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J Neurochem 65:454–458

    Article  PubMed  CAS  Google Scholar 

  23. Hashimoto A, Nishikawa T, Oka T, Takahashi K (1993) Endogenous d-serine in rat brain: N-methyl-d-aspartate receptor-related distribution and aging. J Neurochem 60:783–786

    PubMed  CAS  Google Scholar 

  24. Schell MJ, Molliver ME, Snyder SH (1995) d-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A 92:3948–3952

    PubMed  CAS  Google Scholar 

  25. Schell MJ, Brady RO Jr, Molliver ME, Snyder SH (1997) d-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci 17:1604–1615

    PubMed  CAS  Google Scholar 

  26. Nedergaard M (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263:1768–1771

    PubMed  CAS  Google Scholar 

  27. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte–neuron signalling. Nature 369:744–747

    PubMed  CAS  Google Scholar 

  28. Horiike K, Tojo H, Arai R, Nozaki M, Maeda T (1994) d-amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes. Brain Res 652:297–303

    PubMed  CAS  Google Scholar 

  29. Nagata Y (1992) Involvement of d-amino acid oxidase in elimination of d-serine in mouse brain. Experientia 48:753–755

    PubMed  CAS  Google Scholar 

  30. Hashimoto A, Yoshikawa M, Niwa A, Konno R (2005) Mice lacking d-amino acid oxidase activity display marked attenuation of stereotypy and ataxia induced by MK-801. Brain Res 1033:210–215

    PubMed  CAS  Google Scholar 

  31. Kartvelishvily E, Shleper M, Balan L, Dumin E, Wolosker H (2006) Neuron-derived d-serine release provides a novel means to activate N-methyl-d-aspartate receptors. J Biol Chem 281:14151–14162

    PubMed  CAS  Google Scholar 

  32. Mothet JP, Parent AT, Wolosker H, Brady RO Jr, Linden DJ, Ferris CD, Rogawski MA, Snyder SH (2000) d-serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor. Proc Natl Acad Sci U S A 97:4926–4931

    PubMed  CAS  Google Scholar 

  33. Stevens ER, Esguerra M, Kim PM, Newman EA, Snyder SH, Zahs KR, Miller RF (2003) d-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors. Proc Natl Acad Sci U S A 100:6789–6794

    PubMed  CAS  Google Scholar 

  34. Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S (2003) Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine. Proc Natl Acad Sci U S A 100:15194–15199

    PubMed  CAS  Google Scholar 

  35. Yang S, Qiao H, Wen L, Zhou W, Zhang Y (2005) d-Serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8. Neurosci Lett 379:7–12

    PubMed  CAS  Google Scholar 

  36. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH (2006) Glia-derived d-serine controls NMDA receptor activity and synaptic memory. Cell 125:775–784

    PubMed  CAS  Google Scholar 

  37. D’Aniello A, Vetere A, Petrucelli L (1993) Further study on the specificity of d-amino acid oxidase and d-aspartate oxidase and time course for complete oxidation of d-amino acids. Comp Biochem Physiol B 105:731–734

    PubMed  CAS  Google Scholar 

  38. Shleper M, Kartvelishvily E, Wolosker H (2005) d-serine is the dominant endogenous coagonist for NMDA receptor neurotoxicity in organotypic hippocampal slices. J Neurosci 25:9413–9417

    PubMed  CAS  Google Scholar 

  39. Kim PM, Aizawa H, Kim PS, Huang AS, Wickramasinghe SR, Kashani AH, Barrow RK, Huganir RL, Ghosh A, Snyder SH (2005) Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc Natl Acad Sci U S A 102:2105–2110

    PubMed  CAS  Google Scholar 

  40. Katsuki H, Nonaka M, Shirakawa H, Kume T, Akaike A (2004) Endogenous d-serine is involved in induction of neuronal death by N-methyl-d-aspartate and simulated ischemia in rat cerebrocortical slices. J Pharmacol Exp Ther 311:836–844

    PubMed  CAS  Google Scholar 

  41. Schnackerz KD, Tai CH, Potsch RK, Cook PF (1999) Substitution of pyridoxal 5′-phosphate in d-serine dehydratase from Escherichia coli by cofactor analogues provides information on cofactor binding and catalysis. J Biol Chem 274:36935–36943

    PubMed  CAS  Google Scholar 

  42. Mothet JP, Pollegioni L, Ouanounou G, Martineau M, Fossier P, Baux G (2005) Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter d-serine. Proc Natl Acad Sci U S A 102:5606–5611

    PubMed  CAS  Google Scholar 

  43. Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic–ischemic neuronal death. Annu Rev Neurosci 13:171–182

    PubMed  CAS  Google Scholar 

  44. Furukawa H, Gouaux E (2003) Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core. EMBO J 22:2873–2885

    PubMed  CAS  Google Scholar 

  45. Berger AJ, Dieudonne S, Ascher P (1998) Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol 80:3336–3340

    PubMed  CAS  Google Scholar 

  46. Bergeron R, Meyer TM, Coyle JT, Greene RW (1998) Modulation of N-methyl-d-aspartate receptor function by glycine transport. Proc Natl Acad Sci U S A 95:15730–15734

    PubMed  CAS  Google Scholar 

  47. Chen L, Muhlhauser M, Yang CR (2003) Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 89:691–703

    PubMed  CAS  Google Scholar 

  48. Tsai G, Ralph-Williams RJ, Martina M, Bergeron R, Berger-Sweeney J, Dunham KS, Jiang Z, Caine SB, Coyle JT (2004) Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc Natl Acad Sci U S A 101:8485–8490

    PubMed  CAS  Google Scholar 

  49. Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady RO Jr, Ferris CD, Snyder SH (1999) Purification of serine racemase: biosynthesis of the neuromodulator d-serine. Proc Natl Acad Sci U S A 96:721–725

    PubMed  CAS  Google Scholar 

  50. De Miranda J, Santoro A, Engelender S, Wolosker H (2000) Human serine racemase: molecular cloning, genomic organization and functional analysis. Gene 256:183–188

    PubMed  Google Scholar 

  51. Srinivasan NG, Corrigan JJ, Meister A (1965) Biosynthesis of d-serine in the silkworm, Bombyx mori. J Biol Chem 240:796–800

    PubMed  CAS  Google Scholar 

  52. Uo T, Yoshimura T, Shimizu S, Esaki N (1998) Occurrence of pyridoxal 5′-phosphate-dependent serine racemase in silkworm, Bombyx mori. Biochem Biophys Res Commun 246:31–34

    PubMed  CAS  Google Scholar 

  53. Iwama H, Takahashi K, Kure S, Hayashi F, Narisawa K, Tada K, Mizoguchi M, Takashima S, Tomita U, Nishikawa T (1997) Depletion of cerebral d-serine in non-ketotic hyperglycinemia: possible involvement of glycine cleavage system in control of endogenous d-serine. Biochem Biophys Res Commun 231:793–796

    PubMed  CAS  Google Scholar 

  54. Dunlop DS, Neidle A (1997) The origin and turnover of d-serine in brain. Biochem Biophys Res Commun 235:26–30

    PubMed  CAS  Google Scholar 

  55. Takahashi K, Hayashi F, Nishikawa T (1997) In vivo evidence for the link between l- and d-serine metabolism in rat cerebral cortex. J Neurochem 69:1286–1290

    Article  PubMed  CAS  Google Scholar 

  56. De Miranda J, Panizzutti R, Foltyn VN, Wolosker H (2002) Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-d-aspartate (NMDA) receptor coagonist d-serine. Proc Natl Acad Sci U S A 99:14542–14547

    PubMed  Google Scholar 

  57. Cook SP, Galve-Roperh I, Martinez del Pozo A, Rodriguez-Crespo I (2002) Direct calcium binding results in activation of brain serine racemase. J Biol Chem 277:27782–27792

    PubMed  CAS  Google Scholar 

  58. Strisovsky K, Jiraskova J, Barinka C, Majer P, Rojas C, Slusher BS, Konvalinka J (2003) Mouse brain serine racemase catalyzes specific elimination of l-serine to pyruvate. FEBS Lett 535:44–48

    PubMed  CAS  Google Scholar 

  59. Foltyn VN, Bendikov I, De Miranda J, Panizzutti R, Dumin E, Shleper M, Li P, Toney MD, Kartvelishvily E, Wolosker H (2005) Serine racemase modulates intracellular d-serine levels through an alpha,beta-elimination activity. J Biol Chem 280:1754–1763

    PubMed  CAS  Google Scholar 

  60. Strisovsky K, Jiraskova J, Mikulova A, Rulisek L, Konvalinka J (2005) Dual substrate and reaction specificity in mouse serine racemase: identification of high-affinity dicarboxylate substrate and inhibitors and analysis of the beta-eliminase activity. Biochemistry 44:13091–13100

    PubMed  CAS  Google Scholar 

  61. Basu AC, Kurek JA, Han L, Jiang ZI, Tsai GE, Coyle JT (2005) Initial phenotypic characterization of serine racemase knock-out mice. Society for Neuroscience, Washington, DC, pp 1018–1021

    Google Scholar 

  62. Dumin E, Bendikov I, Foltyn VN, Misumi Y, Ikehara Y, Kartvelishvily E, Wolosker H (2006) Modulation of d-serine levels via ubiquitin-dependent proteasomal degradation of serine racemase. J Biol Chem 281:20291–20302

    PubMed  CAS  Google Scholar 

  63. Fujii K, Maeda K, Hikida T, Mustafa AK, Balkissoon R, Xia J, Yamada T, Ozeki Y, Kawahara R, Okawa M, Huganir RL, Ujike H, Snyder SH, Sawa A (2006) Serine racemase binds to PICK1: potential relevance to schizophrenia. Mol Psychiatry 11:150–157

    PubMed  CAS  Google Scholar 

  64. Konno R (2003) Rat cerebral serine racemase: amino acid deletion and truncation at carboxy terminus. Neurosci Lett 349:111–114

    PubMed  CAS  Google Scholar 

  65. Yi JJ, Ehlers MD (2005) Ubiquitin and protein turnover in synapse function. Neuron 47:629–632

    PubMed  CAS  Google Scholar 

  66. Yoshikawa M, Kobayashi T, Oka T, Kawaguchi M, Hashimoto A (2004) Distribution and MK-801-induced expression of serine racemase mRNA in rat brain by real-time quantitative PCR. Brain Res Mol Brain Res 128:90–94

    PubMed  CAS  Google Scholar 

  67. Takeyama K, Yoshikawa M, Oka T, Kawaguchi M, Suzuki T, Hashimoto A (2006) Ketamine enhances the expression of serine racemase and d-amino acid oxidase mRNAs in rat brain. Eur J Pharmacol 540:82–86

    PubMed  CAS  Google Scholar 

  68. Wu S, Barger SW (2004) Induction of serine racemase by inflammatory stimuli is dependent on AP-1. Ann N Y Acad Sci 1035:133–146

    PubMed  CAS  Google Scholar 

  69. Wu SZ, Bodles AM, Porter MM, Griffin WS, Basile AS, Barger SW (2004) Induction of serine racemase expression and d-serine release from microglia by amyloid beta-peptide. J Neuroinflammation 1:2

    PubMed  Google Scholar 

  70. Fields RD, Stevens-Graham B (2002) New insights into neuron–glia communication. Science 298:556–562

    PubMed  CAS  Google Scholar 

  71. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031

    PubMed  CAS  Google Scholar 

  72. Yasuda E, Ma N, Semba R (2001) Immunohistochemical evidences for localization and production of d-serine in some neurons in the rat brain. Neurosci Lett 299:162–164

    PubMed  CAS  Google Scholar 

  73. Puyal J, Martineau M, Mothet JP, Nicolas MT, Raymond J (2006) Changes in d-serine levels and localization during postnatal development of the rat vestibular nuclei. J Comp Neurol 497:610–621

    PubMed  CAS  Google Scholar 

  74. Williams SM, Diaz CM, Macnab LT, Sullivan RK, Pow DV (2006) Immunocytochemical analysis of d-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons. Glia 53:401–411

    PubMed  Google Scholar 

  75. Yasuda E, Ma N, Semba R (2001) Immunohistochemical demonstration of l-serine distribution in the rat brain. Neuroreport 12:1027–1030

    PubMed  CAS  Google Scholar 

  76. Furuya S, Tabata T, Mitoma J, Yamada K, Yamasaki M, Makino A, Yamamoto T, Watanabe M, Kano M, Hirabayashi Y (2000) l-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons. Proc Natl Acad Sci U S A 97:11528–11533

    PubMed  CAS  Google Scholar 

  77. Verleysdonk S, Hamprecht B (2000) Synthesis and release of l-serine by rat astroglia-rich primary cultures. Glia 30:19–26

    PubMed  CAS  Google Scholar 

  78. Furuya S, Watanabe M (2003) Novel neuroglial and glioglial relationships mediated by l-serine metabolism. Arch Histol Cytol 66:109–121

    PubMed  CAS  Google Scholar 

  79. Ciriacks CM, Bowser MT (2006) Measuring the effect of glutamate receptor agonists on extracellular d-serine concentrations in the rat striatum using online microdialysis-capillary electrophoresis. Neurosci Lett 393:200–205

    PubMed  CAS  Google Scholar 

  80. Pellegrini-Giampietro DE, Gorter JA, Bennett MV, Zukin RS (1997) The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci 20:464–470

    PubMed  CAS  Google Scholar 

  81. Dravid SM, Murray TF (2003) Fluorescent detection of Ca2+-permeable AMPA/kainate receptor activation in murine neocortical neurons. Neurosci Lett 351:145–148

    PubMed  CAS  Google Scholar 

  82. Hoyt KR, Arden SR, Aizenman E, Reynolds IJ (1998) Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons. Mol Pharmacol 53:742–749

    PubMed  CAS  Google Scholar 

  83. Fukasawa Y, Segawa H, Kim JY, Chairoungdua A, Kim DK, Matsuo H, Cha SH, Endou H, Kanai Y (2000) Identification and characterization of a Na(+)-independent neutral amino acid transporter that associates with the 4F2 heavy chain and exhibits substrate selectivity for small neutral d- and l-amino acids. J Biol Chem 275:9690–9698

    PubMed  CAS  Google Scholar 

  84. Helboe L, Egebjerg J, Moller M, Thomsen C (2003) Distribution and pharmacology of alanine–serine–cysteine transporter 1 (asc-1) in rodent brain. Eur J Neurosci 18:2227–2238

    PubMed  Google Scholar 

  85. Matsuo H, Kanai Y, Tokunaga M, Nakata T, Chairoungdua A, Ishimine H, Tsukada S, Ooigawa H, Nawashiro H, Kobayashi Y, Fukuda J, Endou H (2004) High affinity d- and l-serine transporter Asc-1: cloning and dendritic localization in the rat cerebral and cerebellar cortices. Neurosci Lett 358:123–126

    PubMed  CAS  Google Scholar 

  86. Ribeiro CS, Reis M, Panizzutti R, de Miranda J, Wolosker H (2002) Glial transport of the neuromodulator d-serine. Brain Res 929:202–209

    PubMed  CAS  Google Scholar 

  87. Kemp JA, McKernan RM (2002) NMDA receptor pathways as drug targets. Nat Neurosci 5(Suppl):1039–1042

    Google Scholar 

  88. Lipton SA (2004) Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J Alzheimer’s Dis 6:S61–S74

    CAS  Google Scholar 

  89. Dixon SM, Li P, Liu R, Wolosker H, Lam KS, Kurth MJ, Toney MD (2006) Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries. J Med Chem 49:2388–2397

    PubMed  CAS  Google Scholar 

  90. Wake K, Yamazaki H, Hanzawa S, Konno R, Sakio H, Niwa A, Hori Y (2001) Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-d-aspartate receptor-mediated synaptic transmission in mutant mice lacking d-amino-acid oxidase. Neurosci Lett 297:25–28

    PubMed  CAS  Google Scholar 

  91. Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 1003:318–327

    PubMed  CAS  Google Scholar 

  92. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    PubMed  CAS  Google Scholar 

  93. Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377

    PubMed  CAS  Google Scholar 

  94. Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427–436

    PubMed  CAS  Google Scholar 

  95. Javitt DC (2001) Management of negative symptoms of schizophrenia. Curr Psychiatry Rep 3:413–417

    PubMed  CAS  Google Scholar 

  96. Tsai G, Yang P, Chung LC, Lange N, Coyle JT (1998) d-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44:1081–1089

    PubMed  CAS  Google Scholar 

  97. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, Catinari S, Ermilov M (2005) d-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 57:577–585

    PubMed  CAS  Google Scholar 

  98. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M (2003) Decreased serum levels of d-serine in patients with schizophrenia: evidence in support of the N-methyl-d-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576

    PubMed  CAS  Google Scholar 

  99. Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M (2005) Reduced d-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 29:767–769

    PubMed  CAS  Google Scholar 

  100. Yamada K, Ohnishi T, Hashimoto K, Ohba H, Iwayama-Shigeno Y, Toyoshima M, Okuno A, Takao H, Toyota T, Minabe Y, Nakamura K, Shimizu E, Itokawa M, Mori N, Iyo M, Yoshikawa T (2005) Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and d-serine levels. Biol Psychiatry 57:1493–1503

    PubMed  CAS  Google Scholar 

  101. Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, Agam G (2006) A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia. Schizophr Res 90(1–3):41–51

    PubMed  Google Scholar 

  102. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D (2002) Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 99:13675–13680

    PubMed  CAS  Google Scholar 

  103. Mothet JP, Rouaud E, Sinet PM, Potier B, Jouvenceau A, Dutar P, Videau C, Epelbaum J, Billard JM (2006) A critical role for the glial-derived neuromodulator d-serine in the age-related deficits of cellular mechanisms of learning and memory. Aging Cell 5:267–274

    PubMed  CAS  Google Scholar 

  104. Panizzutti R, De Miranda J, Ribeiro CS, Engelender S, Wolosker H (2001) A new strategy to decrease N-methyl-d-aspartate (NMDA) receptor coactivation: inhibition of d-serine synthesis by converting serine racemase into an eliminase. Proc Natl Acad Sci U S A 98:5294–5299

    PubMed  CAS  Google Scholar 

  105. Neidle A, Dunlop DS (2002) Allosteric regulation of mouse brain serine racemase. Neurochem Res 27:1719–1724

    PubMed  CAS  Google Scholar 

  106. O’Brien KB, Bowser MT (2006) Measuring d-serine efflux from mouse cortical brain slices using online microdialysis-capillary electrophoresis. Electrophoresis 27:1949–1956

    PubMed  CAS  Google Scholar 

  107. O’Brien KB, Miller RF, Bowser MT (2005) d-Serine uptake by isolated retinas is consistent with ASCT-mediated transport. Neurosci Lett 385:58–63

    PubMed  CAS  Google Scholar 

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  1. Department of Biochemistry, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel

    Herman Wolosker

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  1. Herman Wolosker
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Correspondence to Herman Wolosker.

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This review is dedicated to the memory of Dr. Marcos Wolosker.

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Wolosker, H. NMDA Receptor Regulation by D-serine: New Findings and Perspectives. Mol Neurobiol 36, 152–164 (2007). https://doi.org/10.1007/s12035-007-0038-6

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  • DOI: https://doi.org/10.1007/s12035-007-0038-6

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