The neurobiology of D-amino acid oxidase and its involvement in schizophrenia

D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain D-amino acids, notably the endogenous N-methyl D-aspartate receptor (NMDAR) co-agonist, D-serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than D-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia?

[1]  H. Baba,et al.  Association analysis of glycine- and serine-related genes in a Japanese population of patients with schizophrenia , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[2]  S. Oliet,et al.  Regulation of N-methyl-d-aspartate receptors by astrocytic d-serine , 2009, Neuroscience.

[3]  R. Panizzutti,et al.  Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity* , 2005, Journal of Biological Chemistry.

[4]  M. Schell.  The N-methyl D-aspartate receptor glycine site and D-serine metabolism: an evolutionary perspective. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[5]  Seong Pil Chung,et al.  The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia , 2010, Journal of psychopharmacology.

[6]  T. Ozawa,et al.  Inhibitory Action of Chlorpromazine on the Oxidation of D-Amino-Acid in the Diencephalon Part of the Brain , 1956, Nature.

[7]  G. He,et al.  Association of DAAO with schizophrenia in the Chinese population , 2004, Neuroscience Letters.

[8]  T. Nishikawa,et al.  Endogenous d‐Serine in Rat Brain: N‐Methyl‐d‐Aspartate Receptor‐Related Distribution and Aging , 1993, Journal of neurochemistry.

[9]  Yuko Fujita,et al.  Effects of D-amino acid oxidase inhibitor on the extracellular D-alanine levels and the efficacy of D-alanine on dizocilpine-induced prepulse inhibition deficits in mice , 2009 .

[10]  Paul J. Harrison,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Genes for Schizophrenia? Recent Findings and Their Pathophysiological Implications , 2022 .

[11]  T. Sakai,et al.  Potential role for astroglial D-amino acid oxidase in extracellular D-serine metabolism and cytotoxicity. , 2006, Journal of biochemistry.

[12]  T. Nishikawa,et al.  Free d-serine in post-mortem brains and spinal cords of individuals with and without neuropsychiatric diseases , 1995, Brain Research.

[13]  A. Morikawa,et al.  Determination of minute amounts of D-leucine in various brain regions of rat and mouse using column-switching high-performance liquid chromatography. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[14]  Solomon H. Snyder,et al.  D-Amino Acids as Putative Neurotransmitters: Focus on D-Serine , 2000, Neurochemical Research.

[15]  Marie-Odile Krebs,et al.  The Role of the Cerebellum in Schizophrenia: an Update of Clinical, Cognitive, and Functional Evidences , 2007, Schizophrenia bulletin.

[16]  L. Pollegioni,et al.  pLG72 Modulates Intracellular D-Serine Levels through Its Interaction with D-Amino Acid Oxidase , 2008, Journal of Biological Chemistry.

[17]  T. Hicks,et al.  Effect of the glycine modulatory site of the N-methyl-d-aspartate receptor on synaptic responses in kitten visual cortex , 2001, Neuroscience Letters.

[18]  J. Konvalinka,et al.  Dual substrate and reaction specificity in mouse serine racemase: identification of high-affinity dicarboxylate substrate and inhibitors and analysis of the beta-eliminase activity. , 2005, Biochemistry.

[19]  M. Gill,et al.  d-Amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia , 2007, Neuroscience Letters.

[20]  M. Furuse,et al.  Intracerebroventricular injection of L-proline and D-proline induces sedative and hypnotic effects by different mechanisms under an acute stressful condition in chicks , 2008, Amino Acids.

[21]  Y. Sakai,et al.  Physiological role of the D‐amino acid oxidase gene, DAO1, in carbon and nitrogen metabolism in the methylotrophic yeast Candida boidinii , 2000, Yeast.

[22]  B. Pouzet,et al.  Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine , 2004, Neuropsychopharmacology.

[23]  I. Weiner,et al.  Modulators of the glycine site on NMDA receptors, d-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia , 2005, Psychopharmacology.

[24]  K. Hashimoto,et al.  d-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats , 2008, Behavioural Brain Research.

[25]  Herman Wolosker,et al.  d‐Amino acids in the brain: d‐serine in neurotransmission and neurodegeneration , 2008, The FEBS journal.

[26]  R. Nardacci,et al.  Immunocytochemical localization of d-amino acid oxidase in rat brain , 1999, Journal of neurocytology.

[27]  H. Tojo,et al.  Immunochemical relationship of D-amino acid oxidases in various tissues and animals. , 1991, Comparative biochemistry and physiology. B, Comparative biochemistry.

[28]  Charles R. Yang,et al.  Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. , 2003, Journal of neurophysiology.

[29]  R. Konno.  Rat D-amino-acid oxidase cDNA: rat D-amino-acid oxidase as an intermediate form between mouse and other mammalian D-amino-acid oxidases. , 1998, Biochimica et biophysica acta.

[30]  M. Tada,et al.  Gene expression of D-amino acid oxidase in rabbit kidney. , 1990, Journal of Biochemistry (Tokyo).

[31]  T. Nishikawa,et al.  Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat. , 1994, The Journal of pharmacology and experimental therapeutics.

[32]  D. Heck,et al.  Cerebellar modulation of frontal cortex dopamine efflux in mice: Relevance to autism and schizophrenia , 2008, Synapse.

[33]  H. Gomi,et al.  Antioxidant enzymes in the brain of zitter rats: abnormal metabolism of oxygen species and its relevance to pathogenic changes in the brain of zitter rats with genetic spongiform encephalopathy , 1994, Brain Research.

[34]  F. Carone,et al.  The nature of D-serine--induced nephrotoxicity. , 1974, The American journal of pathology.

[35]  J. Meador-Woodruff,et al.  NMDA receptors and schizophrenia. , 2007, Current opinion in pharmacology.

[36]  M. Zehl,et al.  Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane , 2009, Proceedings of the National Academy of Sciences.

[37]  A. Neidle,et al.  The origin and turnover of D-serine in brain. , 1997, Biochemical and biophysical research communications.

[38]  M. Gill,et al.  Evidence for association and epistasis at the DAOA/G30 and D‐amino acid oxidase loci in an Irish schizophrenia sample , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[39]  M. Karayiorgou,et al.  Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function , 2008, Molecular Psychiatry.

[40]  S H Snyder,et al.  Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Jason M. Lawrence,et al.  Evidence from gene knockout studies implicates Asc‐1 as the primary transporter mediating d‐serine reuptake in the mouse CNS , 2007, The European journal of neuroscience.

[42]  K. Hamase,et al.  Determination of D-alanine in the rat central nervous system and periphery using column-switching high-performance liquid chromatography. , 2003, Analytical biochemistry.

[43]  H. Beck,et al.  Behavioral changes in G72/G30 transgenic mice , 2009, European Neuropsychopharmacology.

[44]  A. Hashimoto,et al.  Mice lacking d-amino acid oxidase activity display marked attenuation of stereotypy and ataxia induced by MK-801 , 2005, Brain Research.

[45]  A. Carlsson,et al.  Glycine and D-serine decrease MK-801-induced hyperactivity in mice , 2005, Journal of Neural Transmission.

[46]  Yue-Cune Chang,et al.  D-Alanine Added to Antipsychotics for the Treatment of Schizophrenia , 2006, Biological Psychiatry.

[47]  G. Leipnitz,et al.  D-Serine induces lipid and protein oxidative damage and decreases glutathione levels in brain cortex of rats , 2009, Brain Research.

[48]  L. Pollegioni,et al.  Physiological functions of D-amino acid oxidases: from yeast to humans , 2007, Cellular and Molecular Life Sciences.

[49]  C. Palm,et al.  Preferred stereoselective brain uptake of d-serine--a modulator of glutamatergic neurotransmission. , 2005, Nuclear medicine and biology.

[50]  R. Gibbs,et al.  Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Yongxiang Zhang,et al.  d-Serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8 , 2005, Neuroscience Letters.

[52]  R. Huganir,et al.  Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. , 2005, American journal of human genetics.

[53]  A. Morikawa,et al.  Determination of free D-proline and D-leucine in the brains of mutant mice lacking D-amino acid oxidase activity. , 2001, Analytical biochemistry.

[54]  Daniel C Javitt,et al.  Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. , 2007, International review of neurobiology.

[55]  V. Haroutunian,et al.  Serine racemase protein expression in cortex and hippocampus in schizophrenia , 2006, Neuroreport.

[56]  R. Konno,et al.  Amino acid levels in D-alanine-administered mutant mice lacking D-amino acid oxidase. , 1994, Metabolism: clinical and experimental.

[57]  Yuko Fujita,et al.  Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine , 2009, Biological Psychiatry.

[58]  U. Sonnewald,et al.  Glutamine uptake and expression of mRNA’s of glutamine transporting proteins in mouse cerebellar and cerebral cortical astrocytes and neurons , 2004, Neurochemistry International.

[59]  A. Ortega,et al.  Glutamate stimulates [3H]phorbol 12,13-dibutyrate binding in cultured Bergmann glia cells. , 1993, European journal of pharmacology.

[60]  H. Tojo,et al.  Localization of D-amino acid oxidase in Bergmann glial cells and astrocytes of rat cerebellum , 1987, Brain Research Bulletin.

[61]  S. Noda,et al.  The serine racemase mRNA is predominantly expressed in rat brain neurons. , 2007, Archives of histology and cytology.

[62]  K. Hashimoto,et al.  Increased Levels of Glutamate in Brains from Patients with Mood Disorders , 2007, Biological Psychiatry.

[63]  M. Didriksen,et al.  Positive modulation of glutamatergic receptors potentiates the suppressive effects of antipsychotics on conditioned avoidance responding in rats , 2006, Pharmacology Biochemistry and Behavior.

[64]  J. Lieberman,et al.  Cortical Bcl-2 protein expression and apoptotic regulation in schizophrenia , 2000, Biological Psychiatry.

[65]  James M. Stone,et al.  Review: Glutamate and dopamine dysregulation in schizophrenia — a synthesis and selective review , 2007, Journal of psychopharmacology.

[66]  A. Belger,et al.  NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development , 2003, Psychopharmacology.

[67]  R. Panizzutti,et al.  A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia , 2007, Schizophrenia Research.

[68]  T. Hashimoto,et al.  Immunocytochemical localization of D-amino acid oxidase in the central clear matrix of rat kidney peroxisomes. , 1986, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[69]  SUBCELLULAR DISTRIBUTION OF d‐AMINO ACID OXIDASE AND CATALASE IN RAT BRAIN , 1976, Journal of neurochemistry.

[70]  S. Snyder,et al.  d-Serine as a Neuromodulator: Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors , 1997, The Journal of Neuroscience.

[71]  A. Morikawa,et al.  Determination of free D-aspartic acid, D-serine and D-alanine in the brain of mutant mice lacking D-amino acid oxidase activity. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[72]  H. Herzog,et al.  Preferred Stereoselective Transport of the D-isomer of cis-4-[18F]fluoro-proline at the Blood–Brain Barrier , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[73]  S. Cichon,et al.  Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder , 2004, Molecular Psychiatry.

[74]  K. Hashimoto,et al.  Synthesis and biological evaluation of D-amino acid oxidase inhibitors. , 2008, Journal of medicinal chemistry.

[75]  J. Andreesen,et al.  Evidence for the functional importance of Cys298 in D-amino acid oxidase from Trigonopsis variabilis. , 1993, European journal of biochemistry.

[76]  C. Anderson,et al.  Cellular distribution of the neutral amino acid transporter subtype ASCT2 in mouse brain , 2009, Journal of neurochemistry.

[77]  Charles R. Yang,et al.  Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. , 2008, Pharmacology & therapeutics.

[78]  T. Shinkai,et al.  Association analyses of the DAOA/G30 and d-amino-acid oxidase genes in schizophrenia: Further evidence for a role in schizophrenia , 2007, NeuroMolecular Medicine.

[79]  Sachio Takashima,et al.  Embryonic Development and Postnatal Changes in Free d‐Aspartate and d‐Serine in the Human Prefrontal Cortex , 1993, Journal of neurochemistry.

[80]  S. Faraone,et al.  No association of G72 and d-amino acid oxidase genes with schizophrenia , 2006, Schizophrenia Research.

[81]  B. Kee,et al.  Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site , 2007, European Archives of Psychiatry and Clinical Neuroscience.

[82]  Michael Williams.  Commentary: genome-based CNS drug discovery: D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges. , 2009, Biochemical pharmacology.

[83]  G. Fisher,et al.  Free D-aspartate and D-alanine in normal and Alzheimer brain , 1991, Brain Research Bulletin.

[84]  G. Rubin,et al.  Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[85]  Sarah L. Huszar,et al.  The Behavioral and Neurochemical Effects of a Novel d-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and d-Serine , 2008, Journal of Pharmacology and Experimental Therapeutics.

[86]  D. Lancet,et al.  Is the G72/G30 locus associated with schizophrenia? single nucleotide polymorphisms, haplotypes, and gene expression analysis , 2004, Biological Psychiatry.

[87]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[88]  W. Ju,et al.  Glycine binding primes NMDA receptor internalization , 2003, Nature.

[89]  J. Roder,et al.  Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice. , 2008, Learning & memory (Cold Spring Harbor, N.Y.).

[90]  S. Silbernagl,et al.  Why is D-serine nephrotoxic and alpha-aminoisobutyric acid protective? , 2007, American journal of physiology. Renal physiology.

[91]  H. Tojo,et al.  d-Amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes , 1994, Brain Research.

[92]  Y. Miyake,et al.  Molecular cloning and sequence analysis of cDNAs encoding porcine kidney D-amino acid oxidase. , 1987, Biochemistry.

[93]  L. Helboe,et al.  Distribution and pharmacology of alanine–serine–cysteine transporter 1 (asc‐1) in rodent brain , 2003, The European journal of neuroscience.

[94]  R. Panizzutti,et al.  Increased brain d-amino acid oxidase (DAAO) activity in schizophrenia , 2008, Schizophrenia Research.

[95]  Y. Miyake,et al.  Molecular cloning and sequence analysis of cDNA encoding human kidney D‐amino acid oxidase , 1988, FEBS letters.

[96]  Zhongming Zhao,et al.  Candidate genes for schizophrenia: A survey of association studies and gene ranking , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[97]  L. Pollegioni,et al.  Studies on the structural and functional aspects of Rhodotorula gracilis D-amino acid oxidase by limited trypsinolysis. , 1995, The Biochemical journal.

[98]  Paul J. Harrison,et al.  d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia , 2007, The European journal of neuroscience.

[99]  R. Konno,et al.  The presence of free D-alanine, D-proline and D-serine in mice. , 1992, Biochimica et biophysica acta.

[100]  J. Billard,et al.  Age‐related effects of the neuromodulator d‐serine on neurotransmission and synaptic potentiation in the CA1 hippocampal area of the rat , 2006, Journal of neurochemistry.

[101]  Robert Freedman,et al.  Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia , 2004, Psychopharmacology.

[102]  T. Nishikawa,et al.  Free d-serine, d-aspartate and d-alanine in central nervous system and serum in mutant mice lacking d-amino acid oxidase , 1993, Neuroscience Letters.

[103]  Yue-chun Shen,et al.  Transfection of the DAAO gene and subsequent induction of cytotoxic oxidative stress by D-alanine in 9L cells. , 2008, Oncology reports.

[104]  S. Snyder,et al.  d-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[105]  P. Sham,et al.  Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[106]  R. T. Briggs,et al.  Localization of D-amino acid oxidase on the cell surface of human polymorphonuclear leukocytes , 1978, The Journal of cell biology.

[107]  R. Panizzutti,et al.  Glial transport of the neuromodulator d-serine , 2002, Brain Research.

[108]  Y. Kitamura,et al.  d-Serine content and d-[3H]serine binding in the brain regions of the senescence-accelerated mouse , 1998, Mechanisms of Ageing and Development.

[109]  Bita Moghaddam,et al.  Bringing Order to the Glutamate Chaos in Schizophrenia , 2003, Neuron.

[110]  J. Coyle,et al.  Ionotropic glutamate receptors as therapeutic targets in schizophrenia. , 2002, Current drug targets. CNS and neurological disorders.

[111]  T. Kurokawa,et al.  Early appearance of abnormality of microperoxisomal enzymes in the cerebral cortex of senescence-accelerated mouse , 1996, Mechanisms of Ageing and Development.

[112]  P. Wood,et al.  Glycine, glycinamide and d-serine act as positive modulators of signal transduction at the N-Methyl-D-Aspartate (NMDA) receptor in vivo : Differential effects on mouse cerebellar cyclic guanosine monophosphate levels , 1990, Neuropharmacology.

[113]  G. Fisher,et al.  Free d-serine concentration in normal and Alzheimer human brain , 1995, Brain Research Bulletin.

[114]  H. Krebs.  Metabolism of amino-acids: Deamination of amino-acids. , 1935, The Biochemical journal.

[115]  S. Silbernagl,et al.  Why is D-serine nephrotoxic and α-aminoisobutyric acid protective? , 2007 .

[116]  John P A Ioannidis,et al.  Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database , 2008, Nature Genetics.

[117]  J. Olney,et al.  Glutamate receptor dysfunction and schizophrenia. , 1995, Archives of general psychiatry.

[118]  J. Libiger,et al.  D-serine serum levels in patients with schizophrenia: relation to psychopathology and comparison to healthy subjects. , 2008, Neuro endocrinology letters.

[119]  Paul J. Harrison,et al.  Review: The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia , 2008, Journal of psychopharmacology.

[120]  C. Levenes,et al.  NMDA Receptor Contribution to the Climbing Fiber Response in the Adult Mouse Purkinje Cell , 2007, The Journal of Neuroscience.

[121]  Robert F. Miller,et al.  Endogenous D-serine contributes to NMDA-receptor-mediated light-evoked responses in the vertebrate retina. , 2007, Journal of neurophysiology.

[122]  L. Pollegioni,et al.  Characterization of human d‐amino acid oxidase , 2006, FEBS letters.

[123]  A. Akaike,et al.  Endogenous d-Serine Is Involved in Induction of Neuronal Death by N-Methyl-d-aspartate and Simulated Ischemia in Rat Cerebrocortical Slices , 2004, Journal of Pharmacology and Experimental Therapeutics.

[124]  A. Hashimoto,et al.  Effect of systemic administration of D-serine on the levels of D- and L-serine in several brain areas and periphery of rat. , 2004, European journal of pharmacology.

[125]  Paul J. Harrison,et al.  D-Amino acid oxidase activity and expression are increased in schizophrenia , 2008, Molecular Psychiatry.

[126]  A. Akaike,et al.  Contribution of endogenous glycine site NMDA agonists to excitotoxic retinal damage in vivo , 2006, Neuroscience Research.

[127]  R. Burke,et al.  The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia , 2006, Molecular Psychiatry.

[128]  Elena Kartvelishvily,et al.  Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors* , 2006, Journal of Biological Chemistry.

[129]  K. Hashimoto,et al.  Reduced d-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[130]  Paul J. Harrison,et al.  Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia , 2008, Schizophrenia Research.

[131]  K. F. Shad.  Effect of d-serine on the serotonin receptors of human platelets , 2006, Experimental Brain Research.

[132]  R. Ji,et al.  Is endogenous d‐serine in the rostral anterior cingulate cortex necessary for pain‐related negative affect? , 2006, Journal of neurochemistry.

[133]  T. Hyde,et al.  Neuropathology of the cerebellum in schizophrenia—An update: 1996 and future directions , 1997, Biological Psychiatry.

[134]  E. Lock,et al.  Sodium benzoate attenuates D-serine induced nephrotoxicity in the rat. , 2005, Toxicology.

[135]  Paul J. Harrison,et al.  Catechol-o-Methyltransferase, Cognition, and Psychosis: Val158Met and Beyond , 2006, Biological Psychiatry.

[136]  J. Tiihonen,et al.  Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis , 2005, Schizophrenia Research.

[137]  Richard Coppola,et al.  The G72/G30 Gene Complex and Cognitive Abnormalities in Schizophrenia , 2006, Neuropsychopharmacology.

[138]  S. Venkatraman,et al.  The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[139]  Robert F. Miller,et al.  D‐Serine as a glial modulator of nerve cells , 2004, Glia.

[140]  M. Martina,et al.  Role of the glycine site of the N‐methyl‐d‐aspartate receptor in synaptic plasticity induced by pairing , 2005, The European journal of neuroscience.

[141]  S. Snyder,et al.  Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition , 2009, Proceedings of the National Academy of Sciences.

[142]  Elliot S. Gershon,et al.  Genetic associations with schizophrenia: Meta-analyses of 12 candidate genes , 2008, Schizophrenia Research.

[143]  Yasushi Kobayashi,et al.  High affinity d- and l-serine transporter Asc-1: cloning and dendritic localization in the rat cerebral and cerebellar cortices , 2004, Neuroscience Letters.

[144]  W. Banks,et al.  Leucine Modulates Peptide Transport System‐1 Across the Blood‐brain Barrier at a Stereospecific Site within the Central Nervous System , 1991, The Journal of pharmacy and pharmacology.

[145]  T. Nishikawa,et al.  Inhibition of d‐serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3′‐phosphoadenosine 5′‐phosphosulfate transporter gene isolated from the neocortex as d‐serine modulator‐1 , 2006, Journal of neurochemistry.

[146]  M. Tada,et al.  Cloning and expression of a cDNA encoding mouse kidney D-amino acid oxidase. , 1990, Gene.

[147]  V. Kapoor,et al.  Preliminary evidence for a link between schizophrenia and NMDA–glycine site receptor ligand metabolic enzymes, d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT-1) , 2006, Brain Research.

[148]  Y. Miyake,et al.  Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. , 1992, The Journal of biological chemistry.

[149]  B. Curti,et al.  Immunochemical properties of D-amino-acid oxidase. , 1987, Biochimica et biophysica acta.

[150]  Hiroto Takahashi,et al.  Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits , 2002, Nature.

[151]  A. Hashimoto,et al.  MK-801 upregulates the expression of d-amino acid oxidase mRNA in rat brain. , 2004, Brain research. Molecular brain research.

[152]  R. Konno,et al.  Mouse mutant deficient in D-amino acid oxidase activity. , 1983, Genetics.

[153]  H. Matsumoto,et al.  Effects of MK-801 on the expression of serine racemase and d-amino acid oxidase mRNAs and on the D-serine levels in rat brain. , 2007, European journal of pharmacology.

[154]  Xing-zu Zhu,et al.  Spatiotemporal relationships among D-serine, serine racemase, and D-amino acid oxidase during mouse postnatal development. , 2003, Acta pharmacologica Sinica.

[155]  C. Anderson,et al.  Functional and immunocytochemical characterization of D‐serine transporters in cortical neuron and astrocyte cultures , 2009, Journal of neuroscience research.

[156]  M. Perotti,et al.  Immunoelectron microscopic localization of D-amino acid oxidase in rat kidney and liver. , 1987, The Histochemical journal.

[157]  D. Linden,et al.  D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[158]  S. Morimoto,et al.  Isolation of peroxisomes from the dog kidney cortex. , 1975, Biochimica et biophysica acta.

[159]  M. Mansour,et al.  Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors. , 2009, Journal of medicinal chemistry.

[160]  L. Pollegioni,et al.  Relevance of weak flavin binding in human D‐amino acid oxidase , 2009, Protein science : a publication of the Protein Society.

[161]  M. Maekawa,et al.  Spatial learning and long-term potentiation of mutant mice lacking d-amino-acid oxidase , 2005, Neuroscience Research.

[162]  H. Matsumoto,et al.  Mice lacking d-amino acid oxidase activity exhibit marked reduction of methamphetamine-induced stereotypy. , 2008, European journal of pharmacology.

[163]  R. Konno,et al.  A single-base-pair substitution abolishes D-amino-acid oxidase activity in the mouse. , 1992, Biochimica et biophysica acta.

[164]  M. Bowser,et al.  d-Serine uptake by isolated retinas is consistent with ASCT-mediated transport , 2005, Neuroscience Letters.

[165]  Elena Kartvelishvily,et al.  D-Serine Is the Dominant Endogenous Coagonist for NMDA Receptor Neurotoxicity in Organotypic Hippocampal Slices , 2005, The Journal of Neuroscience.

[166]  Paul J. Harrison,et al.  Cerebellar synaptic protein expression in schizophrenia , 2001, Neuroscience.

[167]  D. Javitt.  Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients , 2006, Current opinion in psychiatry.

[168]  S. Djurovic,et al.  DTNBP1, NRG1, DAOA, DAO and GRM3 Polymorphisms and Schizophrenia: An Association Study , 2009, Neuropsychobiology.

[169]  A. Neims,et al.  DISTRIBUTION OF d‐AMINO ACID OXIDASE IN BOVINE AND HUMAN NERVOUS TISSUES * , 1966, Journal of neurochemistry.

[170]  S. Snyder,et al.  D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[171]  L. Cavarec,et al.  In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties , 2008, European Neuropsychopharmacology.

[172]  J. Deitmer,et al.  Long‐lasting modulation of synaptic input to Purkinje neurons by Bergmann glia stimulation in rat brain slices , 2002, The Journal of physiology.

[173]  I. Wilson,et al.  D-Serine-induced nephrotoxicity: a HPLC-TOF/MS-based metabonomics approach. , 2005, Toxicology.

[174]  H. Homma,et al.  Regional distribution and postnatal changes of D-amino acids in rat brain. , 1997, Biochimica et biophysica acta.

[175]  T. Nishikawa,et al.  Cloning of a D-serine-regulated transcript dsr-1 from the rat cerebral cortex. , 2001, Biochemical and biophysical research communications.

[176]  P. Naur,et al.  Modulation of the Dimer Interface at Ionotropic Glutamate-Like Receptor δ2 by d-Serine and Extracellular Calcium , 2009, The Journal of Neuroscience.

[177]  R. Dingledine,et al.  Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. , 1988, Science.

[178]  Elliot S. Gershon,et al.  Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis , 2008, Schizophrenia Research.

[179]  M. S. Pilone,et al.  D-Amino acid oxidase: new findings , 2000, Cellular and Molecular Life Sciences CMLS.

[180]  Siobhan M. Dolan,et al.  Assessment of cumulative evidence on genetic associations: interim guidelines. , 2008, International journal of epidemiology.

[181]  Nicholas Lange,et al.  D-serine added to antipsychotics for the treatment of schizophrenia , 1998, Biological Psychiatry.

[182]  A. Bordey,et al.  Glial Glutamate Transporters Limit Spillover Activation of Presynaptic NMDA Receptors and Influence Synaptic Inhibition of Purkinje Neurons , 2004, The Journal of Neuroscience.

[183]  Donglin Bai,et al.  D-Serine inhibits AMPA receptor-mediated current in rat hippocampal neurons. , 2007, Canadian journal of physiology and pharmacology.

[184]  S. Oliet,et al.  Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory , 2006, Cell.

[185]  J. Coyle,et al.  Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis , 2006, Cellular and Molecular Neurobiology.

[186]  T. Han,et al.  Glycine binding sites of presynaptic NMDA receptors may tonically regulate glutamate release in the rat visual cortex. , 2007, Journal of neurophysiology.

[187]  C. Chiu,et al.  Behavioral and biochemical characterization of a mutant mouse strain lacking d-amino acid oxidase activity and its implications for schizophrenia , 2006, Molecular and Cellular Neuroscience.

[188]  Herman Wolosker.  D-Serine Regulation of NMDA Receptor Activity , 2006, Science's STKE.

[189]  E. Pickering,et al.  Significant Support for DAO as a Schizophrenia Susceptibility Locus: Examination of Five Genes Putatively Associated with Schizophrenia , 2007, Biological Psychiatry.

[190]  R. Barker,et al.  The genetic and biochemical properties of the D‐amino acid oxidases in human tissues , 1977, Annals of human genetics.

[191]  M. Veenhuis,et al.  The cytochemical demonstration of catalase and D-amino acid oxidase in the microbodies of teleost kidney cells , 1977, The Histochemical Journal.

[192]  Toshiyasu Suzuki,et al.  Ketamine enhances the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain. , 2006, European journal of pharmacology.

[193]  D. Goff,et al.  Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia , 2003, Annals of the New York Academy of Sciences.

[194]  S H Snyder,et al.  Novel neurotransmitters and their neuropsychiatric relevance. , 2000, The American journal of psychiatry.

[195]  S. Mosolov,et al.  Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial , 2007, Nature Medicine.

[196]  R. Dingledine,et al.  Structural requirements for activation of the glycine coagonist site of N-methyl-D-aspartate receptors expressed in Xenopus oocytes. , 1989, Molecular pharmacology.

[197]  R. Kahn,et al.  Cerebrospinal fluid d-serine and glycine concentrations are unaltered and unaffected by olanzapine therapy in male schizophrenic patients , 2008, European Neuropsychopharmacology.

[198]  J. Mothet,et al.  d-Serine signalling in the brain: friend and foe , 2006, Trends in Neurosciences.

[199]  S. Ramiro-Fuentes,et al.  Role for D-Serine within the Ventral Tegmental Area in the Development of Cocaine's Sensitization , 2008, Neuropsychopharmacology.

[200]  Bita Moghaddam,et al.  Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia , 2004, Psychopharmacology.

[201]  K. Sakata,et al.  Modulation by L- and D-isoforms of amino acids of the L-glutamate response of N-methyl-D-aspartate receptors. , 1999, Biochemistry.

[202]  V. Ganapathy,et al.  Functional and molecular analysis of D-serine transport in retinal Müller cells. , 2007, Experimental eye research.

[203]  P. Maycox,et al.  Investigation of G72 (DAOA) expression in the human brain , 2008, BMC psychiatry.

[204]  E. Hinoi,et al.  Interference with cellular differentiation by D‐serine through antagonism at N‐methyl‐D‐aspartate receptors composed of NR1 and NR3A subunits in chondrocytes , 2009, Journal of cellular physiology.

[205]  R. Sullivan,et al.  Immunocytochemical analysis of D‐serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons , 2006, Glia.

[206]  K N Sheth,et al.  Purification of serine racemase: biosynthesis of the neuromodulator D-serine. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[207]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[208]  P. Wood,et al.  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 , 1989, Journal of neurochemistry.

[209]  K. Hamase,et al.  Sensitive determination of D-amino acids in mammals and the effect of D-amino-acid oxidase activity on their amounts. , 2005, Biological & pharmaceutical bulletin.

[210]  Marzia Martina,et al.  D‐Serine differently modulates NMDA receptor function in rat CA1 hippocampal pyramidal cells and interneurons , 2003, The Journal of physiology.

[211]  K. Hamase,et al.  Determination of D-serine and D-alanine in the tissues and physiological fluids of mice with various D-amino-acid oxidase activities using two-dimensional high-performance liquid chromatography with fluorescence detection. , 2009, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[212]  N. Brandon,et al.  How has DISC1 enabled drug discovery? , 2008, Molecular and Cellular Neuroscience.

[213]  E. Holtzman,et al.  Ultrastructural localization of D-amino acid oxidase in microperoxisomes of the rat nervous system. , 1979, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[214]  V. Vallès,et al.  Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. , 2008, Journal of psychiatric research.

[215]  N. Andreasen,et al.  The Role of the Cerebellum in Schizophrenia , 2008, Biological Psychiatry.

[216]  A. Neims,et al.  THE DEVELOPMENT OF D‐AMINO ACID OXIDASE IN RAT CEREBELLUM , 1977, Journal of neurochemistry.

[217]  S. Kuramitsu,et al.  Structural basis of D-DOPA oxidation by D-amino acid oxidase: alternative pathway for dopamine biosynthesis. , 2007, Biochemical and biophysical research communications.

[218]  K. Hashimoto,et al.  Identification of Multiple Serine Racemase (SRR) mRNA Isoforms and Genetic Analyses of SRR and DAO in Schizophrenia and d-Serine Levels , 2005, Biological Psychiatry.

[219]  T. Maeda,et al.  Distribution of freed-serine in vertebrate brains , 1994, Brain Research.

[220]  K. Hamase,et al.  Sensitive high-performance liquid chromatographic assay for D-amino-acid oxidase activity in mammalian tissues using a fluorescent non-natural substrate, 5-fluoro-D-tryptophan. , 2006, Journal of chromatography. A.

[221]  Shulin Zhao,et al.  d-Amino acids in rat brain measured by liquid chromatography/tandem mass spectrometry , 2008, Neuroscience Letters.

[222]  R. Panizzutti,et al.  Neurobiology through the looking-glass: d-serine as a new glial-derived transmitter , 2002, Neurochemistry International.

[223]  J. Roder,et al.  Mutant mice with reduced NMDA-NR1 glycine affinity or lack of d-amino acid oxidase function exhibit altered anxiety-like behaviors , 2009, Pharmacology Biochemistry and Behavior.

[224]  K. Summer,et al.  D-amino-acid oxidase is involved in D-serine-induced nephrotoxicity. , 2005, Chemical research in toxicology.

[225]  J. Roder,et al.  Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. , 2009, Human molecular genetics.

[226]  Toshiyasu Suzuki,et al.  Acute treatment with morphine augments the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain. , 2005, European journal of pharmacology.

[227]  Kenji Hashimoto,et al.  Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. , 2003, Archives of general psychiatry.