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Potential pathophysiological role of d-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain

  • Biological Psychiatry - Original Article
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Abstract

d-Amino acid oxidase (DAO) is a peroxisomal flavoenzyme that catalyzes oxidative deamination of a wide range of d-amino acids. Among the possible substrates of DAO in vivo, d-serine is proposed to be a neuromodulator of the N-methyl-d-aspartate (NMDA) type glutamate receptor. The gene for DAO was reported to be associated with schizophrenia. Since DAO is expected to be one of the key enzymes in the regulation of NMDA neurotransmission, the modulation of the enzyme activity is expected to be therapeutical for neuronal disorders. In search of the pathophysiological role of DAO, we analyzed the distribution of DAO mRNA and protein in the rat and human brain. In rat, the distribution of DAO mRNA was newly detected in choroid plexus (CP) epithelial cells in addition to glial cells of pons, medulla oblongata, and especially Bergmann glia of cerebellum. Moreover, to investigate how DAO expression level is altered in schizophrenia, we performed immunohistochemistry in the human brain. In agreement with the results in the rat brain, the immunoreactivity for DAO was detected in glial cells of rhombencephalon and in CP. Furthermore, higher level of DAO expression was observed in schizophrenic CP epithelial cells than that in non-schizophrenic cases. These results suggest that an increase in DAO expression in parts of the brain is involved in aberrant d-amino acid metabolism. In particular, gene expression of DAO in CP suggests that DAO may regulate d-amino acid concentration by modulating the cerebrospinal fluid and may be regarded as a potential therapeutic target for schizophrenia.

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Abbreviations

DAO:

d-Amino acid oxidase

NMDA:

N-Methyl d-aspartate

CP:

Choroid plexus

CSF:

Cerebrospinal fluid

cDNA:

Complementary DNA

dNTP:

Deoxyribonucleoside triphosphate

PBS:

Phosphate buffer saline

DIG:

Digoxigenin

MAS:

Matsunami adhesive silane

TEA:

Triethanolamine

SSC:

Saline sodium citrate

TBS-T:

Tris-buffered saline with Tween-20

NBT:

Nitroblue tetrazolium

BCIP:

5-Bromo-4-chloro-3indolyl-phosphate

ALS:

Amyotrophic lateral sclerosis

CI:

Cerebral infarction

References

  • Abou El-Magd RM, Park HK, Kawazoe T, Iwana S, Ono K, Chung SP, Miyano M, Yorita K, Sakai T, Fukui K (2009) The effect of risperidone on d-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. J Psychopharmacol (in press) doi:10.1177/0269881109102644

  • Bauer D, Hamacher K, Bröer S, Pauleit D, Palm C, Zilles K, Coenen HH, Langen KJ (2005) Preferred stereoselective brain uptake of d-serine—a modulator of glutamatergic neurotransmission. Nucl Med Biol 32:793–797. doi:10.1016/j.nucmedbio.2005.07.004

    Article  PubMed  CAS  Google Scholar 

  • Bendikov I, Nadri C, Amar S, Panizzutti R, Miranda JD, Wolosker H, Agam G (2007) A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia. Schizophr Res 90:41–51. doi:10.1016/j.schres.2006.10.010

    Article  PubMed  Google Scholar 

  • Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, Rosa PL, 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, Duijn CV, 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 USA 99:13675–13680. doi:10.1073/pnas.182412499

    Article  PubMed  CAS  Google Scholar 

  • Fukui K, Watanabe F, Shibata T, Miyake Y (1987) Molecular cloning and sequence analysis of cDNAs encoding porcine kidney d-amino acid oxidase. Biochemistry 26:3612–3618. doi:10.1021/bi00386a054

    Article  PubMed  CAS  Google Scholar 

  • Fukui K, Momoi K, Watanabe F, Miyake Y (1988) In vivo and in vitro expression of porcine d-amino acid oxidase: in vitro system for synthesis of functional enzyme. Biochemistry 27:6693–6697. doi:10.1021/bi00418a008

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1016/0014-5793(92)80397-Y

    Article  PubMed  CAS  Google Scholar 

  • 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. Arch Gen Psychiatry 60:572–576

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindström 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. doi:10.1016/j.pnpbp.2005.04.023

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1016/j.biopsych.2004.12.037

    Article  PubMed  CAS  Google Scholar 

  • Horiike K, Tojo H, Arai R, Yamano T, Nozaki M, Maeda T (1987) Localization of d-amino acid oxidase in Bergmann glial cells and astrocytes of rat cerebellum. Brain Res Bull 19:587–596. doi:10.1016/0361-9230(87)90076-1

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1016/0006-8993(94)90240-2

    Article  PubMed  CAS  Google Scholar 

  • Iwana S, Kawazoe T, Park HK, Tsuchiya K, Ono K, Yorita K, Sakai T, Kusumi T, Fukui K (2008) Chlorpromazine oligomer is a potentially active substance that inhibits human d-amino acid oxidase, product of a susceptibility gene for schizophrenia. J Enzyme Inhib Med Chem 23:901–911. doi:10.1080/14756360701745478

    Article  PubMed  CAS  Google Scholar 

  • Kawazoe T, Tsuge H, Pilone MS, Fukui K (2006) Crystal structure of human d-amino acid oxidase: context-dependent variability of the backbone conformation of the VAAGL hydrophobic stretch located at the si-face of the flavin ring. Protein Sci 15:2708–2717. doi:10.1110/ps.062421606

    Article  PubMed  CAS  Google Scholar 

  • Kawazoe T, Park HK, Iwana S, Tsuge H, Fukui K (2007a) Human d-amino acid oxidase: an update and review. Chem Rec 7:305–315. doi:10.1002/tcr.20129

    Article  PubMed  CAS  Google Scholar 

  • Kawazoe T, Tsuge H, Imagawa T, Aki K, Kuramitsu S, Fukui K (2007b) Structural basis of d-DOPA oxidation by d-amino acid oxidase: alternative pathway for dopamine biosynthesis. Biochem Biophys Res Commun 355:385–391. doi:10.1016/j.bbrc.2007.01.181

    Article  PubMed  CAS  Google Scholar 

  • Krebs HA (1935) Metabolism of amino-acids: deamination of amino-acids. Biochem J 29:1620–1644

    PubMed  CAS  Google Scholar 

  • Madeira C, Freitas ME, Vargas-Lopes C, Wolosker H, Panizzutti R (2008) Increased brain d-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr Res 101:76–83. doi:10.1016/j.schres.2008.02.002

    Article  PubMed  Google Scholar 

  • Mizushima S, Nagata S (1990) pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res 18:5322

    Article  PubMed  CAS  Google Scholar 

  • Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427–436. doi:10.1016/S0092-8674(00)81972-8

    Article  PubMed  CAS  Google Scholar 

  • Momoi K, Fukui K, Watanabe F, Miyake Y (1988) Molecular cloning and sequence analysis of cDNA encoding human kidney d-amino acid oxidase. FEBS Lett 238:180–184. doi:10.1016/0014-5793(88)80252-7

    Article  PubMed  CAS  Google Scholar 

  • Momoi K, Fukui K, Tada M, Miyake Y (1990) Gene expression of d-amino acid oxidase in rabbit kidney. J Biochem 108:406–413

    PubMed  CAS  Google Scholar 

  • Moreno S, Nardacci R, Cimini A, Cerù MP (1999) Immunocytochemical localization of d-amino acid oxidase in rat brain. J Neurocytol 28:169–185. doi:10.1023/A:1007064504007

    Article  PubMed  CAS  Google Scholar 

  • 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 USA 97:4926–4931

    Article  PubMed  CAS  Google Scholar 

  • Nathanson JA, Chun LL (1989) Immunological function of the blood-cerebrospinal fluid barrier. Proc Natl Acad Sci USA 86:1684–1688

    Article  PubMed  CAS  Google Scholar 

  • Nishikawa T (2005) Metabolism and functional roles of endogenous d-serine in mammalian brains. Biol Pharm Bull 28:1561–1565. doi:10.1248/bpb.28.1561

    Article  PubMed  CAS  Google Scholar 

  • Ohnuma T, Sakai Y, Haeshima H, Hatano T, Hanzawa R, Kida S, Shibata N, Suzuki T, Arai H (2008) Changes in plasma glycine, l-serine, and d-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry 32:1905–1912. doi:10.1016/j.pnpbp.2008.07.022

    Article  PubMed  CAS  Google Scholar 

  • Park HK, Shishido Y, Ichise-Shishido S, Kawazoe T, Ono K, Iwana S, Tomita Y, Yorita K, Sakai T, Fukui K (2006) Potential role for astroglial d-amino acid oxidase in extracellular d-serine metabolism and cytotoxicity. J Biochem 139:295–304. doi:10.1093/jb/mvj036

    Article  PubMed  CAS  Google Scholar 

  • Pollegioni L, Fukui K, Massey V (1994) Studies on the kinetic mechanism of pig kidney d-amino acid oxidase by site-directed mutagenesis of tyrosine 224 and tyrosine 228. J Biol Chem 269:31666–31673

    PubMed  CAS  Google Scholar 

  • Raibekas AA, Fukui K, Massey V (2000) Design and properties of human d-amino acid oxidase with covalently attached flavin. Proc Natl Acad Sci USA 97:3089–3093. doi:10.1073/pnas/040559597

    Article  PubMed  CAS  Google Scholar 

  • Redzic ZB, Segal MB (2004) The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Adv Drug Deliv Rev 56:1695–1716. doi:10.1016/j.addr.2004.07.005

    Article  PubMed  CAS  Google Scholar 

  • Schell MJ, Molliver ME, Snyder SH (1995) d-Serine, an endogenous synaptic modulator: Localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92:3948–3952

    Article  PubMed  CAS  Google Scholar 

  • Strazielle N, Khuth ST, Ghersi-Egea JF (2004) Detoxification systems, passive and specific transport for drugs at the blood–CSF barrier in normal and pathological situations. Adv Drug Deliv Rev 56:1717–1740. doi:10.1016/j.addr.2004.07.006

    Article  PubMed  CAS  Google Scholar 

  • Tada M, Fukui K, Momoi K, Miyake Y (1990) Cloning and expression of a cDNA encoding mouse kidney d-amino acid oxidase. Gene 90:293–297. doi:10.1016/0378-1119(90)90193-U

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1046/j.1471-4159.1997.69031286

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1016/S0006-3223(98)00279-0

    Article  PubMed  CAS  Google Scholar 

  • Urai Y, Jinnouchi O, Kwak KT, Suzue A, Nagahiro S, Fukui K (2002) Gene expression of d-amino acid oxidase in cultured rat astrocytes: regional and cell type specific expression. Neurosci Lett 324:101–104. doi:10.1016/S0304-3940(02)00184-2

    Article  PubMed  CAS  Google Scholar 

  • Verrall L, Walker M, Rawlings N, Benzel I, Kew JN, Harrison PJ, Burnet PW (2007) d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. Eur J Neurosci 26:1657–1669. doi:10.1111/j.1460-9568.2007.05769

    Article  PubMed  Google Scholar 

  • Watanabe F, Fukui K, Momoi K, Miyake Y (1988) Effect of site-specific mutagenesis of tyrosine-55, methionine-110 and histidine-217 in porcine kidney d-amino acid oxidase on its catalytic function. FEBS Lett 238:269–272. doi:10.1016/0014-5793(88)80494-0

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:v0.1016/j.biopsych.2005.03.018

    Article  PubMed  CAS  Google Scholar 

  • Yusko CS, Neims AH (1973) d-Aspartate oxidase in mammalian brain and choroid plexus. J Neurochem 21:1037–1039. doi:10.1111/j.1471-4159.1973.tb07555

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan. Human tissue samples were obtained from the Research Resource Network and Tokushima University Hospital. We wish to thank Dr M. Shono (Division of Biomedical Technology, Support Center for Advanced Medical Sciences, The University of Tokushima) for the assistance with the microscopy and helpful comments.

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Authors and Affiliations

  1. Division of Enzyme Pathophysiology, The Institute for Enzyme Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan

    Koji Ono, Yuji Shishido, Hwan Ki Park, Tomoya Kawazoe, Sanae Iwana, Seong Pil Chung, Rabab M. Abou El-Magd, Kazuko Yorita, Mai Okano, Takashi Sakai & Kiyoshi Fukui

  2. Otsuka Pharmaceutical Co. Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan

    Mai Okano & Takeshi Watanabe

  3. Department of Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    Nobuya Sano & Yoshimi Bando

  4. Department of Psychiatry, National Center Hospital of Neurology and Psychiatry, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8551, Japan

    Kunimasa Arima

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  1. Koji Ono
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  2. Yuji Shishido
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  3. Hwan Ki Park
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  9. Mai Okano
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  13. Kunimasa Arima
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  15. Kiyoshi Fukui
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Correspondence to Kiyoshi Fukui.

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Ono, K., Shishido, Y., Park, H.K. et al. Potential pathophysiological role of d-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain. J Neural Transm 116, 1335–1347 (2009). https://doi.org/10.1007/s00702-009-0289-7

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  • DOI: https://doi.org/10.1007/s00702-009-0289-7

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