d-Aspartate, an Atypical Amino Acid with NMDA Receptor Agonist Features: Involvement in Schizophrenia

  • F. ErricoEmail author
  • A. UsielloEmail author
Part of the The Receptors book series (REC, volume 30)


The atypical amino acid d-aspartate is transiently present in the mammalian brain. It is abundant during embryonic phases and strongly decreases after birth, when it is catabolized by the flavoenzyme d-aspartate oxidase (DDO). Pharmacological evidence indicates that d-aspartate binds to and activates NMDA receptors (NMDARs) and occurs at extracellular level where it is released through calcium-dependent mechanism. In the last 10 years, studies on mice with non-physiological high levels of d-aspartate have revealed that this d-amino acid is able to enhance NMDAR-dependent synaptic plasticity, dendritic morphology and spatial memory during adulthood. In line with the hypothesis of a NMDAR hypofunction in the pathogenesis of schizophrenia, it has been also shown that increased d-aspartate reduces prepulse inhibition deficit induced by phencyclidine, and produces corticostriatal adaptations resembling those observed after chronic haloperidol treatment. Moreover, greater d-aspartate levels can significantly inhibit functional circuits activated by phencyclidine, and increase cortico–hippocampal connectivity networks, reported to be altered in patients with schizophrenia. Besides studies in preclinical models, it has been shown that genetic variation in DDO gene, predicting potential increase in d-aspartate levels in post-mortem prefrontal cortex, is associated with greater prefrontal gray matter and activity during working memory. Interestingly, a significant reduction of d-aspartate content has been detected in the post-mortem brain of patients with schizophrenia, associated with increased expression of DDO mRNA. Based on the agonistic role of d-aspartate on NMDARs and on its abundance during prenatal life, future studies will be crucial to address the biological significance of this molecule on developmental processes controlled by NMDARs and relevant to schizophrenia.


d-Aspartate d-Aspartate oxidase NMDA receptor Schizophrenia Synaptic plasticity Prepulse inhibition Cognition Phencyclidine 



Artificial cerebrospinal fluid


Blood oxygen level-dependent


Cornu ammonis area 1


Cerebral blood volume




d-Aspartate oxidase




Early phase long-term potentiation


Functional magnetic resonance imaging


High performance liquid chromatography






Late phase long-term potentiation


N-methyl d-aspartate


N-methyl d-aspartate receptor




Prefrontal cortex


Prepulse inhibition


  1. 1.
    Corrigan JJ. D-amino acids in animals. Science. 1969;164(876):142–9.PubMedCrossRefGoogle Scholar
  2. 2.
    D’Aniello A, Giuditta A. Identification of D-aspartic acid in the brain of Octopus vulgaris Lam. J Neurochem. 1977;29(6):1053–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Dunlop DS, Neidle A, McHale D, Dunlop DM, Lajtha A. The presence of free D-aspartic acid in rodents and man. Biochem Biophys Res Commun. 1986;141(1):27–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Hamase K, Homma H, Takigawa Y, Fukushima T, Santa T, Imai K. Regional distribution and postnatal changes of D-amino acids in rat brain. Biochim Biophys Acta. 1997;1334(2–3):214–22.PubMedCrossRefGoogle Scholar
  5. 5.
    Hashimoto A, Kumashiro S, Nishikawa T, Oka T, Takahashi K, Mito T, et al. Embryonic development and postnatal changes in free D-aspartate and D-serine in the human prefrontal cortex. J Neurochem. 1993;61(1):348–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Neidle A, Dunlop DS. Developmental changes in free D-aspartic acid in the chicken embryo and in the neonatal rat. Life Sci. 1990;46(21):1517–22.PubMedCrossRefGoogle Scholar
  7. 7.
    Hashimoto A, Oka T, Nishikawa T. Anatomical distribution and postnatal changes in endogenous free D-aspartate and D-serine in rat brain and periphery. Eur J Neurosci. 1995;7(8):1657–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Krebs HA. Metabolism of amino-acids: Deamination of amino-acids. Biochem J. 1935;29(7):1620–44.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Still JL, Buell MV, et al. Studies on the cyclophorase system; D-aspartic oxidase. J Biol Chem. 1949;179(2):831–7.PubMedGoogle Scholar
  10. 10.
    Martineau M, Baux G, Mothet JP. D-serine signalling in the brain: friend and foe. Trends Neurosci. 2006;29(8):481–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Wolosker H, Radzishevsky I. The serine shuttle between glia and neurons: implications for neurotransmission and neurodegeneration. Biochem Soc Trans. 2013;41(6):1546–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Billard JM. D-Amino acids in brain neurotransmission and synaptic plasticity. Amino Acids. 2012;43(5):1851–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Van Horn MR, Sild M, Ruthazer ES. D-serine as a gliotransmitter and its roles in brain development and disease. Front Cell Neurosci. 2013;7:39.PubMedGoogle Scholar
  14. 14.
    Kim PM, Aizawa H, Kim PS, Huang AS, Wickramasinghe SR, Kashani AH, et al. Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc Natl Acad Sci U S A. 2005;102(6):2105–10.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Mothet JP, Parent AT, Wolosker H, Brady Jr RO, Linden DJ, Ferris CD, et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 2000;97(9):4926–31.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Papouin T, Ladepeche L, Ruel J, Sacchi S, Labasque M, Hanini M, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell. 2012;150(3):633–46.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenberg D, Artoul S, Segal AC, Kolodney G, Radzishevsky I, Dikopoltsev E, et al. Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity. J Neurosci. 2013;33(8):3533–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Li Y, Sacchi S, Pollegioni L, Basu AC, Coyle JT, Bolshakov VY. Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level. Nat Commun. 2013;4:1760.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A. 2003;100(25):15194–9.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Fossat P, Turpin FR, Sacchi S, Dulong J, Shi T, Rivet JM, et al. Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. Cereb Cortex. 2012;22(3):595–606.PubMedCrossRefGoogle Scholar
  21. 21.
    Meunier CN, Dallerac G, Le Roux N, Sacchi S, Levasseur G, Amar M, et al. D-serine and glycine differentially control neurotransmission during visual cortex critical period. PLoS One. 2016;11(3):e0151233.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Hagiwara H, Iyo M, Hashimoto K. Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine. PLoS One. 2013;8(4):e62438.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, 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. Biol Psychiatry. 2009;65(12):1103–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Kanahara N, Shimizu E, Ohgake S, Fujita Y, Kohno M, Hashimoto T, et al. Glycine and D: -serine, but not D: -cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801. Psychopharmacology. 2008;198(3):363–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Matsuura A, Fujita Y, Iyo M, Hashimoto K. Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. Acta Neuropsychiatr. 2015;27(3):159–67.PubMedCrossRefGoogle Scholar
  26. 26.
    Labrie V, Duffy S, Wang W, Barger SW, Baker GB, Roder JC. Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice. Learn Mem. 2009;16(1):28–37.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    DeVito LM, Balu DT, Kanter BR, Lykken C, Basu AC, Coyle JT, et al. Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology. Genes Brain Behav. 2011;10(2):210–22.PubMedCrossRefGoogle Scholar
  28. 28.
    Basu AC, Tsai GE, Ma CL, Ehmsen JT, Mustafa AK, Han L, et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry. 2009;14(7):719–27.PubMedCrossRefGoogle Scholar
  29. 29.
    Javitt DC, Zukin SR, Heresco-Levy U, Umbricht D. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull. 2012;38(5):958–66.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Labrie V, Wong AH, Roder JC. Contributions of the D-serine pathway to schizophrenia. Neuropharmacology. 2012;62(3):1484–503.PubMedCrossRefGoogle Scholar
  31. 31.
    Coyle JT, Tsai G. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology. 2004;174(1):32–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Sakai K, Homma H, Lee JA, Fukushima T, Santa T, Tashiro K, et al. Emergence of D-aspartic acid in the differentiating neurons of the rat central nervous system. Brain Res. 1998;808(1):65–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Wolosker H, D’Aniello A, Snyder SH. D-aspartate disposition in neuronal and endocrine tissues: ontogeny, biosynthesis and release. Neuroscience. 2000;100(1):183–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Schell MJ, Cooper OB, Snyder SH. D-aspartate localizations imply neuronal and neuroendocrine roles. Proc Natl Acad Sci U S A. 1997;94(5):2013–8.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Long Z, Homma H, Lee JA, Fukushima T, Santa T, Iwatsubo T, et al. Biosynthesis of D-aspartate in mammalian cells. FEBS Lett. 1998;434(3):231–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Kim PM, Duan X, Huang AS, Liu CY, Ming GL, Song H, et al. Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis. Proc Natl Acad Sci U S A. 2010;107(7):3175–9.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Matsuda S, Katane M, Maeda K, Kaneko Y, Saitoh Y, Miyamoto T, et al. Biosynthesis of D-aspartate in mammals: the rat and human homologs of mouse aspartate racemase are not responsible for the biosynthesis of D-aspartate. Amino Acids. 2015;47(5):975–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Tanaka-Hayashi A, Hayashi S, Inoue R, Ito T, Konno K, Yoshida T, et al. Is D-aspartate produced by glutamic-oxaloacetic transaminase-1 like 1 (Got1l1): a putative aspartate racemase? Amino Acids. 2014;47(1):79–86.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Horio M, Ishima T, Fujita Y, Inoue R, Mori H, Hashimoto K. Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice. Neurochem Int. 2013;62(6):843–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Van Veldhoven PP, Brees C, Mannaerts GP. D-aspartate oxidase, a peroxisomal enzyme in liver of rat and man. Biochim Biophys Acta. 1991;1073(1):203–8.PubMedCrossRefGoogle Scholar
  41. 41.
    D’Aniello A, Vetere A, Petrucelli L. 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. 1993;105(3–4):731–4.PubMedGoogle Scholar
  42. 42.
    Setoyama C, Miura R. Structural and functional characterization of the human brain D-aspartate oxidase. J Biochem. 1997;121(4):798–803.PubMedCrossRefGoogle Scholar
  43. 43.
    Pollegioni L, Piubelli L, Sacchi S, Pilone MS, Molla G. Physiological functions of D-amino acid oxidases: from yeast to humans. Cell Mol Life Sci. 2007;64(11):1373–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Sacchi S, Caldinelli L, Cappelletti P, Pollegioni L, Molla G. Structure-function relationships in human D-amino acid oxidase. Amino Acids. 2012;43(5):1833–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Negri A, Ceciliani F, Tedeschi G, Simonic T, Ronchi S. The primary structure of the flavoprotein D-aspartate oxidase from beef kidney. J Biol Chem. 1992;267(17):11865–71.PubMedGoogle Scholar
  46. 46.
    Amery L, Brees C, Baes M, Setoyama C, Miura R, Mannaerts GP, et al. C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a functional peroxisome-targeting signal. Biochem J. 1998;336(Pt 2):367–71.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Katane M, Homma H. D-aspartate oxidase: the sole catabolic enzyme acting on free D-aspartate in mammals. Chem Biodivers. 2010;7(6):1435–49.PubMedCrossRefGoogle Scholar
  48. 48.
    Beard ME. D-aspartate oxidation by rat and bovine renal peroxisomes: an electron microscopic cytochemical study. J Histochem Cytochem. 1990;38(9):1377–81.PubMedCrossRefGoogle Scholar
  49. 49.
    Zaar K, Kost HP, Schad A, Volkl A, Baumgart E, Fahimi HD. Cellular and subcellular distribution of D-aspartate oxidase in human and rat brain. J Comp Neurol. 2002;450(3):272–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Punzo D, Errico F, Cristino L, Sacchi S, Keller S, Belardo C, et al. Age-related changes in d-Aspartate oxidase promoter methylation control extracellular d-Aspartate levels and prevent precocious cell death during brain aging. J Neurosci. 2016;36(10):3064–78.PubMedCrossRefGoogle Scholar
  51. 51.
    Fagg GE, Matus A. Selective association of N-methyl aspartate and quisqualate types of L-glutamate receptor with brain postsynaptic densities. Proc Natl Acad Sci U S A. 1984;81(21):6876–80.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Monahan JB, Michel J. Identification and characterization of an N-methyl-D-aspartate-specific L-[3H]glutamate recognition site in synaptic plasma membranes. J Neurochem. 1987;48(6):1699–708.PubMedCrossRefGoogle Scholar
  53. 53.
    Ogita K, Yoneda Y. Disclosure by triton X-100 of NMDA-sensitive [3H] glutamate binding sites in brain synaptic membranes. Biochem Biophys Res Commun. 1988;153(2):510–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Olverman HJ, Jones AW, Mewett KN, Watkins JC. Structure/activity relations of N-methyl-D-aspartate receptor ligands as studied by their inhibition of [3H]D-2-amino-5-phosphonopentanoic acid binding in rat brain membranes. Neuroscience. 1988;26(1):17–31.PubMedCrossRefGoogle Scholar
  55. 55.
    Ransom RW, Stec NL. Cooperative modulation of [3H]MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines. J Neurochem. 1988;51(3):830–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Errico F, Nistico R, Palma G, Federici M, Affuso A, Brilli E, et al. Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility. Mol Cell Neurosci. 2008;37(2):236–46.PubMedCrossRefGoogle Scholar
  57. 57.
    Errico F, Rossi S, Napolitano F, Catuogno V, Topo E, Fisone G, et al. D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801. J Neurosci. 2008;28(41):10404–14.PubMedCrossRefGoogle Scholar
  58. 58.
    Errico F, Nistico R, Napolitano F, Mazzola C, Astone D, Pisapia T, et al. Increased D-aspartate brain content rescues hippocampal age-related synaptic plasticity deterioration of mice. Neurobiol Aging. 2011;32(12):2229–43.PubMedCrossRefGoogle Scholar
  59. 59.
    Errico F, Nistico R, Napolitano F, Oliva AB, Romano R, Barbieri F, et al. Persistent increase of D-aspartate in D-aspartate oxidase mutant mice induces a precocious hippocampal age-dependent synaptic plasticity and spatial memory decay. Neurobiol Aging. 2011;32(11):2061–74.PubMedCrossRefGoogle Scholar
  60. 60.
    Gong XQ, Frandsen A, Lu WY, Wan Y, Zabek RL, Pickering DS, et al. D-aspartate and NMDA, but not L-aspartate, block AMPA receptors in rat hippocampal neurons. Br J Pharmacol. 2005;145(4):449–59.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Molinaro G, Pietracupa S, Di Menna L, Pescatori L, Usiello A, Battaglia G, et al. D-aspartate activates mGlu receptors coupled to polyphosphoinositide hydrolysis in neonate rat brain slices. Neurosci Lett. 2010;478(3):128–30.PubMedCrossRefGoogle Scholar
  62. 62.
    Krashia P, Ledonne A, Nobili A, Cordella A, Errico F, Usiello A, et al. Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons. Neuropharmacology. 2015;103:69–78.PubMedCrossRefGoogle Scholar
  63. 63.
    Nakatsuka S, Hayashi M, Muroyama A, Otsuka M, Kozaki S, Yamada H, et al. D-Aspartate is stored in secretory granules and released through a Ca(2+)-dependent pathway in a subset of rat pheochromocytoma PC12 cells. J Biol Chem. 2001;276(28):26589–96.PubMedCrossRefGoogle Scholar
  64. 64.
    Davies LP, Johnston GA. Uptake and release of D- and L-aspartate by rat brain slices. J Neurochem. 1976;26(5):1007–14.PubMedCrossRefGoogle Scholar
  65. 65.
    Malthe-Sorenssen D, Skrede KK, Fonnum F. Calcium-dependent release of D-[3H]aspartate evoked by selective electrical stimulation of excitatory afferent fibres to hippocampal pyramidal cells in vitro. Neuroscience. 1979;4(9):1255–63.PubMedCrossRefGoogle Scholar
  66. 66.
    D’Aniello S, Somorjai I, Garcia-Fernandez J, Topo E, D’Aniello A. D-Aspartic acid is a novel endogenous neurotransmitter. FASEB J. 2010;25(3):1014–27.PubMedCrossRefGoogle Scholar
  67. 67.
    Adachi M, Koyama H, Long Z, Sekine M, Furuchi T, Imai K, et al. L-Glutamate in the extracellular space regulates endogenous D-aspartate homeostasis in rat pheochromocytoma MPT1 cells. Arch Biochem Biophys. 2004;424(1):89–96.PubMedCrossRefGoogle Scholar
  68. 68.
    Koyama H, Adachi M, Sekine M, Katane M, Furuchi T, Homma H. Cytoplasmic localization and efflux of endogenous D-aspartate in pheochromocytoma 12 cells. Arch Biochem Biophys. 2006;446(2):131–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Anderson CM, Bridges RJ, Chamberlin AR, Shimamoto K, Yasuda-Kamatani Y, Swanson RA. Differing effects of substrate and non-substrate transport inhibitors on glutamate uptake reversal. J Neurochem. 2001;79(6):1207–16.PubMedCrossRefGoogle Scholar
  70. 70.
    Bak LK, Schousboe A, Waagepetersen HS. Characterization of depolarization-coupled release of glutamate from cultured mouse cerebellar granule cells using DL-threo-beta-benzyloxyaspartate (DL-TBOA) to distinguish between the vesicular and cytoplasmic pools. Neurochem Int. 2003;43(4–5):417–24.PubMedCrossRefGoogle Scholar
  71. 71.
    Palacin M, Estevez R, Bertran J, Zorzano A. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev. 1998;78(4):969–1054.PubMedGoogle Scholar
  72. 72.
    Taxt T, Storm-Mathisen J. Uptake of D-aspartate and L-glutamate in excitatory axon terminals in hippocampus: autoradiographic and biochemical comparison with gamma-aminobutyrate and other amino acids in normal rats and in rats with lesions. Neuroscience. 1984;11(1):79–100.PubMedCrossRefGoogle Scholar
  73. 73.
    Gundersen V, Danbolt NC, Ottersen OP, Storm-Mathisen J. Demonstration of glutamate/aspartate uptake activity in nerve endings by use of antibodies recognizing exogenous D-aspartate. Neuroscience. 1993;57(1):97–111.PubMedCrossRefGoogle Scholar
  74. 74.
    Garthwaite G, Garthwaite J. Sites of D-[3H]aspartate accumulation in mouse cerebellar slices. Brain Res. 1985;343(1):129–36.PubMedCrossRefGoogle Scholar
  75. 75.
    Errico F, Pirro MT, Affuso A, Spinelli P, De Felice M, D’Aniello A, et al. A physiological mechanism to regulate D-aspartic acid and NMDA levels in mammals revealed by D-aspartate oxidase deficient mice. Gene. 2006;374:50–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Errico F, Nistico R, Di Giorgio A, Squillace M, Vitucci D, Galbusera A, et al. Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals. Transl Psychiatry. 2014;4:e417.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37(1):4–15.PubMedCrossRefGoogle Scholar
  78. 78.
    Coyle JT. NMDA receptor and schizophrenia: a brief history. Schizophr Bull. 2012;38(5):920–6.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Coyle JT, Tsai G. NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia. Int Rev Neurobiol. 2004;59:491–515.PubMedCrossRefGoogle Scholar
  80. 80.
    Hashimoto K. Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets. 2014;18(9):1049–63.PubMedCrossRefGoogle Scholar
  81. 81.
    Hashimoto K, Malchow B, Falkai P, Schmitt A. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci. 2013;263(5):367–77.PubMedCrossRefGoogle Scholar
  82. 82.
    Balu DT, Coyle JT. The NMDA receptor ‘glycine modulatory site’ in schizophrenia: D-serine, glycine, and beyond. Curr Opin Pharmacol. 2015;20:109–15.PubMedCrossRefGoogle Scholar
  83. 83.
    Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–45.PubMedCrossRefGoogle Scholar
  84. 84.
    Geyer MA. The family of sensorimotor gating disorders: comorbidities or diagnostic overlaps? Neurotox Res. 2006;10(3–4):211–20.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Errico F, D’Argenio V, Sforazzini F, Iasevoli F, Squillace M, Guerri G, et al. A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice. Transl Psychiatry. 2015;5:e512.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Meyer-Lindenberg A. From maps to mechanisms through neuroimaging of schizophrenia. Nature. 2010;468(7321):194–202.PubMedCrossRefGoogle Scholar
  87. 87.
    Stephan KE, Baldeweg T, Friston KJ. Synaptic plasticity and dysconnection in schizophrenia. Biol Psychiatry. 2006;59(10):929–39.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhou Y, Shu N, Liu Y, Song M, Hao Y, Liu H, et al. Altered resting-state functional connectivity and anatomical connectivity of hippocampus in schizophrenia. Schizophr Res. 2008;100(1–3):120–32.PubMedCrossRefGoogle Scholar
  89. 89.
    Centonze D, Usiello A, Costa C, Picconi B, Erbs E, Bernardi G, et al. Chronic haloperidol promotes corticostriatal long-term potentiation by targeting dopamine D2L receptors. J Neurosci. 2004;24(38):8214–22.PubMedCrossRefGoogle Scholar
  90. 90.
    Arnt J, Skarsfeldt T. Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology. 1998;18(2):63–101.PubMedCrossRefGoogle Scholar
  91. 91.
    Errico F, Napolitano F, Squillace M, Vitucci D, Blasi G, de Bartolomeis A, et al. Decreased levels of d-aspartate and NMDA in the prefrontal cortex and striatum of patients with schizophrenia. J Psychiatr Res. 2013;47(10):1432–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature. 2011;478(7370):519–23.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hardingham GE, Bading H. The Yin and Yang of NMDA receptor signalling. Trends Neurosci. 2003;26(2):81–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Lancelot E, Beal MF. Glutamate toxicity in chronic neurodegenerative disease. Prog Brain Res. 1998;116:331–47.PubMedCrossRefGoogle Scholar
  95. 95.
    Cristino L, Luongo L, Squillace M, Paolone G, Mango D, Piccinin S, et al. d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain. Neurobiol Aging. 2015;36(5):1890–902.PubMedCrossRefGoogle Scholar
  96. 96.
    Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull. 2009;35(3):528–48.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Owen MJ, O’Donovan MC, Thapar A, Craddock N. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry. 2011;198(3):173–5.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Lu L, Mamiya T, Koseki T, Mouri A, Nabeshima T. Genetic animal models of schizophrenia related with the hypothesis of abnormal neurodevelopment. Biol Pharm Bull. 2011;34(9):1358–63.PubMedCrossRefGoogle Scholar
  99. 99.
    Ikonomidou C, Bittigau P, Koch C, Genz K, Hoerster F, Felderhoff-Mueser U, et al. Neurotransmitters and apoptosis in the developing brain. Biochem Pharmacol. 2001;62(4):401–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Nacher J, McEwen BS. The role of N-methyl-D-asparate receptors in neurogenesis. Hippocampus. 2006;16(3):267–70.PubMedCrossRefGoogle Scholar
  101. 101.
    Ritter LM, Vazquez DM, Meador-Woodruff JH. Ontogeny of ionotropic glutamate receptor subunit expression in the rat hippocampus. Brain Res Dev Brain Res. 2002;139(2):227–36.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Laboratory of Behavioural NeuroscienceCeinge Biotecnologie AvanzateNaplesItaly
  2. 2.Department of Molecular Medicine and Medical BiotechnologyUniversity of Naples “Federico II”NaplesItaly
  3. 3.Department of Environmental, Biological and Pharmaceutical Sciences and TechnologiesThe Second University of Naples (SUN)CasertaItaly

Personalised recommendations