Abstract
A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Johnson JW, Ascher P . Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 1987; 325: 529–531.
Kleckner NW, Dingledine R . Requirement for glycine in activation of NMDA receptors expressed in Xenopus oocytes. Science 1988; 241: 835–837.
Fadda E, Danysz W, Wroblewski JT, Costa E . Glycine and D-serine increase the affinity of N-methyl-D-aspartate sensitive glutamate binding sites in rat brain synaptic membranes. Neuropharmacology 1988; 27: 1183–1185.
Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K . Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J Neurochem 1995; 65: 454–458.
Mothet JP, Parent AT, Wolosker H, Brady Jr RO, Linden DJ, Ferris CD et al. -Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 2000; 97: 4926–4931.
Gustafson EC, Stevens ER, Wolosker H, Miller RF . Endogenous D-serine contributes to NMDA-receptor-mediated light-evoked responses in the vertebrate retina. J Neurophysiol 2007; 98: 122–130.
Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA et al. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 2006; 125: 775–784.
Hashimoto A, Nishikawa T, Oka T, Takahashi K . Endogenous D-serine in rat brain: N-methyl-D-aspartate receptor-related distribution and aging. J Neurochem 1993; 60: 783–786.
Schell MJ, Molliver ME, Snyder SH . -Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 1995; 92: 3948–3952.
Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady Jr RO, Ferris CD et al. Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc Natl Acad Sci USA 1999; 96: 721–725.
Wolosker H, Blackshaw S, Snyder SH . Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci USA 1999; 96: 13409–13414.
Coyle JT . Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 2006; 26: 365–384.
Morita Y, Ujike H, Tanaka Y, Otani K, Kishimoto M, Morio A et al. A genetic variant of the serine racemase gene is associated with schizophrenia. Biol Psychiatry 2007; 61: 1200–1203.
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. 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 2002; 99: 13675–13680.
Schumacher J, Abon Jamra A, Freudenberg J, Becker T, Ohlraun S et al. Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry 2004; 9: 203–207.
Detera-Wadleigh SD, McMahon FJ . G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 2006; 60: 106–114.
Shi J, Badner JA, Gershon ES, Liu C . Allelic association of G72/G30 with schizophrenia and bipolar disorder: a comprehensive meta-analysis. Schizophr Res 2008; 98: 89–97.
Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N 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. Arch Gen Psychiatry 2003; 60: 572–576.
Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H et al. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res 2006; 90: 41–51.
Tsai G, Yang P, Chung L, Lange N, Coyle JT . -Serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998; 44: 1081–1089.
Lane H, Chang Y, Liu Y, Chiu C, Tsai GE . Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia. Arch Gen Psychiatry 2005; 62: 1196–1204.
Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P et al. D-Serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005; 57: 577–585.
Tsai GE, Yang P, Chung L, Tsai I, Tsai C, Coyle JT . D-Serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 1999; 156: 1822–1825.
Kartvelishvily E, Shleper M, Balan L, Dumin E, Wolosker H . Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors. J Biol Chem 2006; 281: 14151–14162.
Hashimoto A, Nishikawa T, Oka T, Takahashi K, Hayashi T . 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 1992; 582: 41–48.
Jaffrey SR, Snyder SH . The biotin switch method for the detection of S-nitrosylated proteins. Sci STKE 2001; 86: PL1.
Chen HX, Otmakhov N, Lisman J . Requirements for LTP induction by pairing in hippocampal CA1 pyramidal cells. J Neurophysiol 1999; 82: 526–532.
Martina M, Krasteniakov NV, Bergeron R . -Serine differently modulates NMDA receptor function in rat CA1 hippocampal pyramidal cells and interneurons. J Physiol 2003; 548 (Part 2): 411–423.
Chen L, Muhlhauser M, Yang CR . Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 2003; 89: 691–703.
Bredt DS, Snyder SH . Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990; 87: 682–685.
Stamler JS, Simon DI, Osborne JA, Mullins ME, Jaraki O, Michel T et al. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci USA 1992; 89: 444–448.
Schell MJ, Brady Jr RO, Molliver ME, Snyder SH . -Serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci 1997; 17: 1604–1615.
Cadenhead KS, Swerdlow NR, Shafer KM, Diaz M, Braff DL . Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits. Am J Psychiatry 2000; 157: 1660–1668.
Plappert CF, Rodenbücher AM, Pilz PK . Effects of sex and estrous cycle on modulation of the acoustic startle response in mice. Physiol Behav 2005; 84: 585–594.
Walker DL, Davis M . Anxiogenic effects of high illumination levels assessed with the acoustic startle response in rats. Biol Psychiatry 1997; 42: 461–471.
Davis M, Ressler K, Rothbaum BO, Richardson R . Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 2006; 60: 369–375.
Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry 2008; 13: 173–186.
Acknowledgements
We thank William Carlezon, Jonathan Picker and Uwe Rudolph for helpful discussions and the use of equipment. We thank Joanne Berger-Sweeney, Paul Ardayfio, Amy Lawson-Yuen and Kiersten Smith for helpful discussions, Julia Dewald and Julie Kurek for assistance in behavioral experiments, and Jiamin Feng for animal colony maintenance and genotyping. We thank Hermann Wolosker for anti-SR antibody. This work was supported by the United States National Institutes of Health under grant numbers 2 P50 MH06045-07A1 (JTC), MH051290 (JTC), MH18501 (SHS), and NS37483 (NL), research scientist award DA00074 (SHS) and training grant number 5T32 AG00222-14 (ACB), by a NARSAD Senior Investigator Award (JTC), and by the Canadian Institutes on Health Research (CIHR) under grant number MPO-79360 (RB) and a new investigator award (RB).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Basu, A., Tsai, G., Ma, CL. et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry 14, 719–727 (2009). https://doi.org/10.1038/mp.2008.130
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2008.130
Keywords
This article is cited by
-
Detection and analysis of chiral molecules as disease biomarkers
Nature Reviews Chemistry (2023)
-
d-serine availability modulates prefrontal cortex inhibitory interneuron development and circuit maturation
Scientific Reports (2023)
-
Cross species review of the physiological role of d-serine in translationally relevant behaviors
Amino Acids (2023)
-
Pathway-specific contribution of parvalbumin interneuron NMDARs to synaptic currents and thalamocortical feedforward inhibition
Molecular Psychiatry (2022)
-
Chiral resolution of plasma amino acids reveals enantiomer-selective associations with organ functions
Amino Acids (2022)