Skip to main content
SpringerLink
Log in

Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia.

Objective

We examined the involvement of the glycine coagonist site on the N-methyl-d-aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice.

Materials and methods

Behavioral phenotypes relevant to schizophrenia were assessed in Grin1D481N mice that have reduced NMDAR glycine affinity.

Results

Grin1D481N mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, d-serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1D481N mutant animals showed reduced social approach behaviors that were normalized by d-serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by d-serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1D481N mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty.

Conclusions

Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Atkinson BN, Bell SC, De Vivo M, Kowalski LR, Lechner SM, Ognyanov VI et al (2001) ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol 60:1414–1420

    PubMed  CAS  Google Scholar 

  • Ballard TM, Pauly-Evers M, Higgins GA, Ouagazzal AM, Mutel V, Borroni E et al (2002) Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. J Neurosci 22:6713–6723

    PubMed  CAS  Google Scholar 

  • Berman I, Viegner B, Merson A, Allan E, Pappas D, Green AI (1997) Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia. Schizophr Res 25:1–10

    Article  PubMed  CAS  Google Scholar 

  • Bickel S, Lipp HP, Umbricht D (2007) Early auditory sensory processing deficits in mouse mutants with reduced NMDA receptor function. Neuropsychopharmacology 33:1680–1689. Available at http://www.nature.com/npp/journal/vaop/ncurrent/abs/1301536a

    Google Scholar 

  • Boulay D, Depoortere R, Louis C, Perrault G, Griebel G, Soubrie P (2004) SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats. Neuropharmacology 46:1121–1129

    Article  PubMed  CAS  Google Scholar 

  • Brodkin ES, Hagemann A, Nemetski SM, Silver LM (2004) Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice. Brain Res 1002:151–157

    Article  PubMed  CAS  Google Scholar 

  • Bruins Slot LA, Kleven MS, Newman-Tancredi A (2005) Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat. Neuropharmacology 49:996–1006

    Article  PubMed  CAS  Google Scholar 

  • Capleton RA (1996) Cognitive function in schizophrenia: association with negative and positive symptoms. Psychol Rep 78:123–128

    PubMed  CAS  Google Scholar 

  • Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al (2002) Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 99:13675–13680

    Article  PubMed  CAS  Google Scholar 

  • Cohen E, Sereni N, Kaplan O, Weizman A, Kikinzon L, Weiner I, Lubow RE (2004) The relation between latent inhibition and symptom-types in young schizophrenics. Behav Brain Res 149:113–122

    Article  PubMed  Google Scholar 

  • Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    Article  PubMed  CAS  Google Scholar 

  • Cornblatt BA, Keilp JG (1994) Impaired attention, genetics, and the pathophysiology of schizophrenia. Schizophr Bull 20:31–46

    PubMed  CAS  Google Scholar 

  • Depoortere R, Perrault G, Sanger DJ (1999) Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various site on the NMDA receptor complex. Behav Pharmacol 10:51–62

    Article  PubMed  CAS  Google Scholar 

  • Dickerson F, Boronow JJ, Ringel N, Parente F (1996) Neurocognitive deficits and social functioning in outpatients with schizophrenia. Schizophr Res 21:75–83

    Article  PubMed  CAS  Google Scholar 

  • Duffy S, Labrie V, Roder JC (2007) d-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33:1004–1018 Available at http://www.nature.com/npp/journal/vaop/ncurrent/abs/1301486a.html

    Article  PubMed  CAS  Google Scholar 

  • Duncan GE, Moy SS, Perez A, Eddy DM, Zinzow WM, Lieberman JA et al (2004) Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507–519

    Article  PubMed  CAS  Google Scholar 

  • Ellenbroek BA, Cools AR (2000) Animal models for the negative symptoms of schizophrenia. Behav Pharmacol 11:223–233

    PubMed  CAS  Google Scholar 

  • Frick KM, Gresack JE (2003) Sex differences in the behavioral response to spatial and object novelty in adult C57BL/6 mice. Behav Neurosci 117:1283–1291

    Article  PubMed  Google Scholar 

  • Gaisler-Salomon I, Weiner I (2003) Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol. Psychopharmacology 166:333–342

    PubMed  CAS  Google Scholar 

  • Gaisler-Salomon I, Diamant L, Rubin C, Weiner I (2008) Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered. Psychopharmacology 196:255–267

    Article  PubMed  CAS  Google Scholar 

  • Gal G, Schiller D, Weiner I (2005) Latent inhibition is disrupted by nucleus accumbens shell lesion but is abnormally persistent following entire nucleus accumbens lesion: The neural site controlling the expression and disruption of the stimulus preexposure effect. Behav Brain Res 162:246–255

    Article  PubMed  Google Scholar 

  • Gleason SD, Shannon HE (1997) Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology 129:79–84

    Article  PubMed  CAS  Google Scholar 

  • Goltsov AY, Loseva JG, Andreeva TV, Grigorenko AP, Abramova LI, Kaleda VG et al (2006) Polymorphism in the 5¢-promoter region of serine racemase gene in schizophrenia. Mol Psychiatry 11:325–326

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N et al (2003) Decreased serum levels of d-serine in patients with schizophrenia: evidence in support of the N-methyl-d-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Higgins GA, Ballard TM, Huwyler J, Kemp JA, Gill R (2003) Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition. Neuropharmacology 44:324–341

    Article  PubMed  CAS  Google Scholar 

  • Hlinak Z, Krejci I (1995) Kynurenic acid and 5,7-dichlorokynurenic acids improve social and object recognition in male rats. Psychopharmacology 120:463–469

    Article  PubMed  CAS  Google Scholar 

  • Karcz-Kubica M, Wedzony K, Zajaczkowski W, Danysz W (1999) NMDA receptor antagonists acting at the glycineB site in rat models for antipsychotic-like activity. J Neural Trans 106:1189–1204

    Article  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    PubMed  CAS  Google Scholar 

  • Kew JNC, Koester A, Moreau JL, Jenck F, Quagazzal AM, Mutel V et al (2000) Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site. J Neurosci 20:4037–4049

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Lewis DA, Gonzalez-Burgos G (2006) Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12:1016–1022

    Article  PubMed  CAS  Google Scholar 

  • Lipina T, Labrie V, Weiner I, Roder J (2005) Modulators of the glycine site on NMDA receptors, d-serine and ALX-5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology 179:54–67

    Article  PubMed  CAS  Google Scholar 

  • Mandillo S, Rinaldi A, Oliverio A, Mele A (2003) Repeated administration of phencyclidine, amphetamine and MK-801 selectively impairs spatial learning in mice: a possible model of psychotomimetic drug-induced cognitive deficits. Behav Pharmacol 14:533–544

    Article  PubMed  CAS  Google Scholar 

  • Martucci L, Wong AH, Trakalo J, Cate-Carter T, Wong GW, Macciardi FM, Kennedy JL (2003) N-methyl-d-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. Am J Med Genet B Neuropsychiatr Genet 119:24–27

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ (2005) N-methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179:30–53

    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

    Article  PubMed  CAS  Google Scholar 

  • Morita Y, Ujike H, Tanaka Y, Otani K, Kishimoto M, Morio A et al (2006) A genetic variant of the serine racemase gene is associated with schizophrenia. Biol Psychiatry 61:1200–1203

    Article  PubMed  CAS  Google Scholar 

  • Moser PC, Hitchcock JM, Lister S, Moran PM (2000) The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Rev 33:275–307

    Article  PubMed  CAS  Google Scholar 

  • Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR et al (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3:287–302

    Article  PubMed  CAS  Google Scholar 

  • Moy SS, Perez A, Koller BH, Duncan GE (2006) Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function. Brain Res 1089:186–194

    Article  PubMed  CAS  Google Scholar 

  • Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H (2002) Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 9:49–57

    Article  PubMed  Google Scholar 

  • Murphy BP, Chung YC, Park TW, McGorry PD (2006) Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res 88:5–25

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • O’Tuathaigh CM, Babovic D, O’Sullivan GJ, Clifford JJ, Tighe O, Croke DT et al (2007) Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1. Neuroscience 147:18–27

    Article  PubMed  CAS  Google Scholar 

  • Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, Ell PJ (2006) First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 11:118–119

    Article  PubMed  CAS  Google Scholar 

  • Rascle C, Mazas O, Vaiva G, Tournant M, Raybois O, Goudemand M et al (2001) Clinical features of latent inhibition in schizophrenia. Schizophr Res 51:149–161

    Article  PubMed  CAS  Google Scholar 

  • Rice SR, Niu N, Berman DB, Heston LL, Sobell JL (2001) Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients. Mol Psychiatry 6:274–284

    Article  PubMed  CAS  Google Scholar 

  • Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT (2006) Neurobiology of schizophrenia. Neuron 52:139–153

    Article  PubMed  CAS  Google Scholar 

  • Roullet P, Mele A, Ammassari-Teule M (1996) Involvement of glutamatergic and dopaminergic systems in the reactivity of mice to spatial and non-spatial change. Psychopharmacology 126:55–61

    Article  PubMed  CAS  Google Scholar 

  • Sams-Dodd F (1996) Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol 7:3–23

    PubMed  CAS  Google Scholar 

  • Sargolini F, Roullet P, Oliverio A, Mele A (1999) Effects of lesions to the glutamatergic afferents to the nucleus accumbens in the modulation of reactivity to spatial and non-spatial novelty in mice. Neuroscience 93:855–867

    Article  PubMed  CAS  Google Scholar 

  • Schumacher J, Jamra RA, Freudenberg J, Becker T, Ohlraun S, Otte ACJ et al (2004) Examination of G72 and D-amino acid oxidase as genetic risk factor for schizophrenia and bipolar affective disorder. Mol Psychiatry 9:203–207

    Article  PubMed  CAS  Google Scholar 

  • Single FN, Rozov A, Burnashev N, Zimmermann F, Hanley DF, Forrest D et al (2000) Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R). J Neurosci 20:2558–2566

    PubMed  CAS  Google Scholar 

  • Sotres-Bayon F, Bush DE, LeDoux JE (2007) Acquisition of fear extinction requires activation of NR2B-containing NMDA receptors in the lateral amygdala. Neuropsychopharmacology 32:1929–1940

    Article  PubMed  CAS  Google Scholar 

  • Tovar KR, Westbrook GL (2002) Mobile NMDA receptors at hippocampal synapses. Neuron 34:255–264

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Weiner I (2003) The “two-headed” latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment. Psychopharmacology 169:257–297

    Article  PubMed  CAS  Google Scholar 

  • Weiner I, Feldon J (1992) Phencyclidine does not disrupt latent inhibition in rats: implications for animal models of schizophrenia. Pharmacol Biochem Behav 42:625–631

    Article  PubMed  CAS  Google Scholar 

  • Wersinger SR, Ginns EI, O’Carroll AM, Lolait SJ, Young WS 3rd (2002) Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry 7:975–984

    Article  PubMed  CAS  Google Scholar 

  • Wiley JL, Cristello AF, Balster RL (1995) Effects of site-selective NMDA receptor antagonists in an elevated plus-maze model of anxiety in mice. Eur J Pharmacol 294:101–107

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

VL was supported by a Natural Sciences and Engineering Research Council (NSERC, Canada) studentship. JCR is a Canadian Research Council (CRC) chair. This research was supported by the Canadian Institutes of Health Research (CIHR). The authors thank Dr. Steven Duffy for critical reading of the manuscript.

Disclosure/conflict of interest

The authors (VL, TL, and JCR) declare that there are no potential conflicts of interest that may have biased the presented work in this manuscript.

Author information

Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 860, 600 University Avenue, Toronto, ON, Canada, M5G 1X5

    Viviane Labrie, Tatiana Lipina & John C. Roder

  2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Viviane Labrie & John C. Roder

Authors
  1. Viviane Labrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatiana Lipina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John C. Roder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Viviane Labrie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Labrie, V., Lipina, T. & Roder, J.C. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology 200, 217–230 (2008). https://doi.org/10.1007/s00213-008-1196-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1196-6

Keywords

Search

Navigation