Mice with Reduced NMDA Receptor Glycine Affinity Model Some of the Negative and Cognitive Symptoms of Schizophrenia

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2008 Jul 4

PMID 18597079

Citations 57

Authors

Viviane Labrie

Tatiana Lipina

John C Roder

Affiliations

Soon will be listed here.

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 Grin1(D481N) mice that have reduced NMDAR glycine affinity.

Results: Grin1(D481N) 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, Grin1(D481N) 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 Grin1(D481N) 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.

Citing Articles

Pharmaco-Multiomics: A New Frontier in Precision Psychiatry.

Dhieb D, Bastaki K Int J Mol Sci. 2025; 26(3).

PMID: 39940850 PMC: 11816785. DOI: 10.3390/ijms26031082.

Relevance of diet in schizophrenia: a review focusing on prenatal nutritional deficiency, obesity, oxidative stress and inflammation.

Rarinca V, Vasile A, Visternicu M, Burlui V, Halitchi G, Ciobica A Front Nutr. 2024; 11:1497569.

PMID: 39734678 PMC: 11673491. DOI: 10.3389/fnut.2024.1497569.

Metabolomics, Lipidomics, and Antipsychotics: A Systematic Review.

Burghardt K, Kajy M, Ward K, Burghardt P Biomedicines. 2023; 11(12).

PMID: 38137517 PMC: 10741000. DOI: 10.3390/biomedicines11123295.

Interactions between Glycine and Glutamate through Activation of Their Transporters in Hippocampal Nerve Terminals.

Cortese K, Gagliani M, Raiteri L Biomedicines. 2023; 11(12).

PMID: 38137373 PMC: 10740625. DOI: 10.3390/biomedicines11123152.

Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia.

Vinnakota C, Hudson M, Jones N, Sundram S, Hill R Int J Mol Sci. 2023; 24(14).

PMID: 37511595 PMC: 10380280. DOI: 10.3390/ijms241411835.

References

Mohn A, Gainetdinov R, Caron M, Koller B . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell. 1999; 98(4):427-36. DOI: 10.1016/s0092-8674(00)81972-8. View

OTuathaigh C, Babovic D, OSullivan G, Clifford J, Tighe O, Croke D . Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1. Neuroscience. 2007; 147(1):18-27. DOI: 10.1016/j.neuroscience.2007.03.051. View

Sargolini F, Roullet P, Oliverio A, Mele A . 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. 1999; 93(3):855-67. DOI: 10.1016/s0306-4522(99)00259-6. View

Bickel S, Lipp H, Umbricht D . Early auditory sensory processing deficits in mouse mutants with reduced NMDA receptor function. Neuropsychopharmacology. 2007; 33(7):1680-9. DOI: 10.1038/sj.npp.1301536. View

Boulay D, Depoortere R, Louis C, Perrault G, Griebel G, Soubrie P . 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. 2004; 46(8):1121-9. DOI: 10.1016/j.neuropharm.2004.02.008. View

Wersinger S, Ginns E, OCarroll A, Lolait S, Young 3rd W . Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry. 2002; 7(9):975-84. DOI: 10.1038/sj.mp.4001195. View

Gleason S, Shannon H . Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology (Berl). 1997; 129(1):79-84. DOI: 10.1007/s002130050165. View

Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H . 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. 2002; 99(21):13675-80. PMC: 129739. DOI: 10.1073/pnas.182412499. View

Tovar K, Westbrook G . Mobile NMDA receptors at hippocampal synapses. Neuron. 2002; 34(2):255-64. DOI: 10.1016/s0896-6273(02)00658-x. View

10.

Capleton R . Cognitive function in schizophrenia: association with negative and positive symptoms. Psychol Rep. 1996; 78(1):123-8. DOI: 10.2466/pr0.1996.78.1.123. View

11.

Duncan G, Moy S, Perez A, Eddy D, Zinzow W, Lieberman J . Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res. 2004; 153(2):507-19. DOI: 10.1016/j.bbr.2004.01.008. View

12.

Ross C, Margolis R, Reading S, Pletnikov M, Coyle J . Neurobiology of schizophrenia. Neuron. 2006; 52(1):139-53. DOI: 10.1016/j.neuron.2006.09.015. View

13.

Hlinak Z, Krejci I . Kynurenic acid and 5,7-dichlorokynurenic acids improve social and object recognition in male rats. Psychopharmacology (Berl). 1995; 120(4):463-9. DOI: 10.1007/BF02245819. View

14.

Gaisler-Salomon I, Weiner I . Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol. Psychopharmacology (Berl). 2003; 166(4):333-42. DOI: 10.1007/s00213-002-1311-z. View

15.

Single F, Rozov A, Burnashev N, Zimmermann F, Hanley D, Forrest D . Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R). J Neurosci. 2000; 20(7):2558-66. PMC: 6772252. View

16.

Moser P, Hitchcock J, Lister S, Moran P . The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Brain Res Rev. 2000; 33(2-3):275-307. DOI: 10.1016/s0165-0173(00)00026-6. View

17.

Pilowsky L, Bressan R, Stone J, Erlandsson K, Mulligan R, Krystal J . First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry. 2005; 11(2):118-9. DOI: 10.1038/sj.mp.4001751. View

18.

Cornblatt B, Keilp J . Impaired attention, genetics, and the pathophysiology of schizophrenia. Schizophr Bull. 1994; 20(1):31-46. DOI: 10.1093/schbul/20.1.31. View

19.

Coyle J . Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006; 26(4-6):365-84. PMC: 11881825. DOI: 10.1007/s10571-006-9062-8. View

20.

Murphy B, Chung Y, Park T, McGorry P . Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res. 2006; 88(1-3):5-25. DOI: 10.1016/j.schres.2006.07.002. View