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Psychopharmacology

, Volume 200, Issue 2, pp 217–230 | Cite as

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

  • Viviane LabrieEmail author
  • Tatiana Lipina
  • John C. Roder
Original Investigation

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.

Keywords

NMDA receptor d-serine Glycine coagonist site Latent inhibition Mice Schizophrenia 

Notes

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.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Viviane Labrie
    • 1
    • 2
    Email author
  • Tatiana Lipina
    • 1
  • John C. Roder
    • 1
    • 2
  1. 1.Samuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada
  2. 2.Institute of Medical ScienceUniversity of TorontoTorontoCanada

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