Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia.
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| Title: | Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. |
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| Authors: | Labrie, Viviane, Lipina, Tatiana, Roder, John |
| Source: | Psychopharmacology. Oct2008, Vol. 200 Issue 2, p217-230. 14p. 1 Chart, 6 Graphs. |
| Subjects: | Methyl aspartate, Glycine, Schizophrenia treatment, Neural transmission |
| Abstract: | 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. 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. Behavioral phenotypes relevant to schizophrenia were assessed in Grin1D481N mice that have reduced NMDAR glycine affinity. 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. 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. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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