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

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.