l-701324 and Schizophrenia

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

Topics: Animals; Behavior, Animal; Carrier Proteins; Clozapine; Disease Models, Animal; Glycine; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nerve Tissue Proteins; Phenotype; Quinolones; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Sarcosine; Schizophrenia; Schizophrenic Psychology; Serine; Social Behavior; Space Perception

D-amino acid oxidase (DAO) degrades D-serine, a co-agonist at the NMDA receptor (NMDAR). Hypofunction of the NMDAR has been suggested to contribute to the pathophysiology of schizophrenia. Intriguingly, DAO has been recently identified as a risk factor for schizophrenia through genetic association studies. A naturally occurring mouse strain (ddY/DAO-) has been identified which lacks DAO activity. We have characterized this strain both behaviorally and biochemically to evaluate DAO as a target for schizophrenia. We have confirmed that this strain lacks DAO activity and shown for the first time it has increased occupancy of the NMDAR glycine site due to elevated extracellular D-serine levels and has enhanced NMDAR function in vivo. Furthermore, the ddY/DAO- strain displays behaviors which suggest that it will be a useful tool for evaluation of the clinical benefit of DAO inhibition in schizophrenia.

Topics: Acoustic Stimulation; Animals; Brain Chemistry; Cyclic GMP; D-Amino-Acid Oxidase; Disease Models, Animal; Dose-Response Relationship, Radiation; Excitatory Amino Acid Antagonists; Extremities; Female; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Neural Inhibition; Neurologic Examination; Phencyclidine; Psychomotor Performance; Quinolones; Reaction Time; Reflex, Startle; Schizophrenia; Sex Factors; Swimming