Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia
- 553 Downloads
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.
Materials and methods
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.
KeywordsNMDA receptor d-serine Glycine coagonist site Latent inhibition Mice Schizophrenia
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.
- Bickel S, Lipp HP, Umbricht D (2007) Early auditory sensory processing deficits in mouse mutants with reduced NMDA receptor function. Neuropsychopharmacology 33:1680–1689. Available at http://www.nature.com/npp/journal/vaop/ncurrent/abs/1301536a Google Scholar
- Boulay D, Depoortere R, Louis C, Perrault G, Griebel G, Soubrie P (2004) 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 46:1121–1129PubMedCrossRefGoogle Scholar
- Duffy S, Labrie V, Roder JC (2007) d-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33:1004–1018 Available at http://www.nature.com/npp/journal/vaop/ncurrent/abs/1301486a.html PubMedCrossRefGoogle Scholar
- Gaisler-Salomon I, Diamant L, Rubin C, Weiner I (2008) Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered. Psychopharmacology 196:255–267PubMedCrossRefGoogle Scholar
- Gal G, Schiller D, Weiner I (2005) Latent inhibition is disrupted by nucleus accumbens shell lesion but is abnormally persistent following entire nucleus accumbens lesion: The neural site controlling the expression and disruption of the stimulus preexposure effect. Behav Brain Res 162:246–255PubMedCrossRefGoogle Scholar
- Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N et al (2003) Decreased serum levels of d-serine in patients with schizophrenia: evidence in support of the N-methyl-d-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576PubMedCrossRefGoogle Scholar
- Rice SR, Niu N, Berman DB, Heston LL, Sobell JL (2001) Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients. Mol Psychiatry 6:274–284PubMedCrossRefGoogle Scholar