A schizophrenic mouse?

Abstract

N-methyl-d-aspartate receptor (NMDAR) deficiency has been suggested as a possible cause of schizophrenia. In part, this is because intoxication with three different non-competitive antagonists of NMDARs [phencyclidine (PCP), MK-801 and ketamine] mimics the disorder.Mohn et al.1xMice with reduced NMDA receptor expression display behaviors related to schizophrenia. Mohn, A.R. et al. Cell. 1999; 98: 427–436Abstract | Full Text | Full Text PDF | PubMed | Scopus (715)See all References1 have studied the effect of NMDAR deficiency on murine behaviour. NMDAR complexes consist of one NMDAR subunit 1 (NR1) and one of four NR2 subunits. Mice that lack the NR1 protein die perinatally, so Mohn et al. generated, by insertional mutagenesis, a strain of mice in which NR1 is expressed at only 5–10% of wild-type levels. Although this was found to be sufficient for survival, the mice displayed hyperlocomotion, increased stereotypic behaviour and social withdrawal, which are believed to mirror behaviours seen in schizophrenia. Treatment with the atypical antipsychotic drug clozapine, which treats schizophrenic symptoms without causing severe side effects, reduced the locomotion and stereotypy in the NMDAR-deficient mice to wild-type levels and decreased the levels of social withdrawal; the behaviour of wild-type mice was not affected by the treatment. In addition, PCP and MK-801 had no effect on the NMDAR-deficient mice, suggesting that the behavioural effects of these compounds are mediated through suppression of NMDARs.This work has provided insight into a possible mechanism for some aspects of schizophrenia. In addition, it will allow the study of the effect of long-term NMDAR deficiency, which is important because schizophrenia is thought to be a progressive mental illness.