Is the acute NMDA receptor hypofunction a valid model of schizophrenia?

Abstract

Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD(67)) is at variance with human studies. It is possible that changes in GAD(67) are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity.

Fig. 1.

Expression of parvalbumin (PV) mRNA in the medial prefrontal cortex of the rat. (A) Low magnification pseudocolored picture showing the distribution pattern of PV in a saline-injected rat. (B) High magnification photomicrograph of the area delimited in (A) showing the predominant distribution of PV within layers 3 and 5 in the infralimbic region of the medial prefrontal cortex. (C) Reduced level of PV mRNA after 1 mg/kg of MK-801. (D) Bar graphs showing the mean ± standard error of the mean of PV mRNA of rats injected with saline or MK-801; *P < .05. Dashed line shows the localization of cerebral midline, and Arabic numbers indicate the different cortical layers (note the absence of layer 4 in the medial prefrontal cortex of the rat). Scale bars: 2 mm in (A) and 600 μm in (B) and (C).