Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine.

Repeated administration of phencyclidine (PCP) to mice produces behavioral deficits resembling the negative symptoms and cognitive impairments of schizophrenia, including increased immobility in a forced swimming test and impaired latent learning. These deficits persist after PCP withdrawal and are alleviated by atypical but not typical antipsychotics. PCP treatment reduces spontaneous glutamate levels and impairs NMDA receptor function in the prefrontal cortex, disrupting both pre- and postsynaptic glutamate transmission. Facilitation of NMDA receptor function with glycine-site agonists like D-cycloserine or glycine reverses the abnormal intracellular signaling and behavioral deficits. The findings suggest that disrupted NMDA receptor signaling underlies the emotional and cognitive deficits in this mouse model, which may be useful for studying antipsychotic effects.

Study at a glance

Abstract

In humans, phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate (NMDA) antagonist, reproduces a schizophrenia-like psychosis such as positive/negative symptoms and cognitive deficits. PCP (10 mg/kg/day for 14 days)-treated mice exhibit the enhanced immobility in a forced swimming test as indexes of negative symptoms and impairment of latent learning in a water finding test as indexes of cognitive deficits. These behavioral deficits remain after withdrawal from repeated PCP treatment and are attenuated by atypical antipsychotics, but not by typical antipsychotics. Since it has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia, we investigated an involvement of glutamatergic system in emotional and cognitive deficits in mice treated with PCP repeatedly. Ca(2+)/calmodulin kinase II (CaMKII) is markedly phosphorylated after the forced swimming test and the training trial of water finding test in the prefrontal cortex of saline-treated mice but not PCP-treated mice. Facilitation of NMDA receptor function by NMDA receptor glycine-site agonists such as D-cycloserine and glycine is effective on the abnormal intracellular signaling, and emotional and cognitive deficits in mice treated with PCP repeatedly. The repeated PCP treatment impaired NMDA receptor function and decreased levels of spontaneous extracellular glutamate in the prefrontal cortex, indicating that the repeated PCP treatment impairs both pre- and postsynaptic glutamate transmissions. Our findings suggest that abnormal NMDA receptor signaling is involved in the emotional and cognitive deficits in mice treated with PCP repeatedly. Our PCP-treated mice would be a useful model for studying the effect of antipsychotics on emotional and cognitive deficits in schizophrenia.