Influenza A virus infection and NMDA receptor function : a behavioral and molecular study of relevance for schizophrenia

Schizophrenia is a neuropsychiatric disorder characterized by positive and negative symptoms, as well as cognitive dysfunctions. There is no single cause of schizophrenia, instead complex combinations of genetic and environmental factors may contribute to the disorder, including exposure to viral infections or other environmental insults during early life. Discoveries during the last 30 years have provided increasing evidence for a glutamatergic hypofunction in schizophrenia. This hypothesis arose from the finding that non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists, such as ketamine and phencyclidine (PCP) can reproduce schizophrenia-like symptoms including cognitive dysfunctions in man. This observation, has led to a search for schizophrenia-related animal models based on NMDA-receptor blockade. The main aim of these studies was to investigate if exposure to influenza A virus during early life can result in cognitive dysfunctions during adult life. In addition, to allow studies on the potential role of NMDA receptor systems for cognition, a novel NMDA receptor hypofunction model was developed. Both acute and repeated treatment with NMDA receptor antagonists is known to produce a dose-related spectrum of motor dysfunctions that interfere with cognitive performance in rodents. For this reason, PCP was examined in a dose-dependent study to establish the dose-range of cognitive impairments versus motor side effects. Repeated administration of the 0.5 mg/kg dose of PCP impaired spatial learning and long-term memory without affecting non-spatial learning. The PCP-induced impairments in learning and memory were prevented by concomitant treatment with the atypical antipsychotic drug clozapine (0.5 mg/kg), but not with the typical antipsychotic haloperidol (0.05 mg/kg). To avoid testing with the drug on board , the effects of repeated administration of PCP on cognitive and social behavior were examined 24 h after the final dose of PCP. In addition, this study examined the effect of such treatment on the expression of two genes involved in neuronal plasticity and learning. Repeated doses of PCP (1 and 2 mg/kg) produced long-term impairments in spatial learning and working memory performance in the water maze task, without any apparent sensorimotor deficits. Furthermore, mice treated with 2 mg/kg of PCP spent less time in active social interaction, and showed increased non-social and aggressive behaviors. These behavioral effects were associated wi