Neurotrophic support and apoptosis in an animal model of psychosis based on chronic NMDA-antagonism

Objectives: Alterations of neurotrophic support and apoptotic activity may constitute a major factor in the pathogenesis and progression of schizophrenia, especially considering recent findings supporting the neurodevelopmental hypothesis. Employing immunohistochemical methods for the detection of BDNF and a range of complementary methods for the detection of apoptosis we were able to demonstrate abnormalities in a rat model based on chronic NMDA-antagonism with MK–801 at subanesthetic doses. We hypothesized that abnormal apoptotic activity and disrupted neurotrophic support may lead to cognitive dysfunction. Methods: 48 juvenile rats were treated with MK–801 (0.02mg/kg), haloperidol (1mg/kg), combination of both drugs or saline over a period of 21 days. Extensive behaviour tests were performed. One hippocampus was subjected to microarray analysis, the other hemisphere was stained immunohistochemically for BDNF, cleaved caspase–3, PCNA and TUNEL. Results: Chronic NMDA antagonism led to subtle alterations of apoptotic and neurotrophic activity in strategically important subregions of the brain, which was accompanied by changes of behavioural performance. Conclusions: We could deliver preliminary evidence for distinct alterations of BDNF expression patterns and apoptotic activity in a well-accepted animal model for psychotic disorders. These findings may contribute to a better insight into the behavorial abnormalities exhibited by MK–801 treated rats.