Neuronal proliferation in an animal model of psychosis. Implications for the pathomechanism underlying schizophrenia

Objectives:

Accumulating evidence implicates neurodegenerative mechanisms to be involved in the pathogenesis of schizophrenia. Employing immunohistochemical methods in an animal model based on NMDA-antagonism with MK801 we were able to demonstrate distinct patterns of proliferation and apoptosis in the CNS. These were localized in strategically relevant regions, which may be related to schizophrenia.

Methods:

48 rats were treated over 21d with MK801 (0.02mg/kg), haloperidol (1mg/kg) or a combination. Behavioral assessment was performed. Hippocampi were processed for microarray analysis. One hemisphere was subjected to an immunohistochemical analysis of cell cycle antigens, markers of neuronal subpopulations and TUNEL assay.

Results:

MK801 led to an alteration of proliferation antigens. Neurogenesis was prominent in the dentate gyrus. The effects were reversed by haloperidol, which alone yielded no effect. Genes implicated in survival and apoptosis were differentially expressed, however these data will require validation by quantitative PCR.

Conclusion:

Our data indicate that altered neuronal proliferation and apoptosis in distinct subregions of the CNS may account for the behavioral abnormalities exhibited by MK–801 treated rats. Interestingly antipsychotic drugs appear to interfere with these abnormal proliferation patterns.