Increased neurogenesis in a rat ketamine model of schizophrenia

Background Growing evidence implicates abnormal neurodevelopment in schizophrenia, which manifests itself, for example, in reduced volume and cellular disarray of the hippocampus. This prompted us to investigate if there are indications of an altered neurodevelopment in this brain region. While neuron birth is largely completed by the end of gestation, granule neurons of the dentate gyrus are generated throughout life, thus offering an opportunity to investigate neurogenesis postnatally. Methods We investigated whether repeated application of subanesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine, which has been shown to mimic model aspects of schizophrenia in animals, affects the hippocampal neurogenesis detected by bromodeoxyuridine incorporation. Cells were identified by immunocytochemistry. Results Subanesthetic doses of ketamine applied subchronically enhance neurogenesis in the hippocampal subgranular zone. Conclusions In our animal model of schizophrenia, ketamine may evoke its stimulating effect on neurogenesis via a block of the N-methyl-D-aspartate receptor directly by reducing the c-Fos/c-Jun expression, resulting in a depression of the AP1 transcription factor complex and/or by a reduced nitric oxide production or an enhanced serotonergic activity. The newly formed neurons are not able to overcome the schizophrenia-related loss of parvalbumin expressing neurons and the behavioral abnormalities indicating that their functional integration is crucial.