Comparison of brain and blood gene expression in an animal model of negative symptoms in schizophrenia

Objectives: To investigate the potential of white blood cells as probes for central processes we have measured gene expression in both the anterior cingulate cortex and white blood cells using a putative animal model of negative symptoms in schizophrenia. Methods: The model is based on the capability of ketamine to induce psychotic symptoms in healthy volunteers and to worsen such symptoms in schizophrenic patients. Classical fear conditioning is used to assess emotional processing and cognitive function in animals exposed to sub-chronic ketamine vs. controls. Gene expression was measured using a commercially sourced whole genome rat gene array. Data analyses were performed using ANOVA (Systat 11). Results: In both anterior cingulate cortex and white blood cells a significant interaction between ketamine and fear conditioning could be observed. The outcome is largely supported by our subsequent metagene analysis. Moreover, the correlation between gene expression in brain and blood is about constant when no ketamine is present (r-0.4). With ketamine, however, the correlation becomes very low (r similar to 02) when there is no fear, but it increases to -0.6 when fear and ketamine are both present. Our results show that under normal conditions ketamine lowers gene expression in the brain, but this effect is completely reversed in combination with fear conditioning, indicating a stimulatory action. Conclusion: This paradoxical outcome indicates that extreme care must be taken when using gene expression data from white blood cells as marker for psychiatric disorders, especially when pharmacological and environmental interactions are at play. Crown Copyright (c) 2012 Published by Elsevier Inc. All rights reserved.