Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients

Sabine Bahn (1) , Man Kuan Chan (1) , Laura Harris (1) , Paul Guest (1) , Tsz Tsang (1) , Elaine Holmes (1)

1 Institute of Biotechnology

Extensive research has been conducted on post-mortem brain tissue in schizophrenia, particularly the dorsolateral prefrontal cortex (DLPFC). However, to what extent the reported changes are due to the disorder itself and which are the cumulative effects of lifetime medication remains to be determined. In this study, we employed label-free liquid chromatography-mass spectrometry (LC-MSE) based proteomic and proton nuclear magnetic resonance (1H NMR) based metabonomic profiling approaches to investigate DLPFC tissue from two cohorts of schizophrenia patients grouped according to their lifetime antipsychotic dose, together with tissue from bipolar disorder subjects, and normal controls (n=10 per group). Both techniques showed profound changes in tissue from low-cumulative-medication schizophrenia subjects, but few changes in tissue from medium-cumulative-medication subjects. Protein expression changes were validated by Western blot and investigated further in a third group of subjects who were subjected to high-cumulative-medication over the course of their lifetime. Furthermore, key protein expression and metabolite level changes correlated significantly with lifetime antipsychotic dose. This suggests that the detected changes are present prior to antipsychotic therapy and moreover, may be normalized with treatment. Overall, our analyses revealed novel protein and metabolite changes in low-cumulative-medication subjects associated with synaptogenesis, neuritic dynamics, presynaptic vesicle cycling, amino acid and glutamine metabolism, and energy buffering systems. Most of these markers were altered specifically in schizophrenia as determined by analysis of the same brain region from bipolar disorder patients.

Mots clés: post-mortem brain; schizophrenia; antipsychotic medication; bipolar disorder; LC-MSE; 1H NMR

Sabine Bahn, Man Kuan Chan, Laura Harris, Paul Guest, Tsz Tsang, et al.. Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Molecular Psychiatry, 2010, ⟨10.1038/mp.2010.100⟩. ⟨hal-00583145⟩