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Apoptotic Proteins in the Temporal Cortex in Schizophrenia: High Bax/Bcl-2 Ratio Without Caspase-3 Activation

OBJECTIVE: Neuroimaging findings have identified lower cortical gray matter volume in schizophrenia. Apoptosis (programmed cell death) has been proposed as a contributing pathophysiological mechanism. Levels of antiapoptotic Bcl-2 protein are low in the temporal cortex of schizophrenia patients. Bcl-2 interacts with the proapoptotic Bax protein at an upstream checkpoint to regulate the activation of apoptosis by caspase-3 and other proteolytic caspase proteins. A high Bax/Bcl-2 ratio is associated with greater vulnerability to apoptotic activation, while a high caspase-3 level is often associated with apoptotic activity. It was hypothesized that the Bax/Bcl-2 ratio, but not caspase-3, would be high in the temporal cortex of patients with chronic schizophrenia. METHOD: Bax, Bcl-2, and caspase-3 proteins were measured by semiquantitative Western blot in Brodmann’s area 21 (middle temporal gyrus) of postmortem tissue from patients with schizophrenia (N=15), bipolar disorder (N=15), or major depression (N=15) and nonpsychiatric comparison subjects (N=15). RESULTS: The Bax/Bcl-2 ratio was 50% higher in the schizophrenia patients than the nonpsychiatric comparison subjects. The level of caspase-3 (inactive zymogen and activated subunits) was not significantly different. CONCLUSIONS: The higher Bax/Bcl-2 ratio suggests that cortical cells are vulnerable to apoptosis in chronic schizophrenia. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase. Furthermore, the results appear to distinguish the pathophysiology of schizophrenia from most classic neurodegenerative disorders, in which postmortem caspase-3 levels are high. Further studies are needed to investigate the implications of abnormal apoptotic proteins in schizophrenia.

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