Abstract
An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH.
Highlights
Apoptosis is a cell death mechanism that can be triggered by normal developmental events or by extrinsic factors
We used quantitative real time PCR (qRT-PCR) with TaqMan probes designed to capture all known expressed variants of the selected genes to confirm and replicate the changes observed by others using microarray analysis in the Stanley Medical Research Institute (SMRI) Array collection of dorsolateral prefrontal cortex (DLPFC) tissue
Initial qRT-PCR pilot experiments indicated that Lamin A/C was expressed at very low levels in the DLPFC
Summary
Apoptosis is a cell death mechanism that can be triggered by normal developmental events or by extrinsic factors. An increased ratio of pro-apoptotic BAX to antiapoptotic BCL-2 protein in the dorsolateral prefrontal cortex (DLPFC) from patients compared with controls suggests a bias favoring cell death processes in schizophrenia [5]. In this previous study there was no evidence for increased apoptosis in schizophrenia, as levels of the central apoptotic effector protease, caspase 3, were not changed [5]. Benes and colleagues [7] found fewer apoptotic cells in the anterior cingulate cortex in schizophrenia Together these findings suggest apoptotic signaling may be altered in schizophrenia. It remains unclear whether cell death effectors are increased or decreased, and a direct link between apoptotic signaling and indices of cortical pathology has not been established
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