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.