Different changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders

Abstract

The growing body of evidence implicating tumor necrosis factor-α (TNFα) in the pathophysiology of psychiatric disorders led us to measure levels of that protein in the cortex of subjects with major depressive disorders (MDD). Having reported an increase (458%) in the levels of the transmembrane (tmTNFα), but not the soluble (sTNFα), form of the protein in Brodmann's area (BA) 46, but not 24, in people with the disorder, we decided to examine additional components of TNFα-related pathways in the same regions in people with MDD and extend our studies to the same cortical regions of people with schizophrenia (Sz) and bipolar disorders (BD). Using postmortem tissue, western blots and quantitative PCR, we have now shown there is a significant increase (305%) in tmTNFα in Brodmann's area 24, but not 46, from subjects with BD, and that levels of the protein were not altered in Sz. Levels of sTNFα were not altered in BD or Sz. In addition, we have shown that levels of TNF receptor 1 (TNFR1) mRNA are increased in BA 24 (53%) and BA 46 (82%) in people with Sz, whereas levels of TNFR2 mRNA was decreased in BA 46 in people with mood disorders (MDD=-51%; BD=-67%). Levels of proteins frequently used as surrogate markers of neuronal, astrocytic and microglia numbers, as well as levels of the pro-inflammatory marker (interleukin 1β), were not changed in the cortex of people with mood disorders. Our data suggest there are differential changes in TNFα-related markers in the cortex of people with MDD, BD and Sz that may not be related to classical inflammation and may cause changes in different TNFα-related signaling pathways.

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

“…38,[49][50][51][52][53] A previous study from our group reported increased expres sion of IL4 and IL13, and no differences in IL6, TNFα and IL1β, in the orbitofrontal cortex of individuals who died by suicide compared with controls. 38 This variability in the ex pression of certain cytokines in the brain suggests that cau tion is indicated regarding their use as biological markers of mood disorders.…”

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

“…The tmTNF␣ levels were increased in the postmortem anterior cingulate of bipolar disorder patients [67]. The TNFR2 mRNA level was significantly decreased in the dorsolateral prefrontal cortices of bipolar and major depressive disorder patients [67].…”

“…The tmTNF␣ levels were increased in the postmortem anterior cingulate of bipolar disorder patients [67]. The TNFR2 mRNA level was significantly decreased in the dorsolateral prefrontal cortices of bipolar and major depressive disorder patients [67]. The nuclear protein and mRNA levels of microglial NFKB1 (p50) and NF-Bp65 [40] were significantly increased in the postmortem frontal cortices of bipolar disorder patients.…”

“…The TNF␣ mRNA and protein levels were also significantly increased in frontal cortex samples from schizophrenic patients [27]. Additionally, the TNF receptor type I (TNFR1) mRNA level was significantly increased in both the anterior cingulate and dorsolateral prefrontal cortices of patients with schizophrenia [67]. The protein expression levels of M1-related nuclear transcription factor subunits, NF-Bp50 and NF-Bp65, were significantly increased in the frontal cortices of schizophrenia patients.…”

“…There was no change in the soluble TNF (sTNF) levels in either brain region [70]. Patients with bipolar disorder and major depressive disorder had significant reductions in the TNFR2 mRNA expression in the dorsolateral prefrontal cortex without a reduction in the anterior cingulate cortex levels [67]. Additionally, microgliaspecific actin-binding protein coronin-1a (CORO1A) [71] was decreased in the anterior prefrontal cortices of patients with major depressive disorder [72].…”