CELL DEATH TRANSCRIPTS OF THE TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY ARE INCREASED IN THE MIDBRAINS OF SCHIZOPHRENIA AND BIPOLAR DISORDER WITH HIGH INFLAMMATION AND ARE NEGATIVELY ASSOCIATED WITH DOPAMINE TRANSCRIPTS
Authors: Victoriano *Gerardo Mendez , Zhu Yunting , Middleton Frank , Webster Maree J , Weickert Cynthia S 
Published: February 2025

Abstract

Background
Whereas it is still unclear if cell death occurs in the brains of people with schizophrenia and bipolar disorder, it is well established that neuroinflammation and dopaminergic imbalances are key neuropathological hallmarks of these diseases. It is known that proinflammatory molecules promote the activation of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) cell death pathway, and increased markers of this cell death pathway have been found in the prefrontal cortex, hippocampus, and serum of people with schizophrenia and bipolar disorder. We have previously found increased expression of proinflammatory molecules(1-4) and decreased dopamine-related transcripts in the midbrains of people with schizophrenia and bipolar disorder(5). However, it is not known if transcripts of the TNFRSF cell death pathway are altered in the midbrains of patients who display high Inflammation, nor if the expression of these cell death markers could be associated with the expression of dopamine-related transcripts.

Aims
to evaluate the mRNA expression levels of TNFRSF cell death markers in the midbrains of people with schizophrenia and bipolar disorder with high inflammation compared to healthy controls and correlate them with dopamine-associated mRNA markers.

Methods
Normalized mRNA levels of five TNFRSF receptors TNFR1/2, DR4, FAS and TWEAKR, and 10 downstream transcripts (APAF1, BAX, BID, BCL2, MCL1, P53, caspases 1,3,8 and 9) were measured and compared via reverse transcriptase- quantitative PCR from Human post-mortem midbrains of 61 healthy controls, 63 schizophrenia, and 33 bipolar disorder cases. mRNA expression levels of the TNFRSF receptors were correlated with the expression of dopamine-associated mRNA markers. Results: We found that mRNA levels of all five TNFRSF receptors were significantly increased in schizophrenia and bipolar disorder cases with high inflammation compared to low inflammation controls (all p&lt;0.01). Pro-cell death downstream mRNA markers P53 and caspases 1 and 8 were significantly higher only in the high inflammation schizophrenia group compared to low inflammation controls (all p&lt;0.05). Pro-cell survival downstream mRNA markers were increased in bipolar (BCL2 and MCL1) and schizophrenia (MCL1) high inflammation compared to low inflammation controls (all p&lt;0.01). All five TNFRSF receptors had negative associations with dopamine neuron differentiation, maintenance, survival (NURR1, EN1, and PITX3), and dopamine synthesis (TH) mRNA markers (all p&lt;0.05).

Discussion & Conclusion
Our results suggest a transcriptional activation of TNFRSF cell death pathways in the midbrains of people with schizophrenia and bipolar disorder who exhibit elevated inflammation, and show how this cell death activation could be affecting midbrain dopaminergic neurons. These findings provide insight into the consequences of high inflammation in the midbrain, strengthen the hypothesis of cell death occurring in the brains of people with schizophrenia and bipolar disorder, and provide hints on plausible mechanisms underlying the dopaminergic imbalances present in these psychiatric disorders.

References
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