Involvement of the nuclear factor-\u03baB transcriptional complex in prefrontal cortex immune activation in bipolar disorder

Kaitlyn M Roman,David A Lewis,David W Volk,Aaron K Jenkins

doi:10.1038/s41398-020-01092-x

Abstract

Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.

Highlights

Bipolar disorder shares several clinical and genetic features with schizophrenia
In this study, we investigated nuclear factor-κB (NF-κB) signaling in the prefrontal cortex (PFC) of bipolar disorder subjects by quantifying mRNA levels for NF-κB family members (NF-κB1, NF-κB2, RelA, RelB, and cRel), receptors that initiate NF-κB signaling (IL-1R, TNFR), NF-κB transcriptional activity-regulated products (IFITMs), and an NF-κB inhibitor (HIVEP2)
We found that bipolar disorder subjects have higher mRNA levels for three NF-κB family members, NF-κB2, RelA, and cRel, relative to unaffected comparison subjects

Summary

Introduction

Bipolar disorder shares several clinical and genetic features with schizophrenia. Certain clinical features, including cognitive dysfunction and psychotic symptoms[1], are present in both schizophrenia and bipolar disorder. Schizophrenia and bipolar disorder share some genetic risk, including overlapping susceptibility loci in immune-related genes[2,3,4,5]. Recent studies have uncovered molecular evidence indicating the presence of cortical immune activation in individuals with schizophrenia. Elevated NF-κB activity appears to play a central role in cortical immune activation in schizophrenia. These findings raise the question of whether the elevated NF-κB activity seen in schizophrenia is present in bipolar disorder

Methods

Results

Conclusion