Cortical Transcriptomic Profiling Reveals Cellular and Mitochondrial Adaptive Stress Signatures That Differ Between...

Identifying the nature of mitochondrial perturbations in brain regions dysfunctional in schizophrenia (SZ) and bipolar disorder (BP) is essential to decipher their disease processes. Employing "threshold-free" analytical approaches that evaluate patterns of gene expression differences and functional pathway enrichment can inform the shared and distinct aspects of SZ and BP disease processes. We hypothesized that transcriptomic signatures will be concordant, selectively within brain regions affected in both disorders.

SZ and BP transcriptomic signatures were evaluated in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), 2 regions that mediate different functions and are differentially affected by the disorders. Rank-rank hypergeometric overlap and gene-set enrichment analysis, 2 complementary analytical approaches that incorporate multiple quantitative measures to identify patterns of gene expression differences, were applied for transcriptome-wide and Gene Ontology "Mitochondria" (GO_Mito) analysis.

SZ disease effects were highly concordant across the DLPFC and ACC; findings reflected lower oxidative phosphorylation (OXPHOS) and greater translational repression. BP disease effects were weakly concordant across the DLPFC and ACC. Cross-diagnostic comparisons revealed transcriptomic concordance predominately within the ACC, especially for OXPHOS genes.

The SZ and BP disease effects on biological processes, particularly OXPHOS, are similar within the ACC but not the DLPFC. The overall constellation of findings in SZ was highly consistent with protective cellular responses that re-establish homeostasis after pathogenic insults. Together, these findings provide key insight into the potential substrates of DLPFC and ACC dysfunction that is associated with cognitive and affective dysregulation, respectively, in SZ and BP.