The Toll‐Like Receptor Signalling Pathway Is Altered in iPSC ‐Derived Cortical Networks From People With Bipolar Disorder

BACKGROUND: Induced pluripotent stem cell (iPSC)-derived brain cells are widely utilised as in vitro models for several neuropsychiatric disorders, as they retain the donor's genetic profile, offering a unique opportunity to study living human brain cells and perform controlled experimental manipulations. In this study, we conducted whole transcriptome sequencing of cortical networks (co-cultures of neurons and astrocytes) derived from 12 participants with bipolar disorder (BD) and 12 participants without a history of mental health disorders. Aiming to identify new molecular mechanisms underlying the pathophysiology of bipolar disorder. METHODS: iPSCs were generated by reprogramming peripheral blood mononuclear cells (PBMCs) using episomal vectors. iPSCs were then differentiated into neural progenitor cells (NPCs) and matured into cortical networks (CNs) that express markers of neurons and astrocytes. Whole transcriptome data were obtained using the Illumina NovaSeq X sequencing platform. Differential expression analysis was performed using DESeq2 in R. RESULTS: Gene set enrichment analysis identified 191 enriched pathways in BD, 171 were downregulated, and around 10% were associated with the immune system. Of these, the toll-like signalling pathway, which is downregulated in BD, was further investigated. CONCLUSION: Our results suggest a profound immune dysregulation in BD, with downregulation of the sensing innate immune system, particularly highlighting the immune system's role as a complex signalling network.