FUNCTIONAL AND MOLECULAR PROFILING OF IPSC-DERIVED CELL TYPES FROM BIPOLAR DISORDER PATIENTS IN SPANISH MULTIPLEX FAMILIES

Bipolar Disorder (BD) is a highly heritable neuropsychiatric condition, yet the molecular and cellular mechanisms linking genetic risk to neural function remain poorly understood. This study utilises induced pluripotent stem cells (iPSC)-derived cell types to investigate cell type-specific disease relevant phenotypes associated with BD type 1. Our central hypothesis is that patient-derived iPSCs exhibit alterations in neurodevelopmental trajectories and calcium signalling across distinct cellular lineages. We differentiated iPSC lines from four BD type 1 patients (from multiplex families) and four age- and sex-matched unrelated controls into cortical progenitors, neurons, and astrocytes. To characterise molecular and cellular differences, we conducted transcriptomic profiling and high throughput immunocytochemistry using the Opera Phenix (PerkinElmer/Revvity) platform. In cortical progenitors, differential expression analysis revealed dysregulation of neurodevelopmental genes, notable members of the ephrin signalling family. BD iPSC-derived neurons exhibited altered expression of protocadherin family genes, along with key neuropsychiatric risk genes including DISC1 and NRXN1. BD iPSC-derived astrocytes displayed differential expression of astrocytic glutamate transporter genes, potentially indicating dysregulated maturation and potential cellular stress responses. Integrative transcriptomic analysis revealed consistent dysregulation of calcium signalling across the cell types. We are currently in the process of validating the above findings and correlating them with morphological and electrophysiological alterations. Through this cell type specific approach, we attempt to uncover key pathways underlying BD pathophysiology and for the development of pathway-based therapeutic strategies.