THE ROLE OF <EM>CACNA1C</EM> DURING NEURAL DEVELOPMENT IN BIPOLAR DISORDER

Bipolar disorder (BD) is a serious psychiatric condition characterized by episodes of depression and mania, affecting millions of people worldwide. While BD is highly heritable, its biological mechanisms remain poorly understood. Studies have identified CACNA1C, a calcium channel gene crucial for brain development and neural function, as a major genetic risk factor for BD. The strongest association is with a single nucleotide polymorphism (SNP) located in the third intronic region of the gene, but its effects on brain development are still unclear. To address this, we use an integrative approach combining patient-derived stem cell models, CRISPR-engineered isogenic lines, and advanced three-dimensional forebrain organoid systems. Neural progenitor cells (NPCs) and cortical neurons are generated from BD patient and control-derived human induced pluripotent stem cells. In these model systems, we aim to capture disease-relevant genetic backgrounds, with transcriptional profiles examined using bulk RNA sequencing. In parallel, Oxford Nanopore long-read sequencing is used to explore CACNA1C transcript diversity across developmental stages. Using isogenic lines carrying the CACNA1C risk variant, we observe differences in the proportion of cells expressing markers associated with neural progenitors (Ki67⁺) and neuronal differentiation (MAP2⁺), suggesting alterations in neurodevelopmental progression. To further investigate potential molecular mechanisms, single-cell multiome sequencing is performed to relate gene expression changes to chromatin accessibility at cell-type resolution. Together, this work uses a set of human-specific cellular models to examine how CACNA1C risk variation may influence early neurodevelopmental processes relevant to BD.