95. EFFECTS OF MOOD STABILIZING DRUGS IN CELL VILLAGES OF HUMAN IPSC-DERIVED CORTICAL NEURONS

Background Bipolar disorder (BD) is a highly heritable, lifelong mood disorder that impairs quality of life and is a strong risk factor for suicide. Lithium (LiCl) and valproic acid (VPA) are first-line BD treatments used as monotherapy or in combination. Although extensively studied, the precise molecular mechanisms underlying their mood-stabilizing effects remain elusive. A better understanding of shared molecular mechanisms would inform and assist novel drug development. Methods We investigated whether LiCl and VPA exert convergent gene expression changes using human iPSC-derived neurons and “cell villages,” in which thousands of cells from multiple donors are pooled and differentiated together. iPSCs from 14 unaffected individuals were differentiated into neural progenitors, pooled, then further differentiated into cortical neurons. After four weeks, neurons were assigned to one of three conditions: a) untreated controls, b) 1 mM LiCl for two weeks, c) 1 mM VPA for 72 hours. Single-cell RNA sequencing was performed, and transcribed SNPs were used to assign cells to donors. Results Transcriptomic analysis revealed differential expression of numerous genes, especially after VPA treatment. More than 500 differentially expressed genes were affected by both LiCl and VPA – a significant overlap – with convergence largely driven by upregulated genes. Gene set enrichment analysis revealed that upregulated genes were enriched for mitochondrial function and ATP synthesis pathways, suggesting that neuronal energy metabolism may be a convergent downstream target of mood stabilizers. Discussion LiCl and VPA induced convergent transcriptomic effects in neurons. This convergence highlights mitochondrial and bioenergetic pathways, suggesting shared downstream mechanisms for these drugs despite distinct primary modes of action. Ongoing work includes confirmatory assays of mitochondrial function, gene regulatory network analyses, and expansion of cell villages to increase sample size and assay other psychotropics. A shared molecular signature of mood stabilizing drugs would be an important step toward novel, rational therapeutics.