Transcriptomic effects of mood stabilizing drugs on the gene regulatory network in cell villages of human iPSC-derived cortical neurons

Authors

  • LN Lacbawan
  • SD Detera-Wadleigh
  • N Akula
  • FJ McMahon

Abstract

Lithium (LiCl) and valproic acid (VPA) are first-line treatments for bipolar disorder (BD). Our study used renewable human iPSC-derived neuronal cells and a “cell village” culture approach to determine the impact of mood stabilizers on gene expression and transcriptional regulation. iPSCs from four healthy, unrelated individuals were differentiated into neural progenitor cells, pooled into a “cell village,” and differentiated into cortical neurons. Neurons grown post differentiation up to six weeks were divided into groups: a) untreated, b) treated with 1 mM LiCl for two weeks, and c) treated with 1 mM VPA for 72 hours. Transcriptomic analysis of lithium treated villages showed ~70 genes were significantly differentially expressed (p adj<0.05). VPA treatment revealed ~5900 genes were significantly differentially expressed (p adj<0.05), and g:Profiler analysis showed enrichment in synapse organization, axon guidance, and nervous system development. VPA treatment also revealed downregulation of several genes previously implicated in neuropsychiatric disorders including CACNA1C, which lies within a BD and schizophrenia (SCZ) GWAS locus and encodes a voltage-dependent calcium channel, and AKAP11 a risk gene for BD and SCZ. VPA treatment showed upregulation of several HDAC genes which are involved in chromatin remodeling. This study shows the strong effect of VPA on gene regulation in living neurons that may be relevant to its mood stabilizing action. The “cell village” strategy applied to human iPSC-derived neurons provides a potentially effective model to investigate drug mechanisms in the central nervous system. Additionally, differentially expressed genes and enriched pathways are possible targets for investigations into novel therapeutics.

Scientific Focus Area: Neuroscience

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