Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids

Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/beta-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.

Automated summary

Exposure to valproic acid during pregnancy increases the risk of autism spectrum disorder in children. In this study, human dorsal forebrain organoids were used to model the effects of VPA exposure on cortical neurogenesis. The findings showed that VPA exposure reduced the size of neural progenitor cells and impaired their proliferation and expansion. It also delayed the development of certain types of cells and influenced the expression of ASD risk genes. The activation of the Wnt/beta-catenin signaling pathway was identified as essential for sustaining cortical neurogenesis.