2. Academic Validation
  3. Human forebrain organoids reveal connections between valproic acid exposure and autism risk

Human forebrain organoids reveal connections between valproic acid exposure and autism risk

  • Transl Psychiatry. 2022 Mar 29;12(1):130. doi: 10.1038/s41398-022-01898-x.
Qingtuan Meng 1,  Wendiao Zhang 2,  Xuan Wang 2,  Chuan Jiao 3,  Sheng Xu 2,  Chunyu Liu 3,  Beisha Tang 4,  Chao Chen 5 6 7
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China.
  • 2 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
  • 3 Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
  • 4 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China. [email protected].
  • 5 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. [email protected].
  • 6 Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, 410008, Changsha, Hunan, China. [email protected].
  • 7 Hunan Key Laboratory of Molecular Precision Medicine, Central South University, 410008, Changsha, Hunan, China. [email protected].
PMID: 35351869 DOI: 10.1038/s41398-022-01898-x
Abstract

Valproic acid (VPA) exposure as an environmental factor that confers risk of autism spectrum disorder (ASD), its functional mechanisms in the human brain remain unclear since relevant studies are currently restricted to two-dimensional cell cultures and animal models. To identify mechanisms by which VPA contribute to ASD risk in human, here we used human forebrain organoids (hFOs), in vitro derived three-dimensional cell cultures that recapitulate key human brain developmental features. We identified that VPA exposure in hFOs affected the expression of genes enriched in neural development, synaptic transmission, oxytocin signaling, calcium, and potassium signaling pathways, which have been implicated in ASD. Genes (e.g., CAMK4, CLCN4, DPP10, GABRB3, KCNB1, PRKCB, SCN1A, and SLC24A2) that affected by VPA were significantly overlapped with those dysregulated in brains or organoids derived from ASD patients, and known ASD risk genes, as well as genes in ASD risk-associated gene coexpression modules. Single-cell RNA sequencing analysis showed that VPA exposure affected the expression of genes in choroid plexus, excitatory neuron, immature neuron, and medial ganglionic eminence cells annotated in hFOs. Microelectrode array further identified that VPA exposure in hFOs disrupted synaptic transmission. Taken together, this study connects VPA exposure to ASD pathogenesis using hFOs, which is valuable for illuminating the etiology of ASD and screening for potential therapeutic targets.

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