Human forebrain organoids reveal connections between valproic acid exposure and autism risk
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-03-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-022-01898-x |
| _version_ | 1819049250453979136 |
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| author | Qingtuan Meng Wendiao Zhang Xuan Wang Chuan Jiao Sheng Xu Chunyu Liu Beisha Tang Chao Chen |
| author_facet | Qingtuan Meng Wendiao Zhang Xuan Wang Chuan Jiao Sheng Xu Chunyu Liu Beisha Tang Chao Chen |
| author_sort | Qingtuan Meng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T11:29:10Z |
| format | Article |
| id | doaj.art-0a8ca4d5c9cd4ceaaa3a5c48d51e25c7 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-21T11:29:10Z |
| publishDate | 2022-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-0a8ca4d5c9cd4ceaaa3a5c48d51e25c72022-12-21T19:05:36ZengNature Publishing GroupTranslational Psychiatry2158-31882022-03-011211810.1038/s41398-022-01898-xHuman forebrain organoids reveal connections between valproic acid exposure and autism riskQingtuan Meng0Wendiao Zhang1Xuan Wang2Chuan Jiao3Sheng Xu4Chunyu Liu5Beisha Tang6Chao Chen7The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South UniversityCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South UniversityDepartment of Psychiatry, SUNY Upstate Medical UniversityCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South UniversityDepartment of Psychiatry, SUNY Upstate Medical UniversityThe First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South UniversityAbstract 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.https://doi.org/10.1038/s41398-022-01898-x |
| spellingShingle | Qingtuan Meng Wendiao Zhang Xuan Wang Chuan Jiao Sheng Xu Chunyu Liu Beisha Tang Chao Chen Human forebrain organoids reveal connections between valproic acid exposure and autism risk Translational Psychiatry |
| title | Human forebrain organoids reveal connections between valproic acid exposure and autism risk |
| title_full | Human forebrain organoids reveal connections between valproic acid exposure and autism risk |
| title_fullStr | Human forebrain organoids reveal connections between valproic acid exposure and autism risk |
| title_full_unstemmed | Human forebrain organoids reveal connections between valproic acid exposure and autism risk |
| title_short | Human forebrain organoids reveal connections between valproic acid exposure and autism risk |
| title_sort | human forebrain organoids reveal connections between valproic acid exposure and autism risk |
| url | https://doi.org/10.1038/s41398-022-01898-x |
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