Forebrain assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects Journal Article
| Authors: | Walsh, R. M.; Crabtree, G. W.; Kalpana, K.; Jubierre, L.; Koo, S. Y.; Ciceri, G.; Gogos, J. A.; Kruglikov, I.; Studer, L. |
| Article Title: | Forebrain assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects |
| Abstract: | Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during development remains poorly understood. The protracted, postnatal maturation of PVALB+ cortical interneurons has complicated human pluripotent stem cell (hPSC)-based models for studying their role in neuropsychiatric disease. Here, we present a forebrain assembloid system yielding PVALB+ cortical interneurons that match the molecular identity and distinctive electrophysiology of primary PVALB+ interneurons. We further established a series of isogenic hPSC lines carrying structural variants associated with schizophrenia and identified variant-specific phenotypes affecting cortical interneuron migration, the molecular profile of PVALB+ cortical interneurons, and their ability to regulate cortical network activity, including γ-band oscillations. These findings offer plausible mechanisms for how the disruption of cortical interneuron development may impact schizophrenia risk and provide a human experimental platform to study PVALB+ cortical interneurons in health and disease. © 2025 The Authors |
| Keywords: | interneuron; schizophrenia; parvalbumin; organoid; human disease modeling; assembloid; human psc |
| Journal Title: | Neuron |
| ISSN: | 08966273 |
| Publisher: | The Authors |
| Publication status: | Online ahead of print |
| Date Published: | 2025-01-01 |
| Online Publication Date: | 2025-01-01 |
| Language: | English |
| DOI: | 10.1016/j.neuron.2025.06.017 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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