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. 2025 Oct 1;113(19):3185-3203.e7.
doi: 10.1016/j.neuron.2025.06.017. Epub 2025 Jul 21.

Forebrain assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects

Ryan M Walsh  1 , Gregg W Crabtree  2 , Kriti Kalpana  3 , Luz Jubierre  4 , So Yeon Koo  5 , Gabriele Ciceri  4 , Joseph A Gogos  6 , Ilya Kruglikov  3 , Lorenz Studer  7
Affiliations

Forebrain assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects

Ryan M Walsh et al. Neuron. .

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.

Keywords: assembloid; human PSC; human disease modeling; interneuron; organoid; parvalbumin; schizophrenia.

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Conflict of interest statement

Declaration of interests L.S. is a cofounder and consultant of BlueRock Therapeutics and DaCapo Brainscience Inc. and is listed on several patents owned by MSKCC related to this work.

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