Shao Z, Noh H, Bin Kim W, Ni P, Nguyen C, Cote SE, Noyes E, Zhao J, Parsons T, Park JM, Zheng K, Park JJ, Coyle JT, Weinberger DR, Straub RE, Berman KF, Apud J, Ongur D, Cohen BM, McPhie DL, Rapoport JL, Perlis RH, Lanz TA, Xi HS, Yin C, Huang W, Hirayama T, Fukuda E, Yagi T, Ghosh S, Eggan KC, Kim HY, Eisenberg LM, Moghadam AA, Stanton PK, Cho JH, Chung S. 2019. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nature neuroscience. 22(2):229-242. Pubmed: 30664768 DOI:10.1038/s41593-018-0313-z


We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

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Kevin Eggan investigates the mechanisms that cause motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS), and seeks to translate new discoveries into new therapeutic options for patients.

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