Nat Neurosci. 2019 Jan 21. doi: 10.1038/s41593-018-0313-z. [Epub ahead of print]

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

Shao Z^1,2, Noh H^1,3, Bin Kim W⁴, Ni P^1,3, Nguyen C¹, Cote SE¹, Noyes E¹, Zhao J¹, Parsons T¹, Park JM³, Zheng K³, Park JJ³, Coyle JT¹, Weinberger DR⁵, Straub RE⁵, Berman KF⁶, Apud J⁶, Ongur D¹, Cohen BM¹, McPhie DL¹, Rapoport JL⁷, Perlis RH⁸, Lanz TA⁹, Xi HS¹⁰, Yin C¹¹, Huang W¹¹, Hirayama T^12,13, Fukuda E¹², Yagi T¹², Ghosh S¹⁴, Eggan KC¹⁴, Kim HY¹⁵, Eisenberg LM¹⁶, Moghadam AA³, Stanton PK³, Cho JH¹⁷, Chung S^18,19.

Abstract

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.