Pharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation

• Authors: Nam-Shik Kim, University of Pennsylvania; Zhexing Wen, Emory University; Jing Liu, University of Texas Health Science Center at San Antonio; Ying Zhou, Emory University; Ziyuan Guo, University of Pennsylvania; Chongchong Xu, Emory University; Yuting Lin, Emory University; Ki-Jun Yoon, University of Pennsylvania; Junhyun Park, Johns Hopkins University; Michelle Cho, Johns Hopkins University; Minji Kim, Johns Hopkins University; Xinyuan Wang, University of Pennsylvania; Huimei Yu, Johns Hopkins University; Srilatha Salamuru, National Center for Advancing Translational Sciences MD; Kimberly M Christian, University of Pennsylvania; Kuei-Sen Hsu, Natl Cheng Kung Univ; Menghang Xia, National Center for Advancing Translational Sciences MD; Weidong Li, Shanghai Jiao Tong University; Christopher A Ross, Johns Hopkins University; Russell L Margolis, Johns Hopkins University; Xin-Yun Lu, Univ Texas Hlth Sci Ctr San Antonio; Hongjun Song, University of Pennsylvania; Guo-Li Ming, University of Pennsylvania
• Journal Title: NATURE COMMUNICATIONS
• Volume: Volume 12, Number 1
• Publisher: NATURE RESEARCH | 2021-03-03, Pages 1398-1398
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-021-21713-3
• Subjects: Health Sciences, Pharmacology; Biology, Neuroscience; Biology, Cell
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics

Abstract

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.