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

Nam-Shik Kim, Zhexing Wen, Jing Liu, Ying Zhou, Ziyuan Guo, Chongchong Xu, Yu-Ting Lin, Ki-Jun Yoon, Junhyun Park, Michelle Cho, Minji Kim, Xinyuan Wang, Huimei Yu, Srilatha Sakamuru, Kimberly M. Christian, Kuei-sen Hsu, Menghang Xia, Weidong Li, Christopher A. Ross, Russell L. Margolis, Xin-Yun Lu (), Hongjun Song () and Guo-li Ming ()
Additional contact information
Nam-Shik Kim: University of Pennsylvania
Zhexing Wen: Emory University School of Medicine
Jing Liu: University of Texas Health Science Center at San Antonio
Ying Zhou: Johns Hopkins University School of Medicine
Ziyuan Guo: University of Pennsylvania
Chongchong Xu: Emory University School of Medicine
Yu-Ting Lin: Johns Hopkins University School of Medicine
Ki-Jun Yoon: University of Pennsylvania
Junhyun Park: Johns Hopkins University School of Medicine
Michelle Cho: Johns Hopkins University School of Medicine
Minji Kim: Johns Hopkins University School of Medicine
Xinyuan Wang: University of Pennsylvania
Huimei Yu: Johns Hopkins University School of Medicine
Srilatha Sakamuru: National Institutes of Health, 9800 Medical Center Drive
Kimberly M. Christian: University of Pennsylvania
Kuei-sen Hsu: National Cheng Kung University
Menghang Xia: National Institutes of Health, 9800 Medical Center Drive
Weidong Li: Shanghai Jiao Tong University
Christopher A. Ross: Johns Hopkins University School of Medicine
Russell L. Margolis: Johns Hopkins University School of Medicine
Xin-Yun Lu: University of Texas Health Science Center at San Antonio
Hongjun Song: University of Pennsylvania
Guo-li Ming: University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21713-3

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