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 Salamuru, Kimberly M. Christian, Kuei sen Hsu, Menghang Xia, Weidong Li, Christopher A. Ross, Russell L. MargolisXin Yun Lu, Hongjun Song, Guo li Ming

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Article number1398
JournalNature communications
Issue number1
StatePublished - Dec 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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