Pharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation
Open Access
- 3 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-11
- https://doi.org/10.1038/s41467-021-21713-3
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U19MH106434, R01MH105128)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R35NS116843, R35NS097370)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke
This publication has 48 references indexed in Scilit:
- DISC1–ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1Molecular Psychiatry, 2013
- Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling PathwayPLOS ONE, 2011
- DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathwayNeuroscience Research, 2011
- Activation of silent and weak synapses by cAMP-dependent protein kinase in cultured cerebellar granule neuronsJournal Of Physiology-London, 2011
- Modelling schizophrenia using human induced pluripotent stem cellsNature, 2011
- Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutationMolecular Psychiatry, 2011
- Reversal of long-term dendritic spine alterations in Alzheimer disease modelsProceedings of the National Academy of Sciences of the United States of America, 2009
- Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memoryProceedings of the National Academy of Sciences of the United States of America, 2009
- Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humansProceedings of the National Academy of Sciences of the United States of America, 2007