Modelling schizophrenia using human induced pluripotent stem cells

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  • A Corrigendum to this article was published on 19 October 2011

Abstract

Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80–85%1. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue2 and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD3, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood4,5,6. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.

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Figure 1: Patient-specific hiPSCs, NPCs and neurons.
Figure 2: Decreased neuronal connectivity in SCZD hiPSC neurons.
Figure 3: Decreased neurites and synaptic protein levels but normal electrophysiological and spontaneous calcium transient activity in SCZD hiPSC neurons.
Figure 4: RNA expression analysis of control and SCZD hiPSC neurons.

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Primary accessions

Gene Expression Omnibus

Data deposits

The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE25673. As per our agreement with Coriell Cell Repository, all hiPSC lines generated from control and schizophrenic fibroblasts will only be available from Coriell.

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Acknowledgements

L. Moore, B. Miller, K. Stecker, J. Jepsen, D. Sepp, S. Larkin and L. Johnson provided technical assistance. T. Berggren directs, and M. Lutz manages, the Salk Stem Cell facility. D. Gibbs directs the Salk Viral Vector Core. J. Nguyen and L. Ouyang provided gene expression support. D. Chambers and J. Barrie provided FACS support. E. Callaway and I. Wickersham provided rabies trans-neuronal tracing viruses and invaluable advice and scientific feedback. M. Lawson provided assistance with statistical analysis. Thanks to G. Yeo, M. McConnell, S. Aigner, C. Marchetto and L. Boyer for advice and conversation. K.J.B. is supported by a training grant from the California Institute for Regenerative Medicine. The Gage Laboratory, and this project, is partially funded by CIRM Grant RL1-00649-1, The Lookout and Mathers Foundation, the Helmsley Foundation as well as Sanofi-Aventis.

Author information

K.J.B. designed the experiments with F.H.G. K.J.B. completed the experiments and wrote the manuscript. A.S. contributed to the microarray analysis and qPCR experiments. J.J. established the synaptic density assay and completed the calcium transient experiments. C.G.-B. and S.S. performed most of the synaptic protein experiments. N.T. analysed the rabies data. N.T. and S.S. together counted neurites. Y.L., Y.M. and G.C. performed electrophysiology. D.Y. established the calcium transient assay. S.M.C. and J.S. completed the CNV analysis.

Correspondence to Fred H. Gage.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Information The file contains Supplementary Tables 1-8 and Supplementary Figures 1-12 with legends. This file was replaced on 19 October 2011; see accompanying corrigendum doi:10/1038 nature 10603 for details. (PDF 7519 kb)

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Brennand, K., Simone, A., Jou, J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011) doi:10.1038/nature09915

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