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Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons

Molecular Psychiatry volume 20, pages 1350–1365 (2015)Cite this article

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Abstract

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.

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Acknowledgements

The work was supported by grants from the California Institute for Regenerative Medicine (CIRM) TR2-01814, the National Institutes of Health through the NIH Director’s New Innovator Award Program (1-DP2-OD006495-01), A NARSAD Independent Investigator Grant to ARM; a NIH predoctoral training grant T32 GM008666 to AA; Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and by NIH (NS047344) and SAFRI to HS; NIH (NS048271, HD069184), NARSAD and MSCRF to GL; NIH (K08MH087639) to ARG; and NIH (RC2MH089956) to MWS. We would like to thank the ASD individuals and their families, Daniela Franco Bueno and Gerson Shigeru Kobayashi for the DPC control samples, Kristin Rose for technical support, and Dr Willmar Schwabe, GmbH & Co, Karlsruhe, Germany, for providing hyperforin.

Author information

Author notes

  1. K Griesi-Oliveira and A Acab: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California San Diego, School of Medicine, La Jolla, CA, USA

    K Griesi-Oliveira, A Acab, T Chailangkarn, Y Nunez & A R Muotri

  2. Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil

    K Griesi-Oliveira, D Y Sunaga & M R Passos-Bueno

  3. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA,

    A R Gupta

  4. Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA,

    X Nicol & N Spitzer

  5. Departments of Genetics and Psychiatry, Program on Neurogenetics, Child Study Center, Yale University School of Medicine, New Haven, CT, USA

    M F Walker, J D Murdoch, S J Sanders, T V Fernandez & M W State

  6. Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

    W Ji & R P Lifton

  7. Instituto de Psiquiatria do Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil

    E Vadasz

  8. Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, Germany

    A Dietrich

  9. The Solomon H Snyder Department of Neuroscience/Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Pradhan, H Song & G-l Ming

  10. Department of Pediatrics/Rady Children's Hospital San Diego, Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA

    X Gu & G Haddad

  11. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA

    M C N Marchetto

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  1. K Griesi-Oliveira
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Correspondence to A R Muotri.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Griesi-Oliveira, K., Acab, A., Gupta, A. et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 20, 1350–1365 (2015). https://doi.org/10.1038/mp.2014.141

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  • DOI: https://doi.org/10.1038/mp.2014.141

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