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Abstract

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

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Acknowledgements

This work was supported by grants from the California Institute for Regenerative Medicine (CIRM) TR2-01814 and TR4-06747, the National Institutes of Health through the NIH Director’s New Innovator Award Program (1-DP2-OD006495-01), an R01 MH100175-01 and U19MH107367 from NIMH, the International Rett Syndrome Foundation (IRSF Grant No. 2915); a NARSAD Independent Investigator Award to ARM, and NIMH Autism Center of Excellence Program Project grant (to EC, KP, AW-B and FHG); this work was also supported by the Helmsley Trust, the JPB Foundation, the Engmann Foundation, a grant from the CDMRP Autism Research Program (to AW-B and FHG); a KL2 CTRI (KL2TR00099) to TP and Postdoctoral Translational Fellowship from Autism Speaks to HB.

Author information

Author notes

    • M C Marchetto
    •  & H Belinson

    These two authors contributed equally to this work.

Affiliations

  1. Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA

    • M C Marchetto
    • , K C Vadodaria
    • , A P D Mendes
    • , Y Nunez
    • , H Ghosh
    • , R Wright
    •  & F H Gage
  2. Department of Pediatrics, Institute for Human Genetics, University of California, San Francisco, CA, USA

    • H Belinson
    •  & A Wynshaw-Boris
  3. Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    • Y Tian
    • , J Ou
    •  & D H Geschwind
  4. Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, University of California, San Diego, La Jolla, CA, USA

    • B C Freitas
    • , P C Beltrao-Braga
    • , C A Trujillo
    • , Y Nunez
    •  & A R Muotri
  5. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    • C Fu
    •  & A Wynshaw-Boris
  6. Department of Obstetrics and Surgery, Center for Cellular and Molecular Therapy, University of São Paulo, São Paulo, Brazil

    • P C Beltrao-Braga
  7. Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    • K Padmanabhan
  8. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • K J Brennand
  9. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    • K Pierce
    • , L Eichenfield
    • , T Pramparo
    • , L T Eyler
    • , C C Barnes
    •  & E Courchesne

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to A Wynshaw-Boris or A R Muotri.

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DOI

https://doi.org/10.1038/mp.2016.95

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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