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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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.
The authors declare no conflict of interest.
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Marchetto, M., Belinson, H., Tian, Y. et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 22, 820–835 (2017). https://doi.org/10.1038/mp.2016.95
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