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Mol Psychiatry. 2017 Jun;22(6):820-835. doi: 10.1038/mp.2016.95. Epub 2016 Jul 5.

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals.

Author information

1
The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
2
University of California San Francisco, Department of Pediatrics, Institute for Human Genetics, CA 94143, USA.
3
University of California Los Angeles, Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, Los Angeles, CA 90402, USA.
4
University of California San Diego, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA 92093-0695, USA.
5
Case Western Reserve University, Department of Genetics and Genome Sciences, Cleveland, OH 44106, USA.
6
University of São Paulo, Department of Obstetrics, Department of Surgery, Center for Cellular and Molecular Therapy, São Paulo, Brazil.
7
University of Rochester School of Medicine and Dentistry, Department of Neuroscience, 601 Elmwood Avenue, Box 603 Rochester, NY 14642.
8
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
9
University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
#
Contributed equally

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.

PMID:
27378147
PMCID:
PMC5215991
DOI:
10.1038/mp.2016.95
[Indexed for MEDLINE]
Free PMC Article

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