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

Marchetto, Maria C.; Belinson, Haim; Tian, Yuan; Freitas, Beatriz C.; Fu, Chen; Vadodaria, Krishna; Beltrao-Braga, Patricia; Trujillo, Cleber A.; Mendes, Ana P.D.; Padmanabhan, Krishnan; Nunez, Yanelli; Ou, Jing; Ghosh, Himanish; Wright, Rebecca; Brennand, Kristen; Pierce, Karen; Eichenfield, Lawrence; Pramparo, Tiziano; Eyler, Lisa; Barnes, Cynthia C.; Courchesne, Eric; Geschwind, Daniel H.; Gage, Fred H.; Wynshaw-Boris, Anthony; Muotri, Alysson R.

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

July 05 2016

By Marchetto, Maria C. ; Belinson, Haim ; Tian, Yuan ; ...

Source: Mol Psychiatry. 22(6):820-835

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Alternative Title:

Mol Psychiatry

Personal Author:

Marchetto, Maria C. ; Belinson, Haim ; Tian, Yuan ; Freitas, Beatriz C. ; Fu, Chen ; ... More +

Description:

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.

Subject:

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Source:

Mol Psychiatry. 22(6):820-835

Pubmed ID:

27378147

Pubmed Central ID:

PMC5215991

Document Type:

Journal Article

Funding:

KL2 TR000099/NCATS NIH HHS/National Center for Advancing Translational Sciences/United States ; DP2 OD006495/ODCDC CDC HHS/Office of the Director/United States ; R01 MH113924/NIMH NIH HHS/National Institute of Mental Health/United States ; R01 MH100175/NIMH NIH HHS/National Institute of Mental Health/United States ; R01 MH094753/NIMH NIH HHS/National Institute of Mental Health/United States ; ... More +

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CDC Public Access

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