학술논문
Altered proliferation and networks in neural cells derived from idiopathic autistic individuals
Document Type
article
Author
Marchetto, MC; Belinson, H; Tian, Y; Freitas, BC; Fu, C; Vadodaria, KC; Beltrao-Braga, PC; Trujillo, CA; Mendes, APD; Padmanabhan, K; Nunez, Y; Ou, J; Ghosh, H; Wright, R; Brennand, KJ; Pierce, K; Eichenfield, L; Pramparo, T; Eyler, LT; Barnes, CC; Courchesne, E; Geschwind, DH; Gage, FH; Wynshaw-Boris, A; Muotri, AR
Source
Molecular Psychiatry. 22(6)
Subject
Language
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.