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

• Published in: Molecular psychiatry Vol. 22; no. 6; pp. 820 - 835
• Main Authors: Marchetto, M C, Belinson, H, Tian, Y, Freitas, B C, Fu, C, Vadodaria, K C, Beltrao-Braga, P C, Trujillo, C A, Mendes, A P D, Padmanabhan, K, Nunez, Y, Ou, J, Ghosh, H, Wright, R, Brennand, K J, Pierce, K, Eichenfield, L, Pramparo, T, Eyler, L T, Barnes, C C, Courchesne, E, Geschwind, D H, Gage, F H, Wynshaw-Boris, A, Muotri, A R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2017; Nature Publishing Group
• Subjects: 13; 13/100; 13/106; 631/532; Adolescent; Autism; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - physiopathology; Autistic Disorder - metabolism; Autistic Disorder - pathology; Autistic persons; Behavior; Behavioral Sciences; beta Catenin - metabolism; Biological Psychology; Brain - metabolism; Brain research; Cell culture; Cell cycle; Cell proliferation; Cell Proliferation - genetics; Cells, Cultured; Child; Child, Preschool; Children & youth; Clinical trials; Disease; Female; Fibroblasts; Fibroblasts - metabolism; Gene expression; Genetic aspects; Genetics; Genomes; Growth; Growth factors; Health aspects; Humans; Induced Pluripotent Stem Cells - metabolism; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - therapeutic use; Magnetic resonance imaging; Male; Medicine; Medicine & Public Health; Molecular modelling; Neural networks; Neural stem cells; Neural Stem Cells - metabolism; Neurodevelopmental disorders; Neurogenesis; Neuroimaging; Neurons; Neurons - metabolism; Neurons - physiology; Neurosciences; original-article; Pathogenesis; Pathophysiology; Pediatrics; Pharmacotherapy; Pluripotency; Progenitor cells; Psychiatry; Stem cells; Synaptogenesis; Tissue Culture Techniques - methods; Toddlers; Transcription; β-Catenin; La Jolla California; United States > US; California
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2016.95

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.