Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder

• DOI: 10.1016/j.celrep.2017.11.037
• Publication Date: 2017-12-05T19:43:38Z
• Authors: Aditi Deshpande; Smita Yadav; Dang Q. Dao; Zhi-Yong Wu; Kenton C. Hokanson; Michelle K. Cahill; Arun P. Wiita; Yuh-Nung Jan; Erik M. Ullian; Lauren A. Weiss
• Keywords: 0301 basic medicine; Autism Spectrum Disorder; Autism; Medical Physiology; neurons; Models; Chromosome Duplication; 2.1 Biological and endogenous factors; deletion; microcephaly; Biology (General); Pediatric; Neurons; iPSC; Stem Cell Research - Induced Pluripotent Stem Cell - Human; neurodevelopmental disorders; Cell Differentiation; Biological Sciences; Mental Illness; Biological sciences; Mental Health; duplication; Neurological; Microcephaly; Mental health; Chromosome Deletion; Human; 570; DNA Copy Number Variations; QH301-705.5; Intellectual and Developmental Disabilities (IDD); 1.1 Normal biological development and functioning; Induced Pluripotent Stem Cells; 610; autism; macrocephaly; Chromosomes; 03 medical and health sciences; Genetic; Genetics; Humans; Autistic Disorder; Stem Cell Research - Induced Pluripotent Stem Cell; Models, Genetic; Pair 16; Neurosciences; Stem Cell Research; Megalencephaly; Brain Disorders; 16p11.2 CNV; Schizophrenia; Biochemistry and Cell Biology; Chromosomes, Human, Pair 16

A deletion or duplication in the 16p11.2 region is associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. In addition to clinical characteristics, carriers of the 16p11.2 copy-number variant (CNV) manifest opposing neuroanatomical phenotypes-e.g., macrocephaly in deletion carriers (16pdel) and microcephaly in duplication carriers (16pdup). Using fibroblasts obtained from 16pdel and 16pdup carriers, we generated induced pluripotent stem cells (iPSCs) and differentiated them into neurons to identify causal cellular mechanisms underlying neurobiological phenotypes. Our study revealed increased soma size and dendrite length in 16pdel neurons and reduced neuronal size and dendrite length in 16pdup neurons. The functional properties of iPSC-derived neurons corroborated aspects of these contrasting morphological differences that may underlie brain size. Interestingly, both 16pdel and 16pdup neurons displayed reduced synaptic density, suggesting that distinct mechanisms may underlie brain size and neuronal connectivity at this locus.