title: Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons.
abstract: Autism spectrum disorder is a complex neurodevelopmental disorder whose pathophysiology remains elusive as a consequence of the unavailability for study of patient brain neurons; this deficit may potentially be circumvented by neural differentiation of induced pluripotent stem cells. Rare syndromes with single gene mutations and autistic symptoms have significantly advanced the molecular and cellular understanding of autism spectrum disorders; however, in aggregate, they only represent a fraction of all cases of autism. In an effort to define the cellular and molecular phenotypes in human neurons of non-syndromic autism, we generated induced pluripotent stem cells (iPSCs) from three male autism spectrum disorder patients who had no identifiable clinical syndromes, and their unaffected male siblings and subsequently differentiated these patient-specific stem cells into electrophysiologically active neurons. iPSC-derived neurons from these autistic patients displayed decreases in the frequency and kinetics of spontaneous excitatory postsynaptic currents relative to controls, as well as significant decreases in Na+and inactivating K+voltage-gated currents. Moreover, whole-genome microarray analysis of gene expression identified 161 unique genes that were significantly differentially expressed in autistic patient iPSC-derived neurons (>twofold, FDR < 0.05). These genes were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions, and were enriched for genes previously associated with autism spectrum disorder. Our data demonstrate aberrant voltage-gated currents and underlying molecular changes related to synaptic function in iPSC-derived neurons from individuals with idiopathic autism as compared to unaffected siblings controls.
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.|School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiaozhuo
authors.identifier: 0000-0003-2237-1016
authors.initials: X
authors.lastname: Liu
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Development Neuroscience, NICHD, NIH, 35 Convent Drive, MSC 4995, Porter Neuroscience Research Center Building 35, Room 3C-905, Bethesda, MD, 20892-4995, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Campanac
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.|CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hoi-Hung
authors.initials: HH
authors.lastname: Cheung
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.|Baylor College of Medicine, Houston, TX, 77030, USA.|University at Cambridge, Cambridge, CB3 9AN, UK.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Ziats
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.
authors.forename: Lucile
authors.initials: L
authors.lastname: Canterel-Thouennon
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Raygada
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Baxendale
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.
authors.forename: Alan Lap-Yin
authors.initials: AL
authors.lastname: Pang
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health (NIMH), NIH, Bethesda, MD, 20892, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Swedo
authors.affiliation: Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health (NIMH), NIH, Bethesda, MD, 20892, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Thurm
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Tin-Lap
authors.initials: TL
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.|CUHK-GIBH CAS Joint Research Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wai-Yee
authors.initials: WY
authors.lastname: Chan
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Development Neuroscience, NICHD, NIH, 35 Convent Drive, MSC 4995, Porter Neuroscience Research Center Building 35, Room 3C-905, Bethesda, MD, 20892-4995, USA. hoffmand@mail.nih.gov.
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
authors.affiliation: Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), 10 Center Drive, MSC 1255, Building 10, Room 1C-250, Bethesda, MD, 20892-1255, USA. rennerto@mail.nih.gov.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation; D002460:Cell Line; D002648:Child; D019706:Excitatory Postsynaptic Potentials; D020869:Gene Expression Profiling; D063990:Gene Ontology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D015640:Ion Channel Gating; D008297:Male; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D015221:Potassium Channels / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D015221:Potassium Channels; D015222:Sodium Channels
keywords: Autism spectrum disorder (ASD); Gene expression; Induced pluripotent stem cell (iPSC); Synaptic transmission; iPSC-derived neuron