Journal Article

Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI) ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude des Cellules Souches (CECS), Vitrac, Aline, Cloëz-Tayarani, Isabelle, Université Paris-Saclay, Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE) ; Institut National de la Recherche Agronomique (INRA), Goubran-Botros, Hany, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Recherche en Génomique Humaine (CNRGH) ; Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Tinevez, Jean

2019

Overview

The synaptic protein SHANK3 encodes a multidomain scafold protein expressed at the postsynapticdensity of neuronal excitatory synapses. We previously identifed de novo SHANK3 mutations inpatients with autism spectrum disorders (ASD) and showed that SHANK3 represents one of the majorgenes for ASD. Here, we analyzed the pyramidal cortical neurons derived from induced pluripotent stemcells from four patients with ASD carrying SHANK3 de novo truncating mutations. At 40–45 days afterthe diferentiation of neural stem cells, dendritic spines from pyramidal neurons presented variablemorphologies: flopodia, thin, stubby and muschroom, as measured in 3D using GFP labeling andimmunofuorescence. As compared to three controls, we observed a signifcant decrease in SHANK3mRNA levels (less than 50% of controls) in correlation with a signifcant reduction in dendritic spinedensities and whole spine and spine head volumes. These results, obtained through the analysis of denovo SHANK3 mutations in the patients’ genomic background, provide further support for the presenceof synaptic abnormalities in a subset of patients with ASD.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK
• Subject: 13/100 / 13/106 / 13/44 / 13/51 / 14/19 / 38 / 38/39 / 38/90 / 45/91 / 631/378/2597 / 631/45/500 / 631/80 / Autism / Autistic Disorder - genetics / Autistic Disorder - pathology / Cell Differentiation / Dendrites - pathology / Dendritic spines / Filopodia / Humanities and Social Sciences / Humans / Immunofluorescence / Induced Pluripotent Stem Cells - physiology / Life Sciences / Microscopy, Fluorescence / mRNA / multidisciplinary / Mutation / Nerve Tissue Proteins - deficiency / Nerve Tissue Proteins - genetics / Neural stem cells / Pluripotency / Postsynaptic density / Pyramidal cells / Pyramidal Cells - cytology / Pyramidal Cells - pathology / Science / Science (multidisciplinary) / Sequence Deletion / Spine / Stem cells / Synapses
• ISBN: 0004555923000