title: Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits.
abstract: Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8+/-mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8+/-animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland; Department of Chemistry, University of Basel, Basel 4056, Switzerland. Electronic address: rplatt@ethz.ch.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Platt
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Slaymaker
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ashwin S
authors.initials: AS
authors.lastname: Shetty
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland.
authors.forename: Niels R
authors.initials: NR
authors.lastname: Weisbach
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Radiology, Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.
authors.forename: Mitul
authors.initials: M
authors.lastname: Desai
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sood
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Kempton
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Crabtree
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: zhang@broadinstitute.org.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics; D003342:Corpus Striatum / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D018095:Germ-Line Mutation; D006657:Histones / Q000235:genetics; D006801:Humans; D058627:Megalencephaly / Q000235:genetics* / Q000473:pathology; D051379:Mice; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C515814:duplin protein, mouse
keywords: CRISPR; Cas9 knockin mouse; ChIP-seq; MRI; RNA-seq; adeno-associated virus; autism spectrum disorder; behavior; neocortical development; physiology