Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits
Randall J. Platt,
Yang Zhou,
Ian M. Slaymaker,
Ashwin S. Shetty,
Niels R. Weisbach,
Jin-Ah Kim,
Jitendra Sharma,
Mitul Desai,
Sabina Sood,
Hannah R. Kempton,
Gerald R. Crabtree,
Guoping Feng,
Feng Zhang
Affiliations
Randall J. Platt
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; Corresponding author
Yang Zhou
Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA
Ian M. Slaymaker
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
Ashwin S. Shetty
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
Niels R. Weisbach
Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland
Jin-Ah Kim
Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA
Jitendra Sharma
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
Mitul Desai
Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA
Sabina Sood
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
Hannah R. Kempton
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Gerald R. Crabtree
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
Guoping Feng
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
Feng Zhang
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; Corresponding author
Summary: 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. : Platt et al. demonstrate that loss-of-function mutation of the high-confidence ASD-associated gene Chd8 results in behavioral and synaptic defects in mice. Keywords: CRISPR, autism spectrum disorder, MRI, behavior, RNA-seq, ChIP-seq, physiology, neocortical development, adeno-associated virus, Cas9 knockin mouse
