La mutation Chd8 conduit à des comportements autistiques et des circuits striatés détériorés

Aperçu: G.M.

Les chercheurs ont généré des souris mutantes de la lignée germinale avec des mutations de perte de fonction dans Chd8, une mutation de novo fortement associée aux TSA, et isl démontrent que ces souris présentent des comportements caractéristiques du TSA, une macrocéphalie et des anomalies craniofaciales similaires aux phénotypes des personnes avec un diagnostic de TSA.

Les souris Chd8 +/- présentent une large dérégulation spécifique de la région du cerveau des principaux processus de régulation et cellulaires, notamment la modification des histones et de la chromatine, le traitement des ARNm et des protéines, la signalisation Wnt et la régulation du cycle cellulaire, ainsi qu'une physiologie synaptique altérée dans les neurones épineux moyens du noyau accumbens. La perturbation du Chd8 chez les souris adultes récapitule l'amélioration du comportement d'apprentissage moteur acquis chez les animaux Chd8 +/-, ce qui suggère un rôle pour la CHD8 dans les circuits du stratum des adultes.  

Ces résultats supportent un mécanisme reliant la modification de la chromatine au dysfonctionnement striatal et la pathologie moléculaire des TSA. 

Cell Rep. 2017 Apr 11;19(2):335-350. doi: 10.1016/j.celrep.2017.03.052.

Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits

Platt RJ¹, Zhou Y², Slaymaker IM³, Shetty AS⁴, Weisbach NR⁵, Kim JA², Sharma J⁶, Desai M², Sood S⁷, Kempton HR⁸, Crabtree GR⁷, Feng G⁹, Zhang F¹⁰.

Author information

1

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

2

Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.

3

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.

4

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.

5

Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland.

6

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.

7

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.

8

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

9

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.

10

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

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.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 28402856

DOI: 10.1016/j.celrep.2017.03.052