title: Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.
abstract: Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kaiser
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; PhD Program in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, 3000-214 Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Monteiro
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Marie S
authors.initials: MS
authors.lastname: Van der Goes
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wang
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Boaz
authors.initials: B
authors.lastname: Barak
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Life Science, Center of Systems Biology and Human Health, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong.
authors.forename: Menglong
authors.initials: M
authors.lastname: Zeng
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Li
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Congyi
authors.initials: C
authors.lastname: Lu
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wells
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aldo
authors.initials: A
authors.lastname: Amaya
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Nguyen
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Neville
authors.initials: N
authors.lastname: Sanjana
authors.affiliation: Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China.
authors.forename: Yongdi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Life Science, Center of Systems Biology and Human Health, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Zhanyan
authors.initials: Z
authors.lastname: Fu
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, 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: fengg@mit.edu.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
mesh_terms: D000375:Aging; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012919:Social Behavior; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C512412:SHANK1 protein, mouse; C488222:Shank2 protein, mouse; C492356:Shank3 protein, mouse