title: Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub.
abstract: The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein-protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Blizinsky
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Blanca
authors.initials: B
authors.lastname: Diaz-Castro
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Marc P
authors.initials: MP
authors.lastname: Forrest
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Britta
authors.initials: B
authors.lastname: Schürmann
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Bach
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Martin-de-Saavedra
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: John G
authors.initials: JG
authors.lastname: Csernansky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, IL 60637; Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201.
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; p-penzes@northwestern.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Penzes
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D058674:Chromosome Duplication; D033481:Chromosomes, Mammalian / Q000235:genetics*; D056915:DNA Copy Number Variations; D003712:Dendrites / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D006801:Humans; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D060066:Protein Interaction Maps; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism
chemical_list: D048052:Mitogen-Activated Protein Kinase 3
keywords: CNV; ERK; MAPK3; autism; schizophrenia