Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

Katherine D Blizinsky, Blanca Diaz-Castro, Marc P Forrest, Britta Schürmann, Anthony P Bach, Maria Dolores Martin-de-Saavedra, Lei Wang, John G Csernansky, Jubao Duan, Peter Penzes

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8520-8525
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume113
Issue number30
Early online date11 Jul 2016
DOIs
Publication statusPublished - 26 Jul 2016

Keywords

  • Animals
  • Autistic Disorder/genetics
  • Cells, Cultured
  • Chromosome Duplication
  • Chromosomes, Mammalian/genetics
  • DNA Copy Number Variations
  • Dendrites/metabolism
  • Disease Models, Animal
  • Gene Expression Profiling/methods
  • Gene Regulatory Networks
  • Humans
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 3/genetics
  • Phenotype
  • Protein Interaction Maps
  • Pyramidal Cells/cytology
  • Schizophrenia/genetics

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