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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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 (US)
Pages (from-to)8520-8525
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number30
DOIs
StatePublished - Jul 26 2016

Keywords

  • Autism
  • CNV
  • ERK
  • MAPK3
  • Schizophrenia

ASJC Scopus subject areas

  • General

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