Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):8520-5. doi: 10.1073/pnas.1607014113. Epub 2016 Jul 11.

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

Author information

1
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;
2
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
3
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;
4
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
5
Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, IL 60637; Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201.
6
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.

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.

KEYWORDS:

CNV; ERK; MAPK3; autism; schizophrenia

PMID:
27402753
PMCID:
PMC4968749
DOI:
10.1073/pnas.1607014113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center