Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub
Open accessAbstract
Significance: The architecture of neuronal dendritic trees is crucial for brain connectivity, whereas dendritic abnormalities are associated with psychiatric disorders. Rare copy number variations (CNVs) are a category of mutations often associated with schizophrenia, autism, and other mental disorders. However, the genetic complexity of CNV disorders poses a serious challenge for the identification of experimentally approachable mechanisms. Here we used network analysis to identify the most topologically important hub in protein–protein interaction networks within such a CNV, and in broader gene networks of psychiatric CNVs. We then show that pharmacological targeting of this node reverses dendritic alterations in a neuronal model of this CNV, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.
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Cultured pyramidal neurons from 16p11.2dp/+ mice exhibit increased ERK1 phosphorylation and greater dendritic arborization, which can be reversed by ERK inhibition.
“Cultured pyramidal neurons from 16p11.2dp/+ mice exhibit increased ERK1 phosphorylation, and greater dendritic arborization, which can be reversed by ERK inhibition [81].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [81]
Dysregulation of MAPK signaling has been reported in transgenic mice carrying the 16p11.2 microdeletion and in other mouse models of social impairment.
“The dysregulation of MAPK signaling has also been reported in transgenic mice carrying the ASD-associated microdeletion of 16p11.2 (Blizinsky et al., 2016; Pucilowska et al., 2015) and in other mouse models of social impairment (Faridar et al., 2014).”
From Getting to the cores of autism (2019) · cites this paper as Blizinsky et al., 2016
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“2 (Blizinsky et al., 2016; Pucilowska et al., 2015) and in other mouse models of social impairment (Faridar et al.”
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- Authors
- Blizinsky, K. D., Diaz-Castro, B., Forrest, M. P., Schürmann, B., Bach, A. P., Martin-de-Saavedra, M. D., Wang, L., Csernansky, J. G., Duan, J., & Penzes, P.
- Affiliations
- Northwestern University (US)
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
- Endeavor Health (US)
- Corresponding author
- Penzes, Peter
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-07-11
- Volume
- 113
- Issue
- 30
- Pages
- 8520-8525
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4968749
- OpenAlex
- W2465467919
- Cited by
- 76
- References
- 60
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 3 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 11 · 2017: 9 · 2016: 1
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (MH071316, MH097216, MH071616, MH084803, R21MH102685)
- Swiss National Science Foundation (P2SKP3_161675)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- copy number variation, dendritic branching, cortical pyramidal neurons, ERK1, protein-protein interaction network, schizophrenia, autism spectrum disorder, mouse model, mental illness
- MeSH terms
- Animals, Autistic Disorder, Cells, Cultured, Dendrites, Disease Models, Animal, Humans, Mice, Inbred C57BL, Phenotype, Schizophrenia, Pyramidal Cells, Gene Expression Profiling, Chromosomes, Mammalian, Mitogen-Activated Protein Kinase 3, Gene Regulatory Networks, DNA Copy Number Variations, Mice, 129 Strain, Chromosome Duplication, Protein Interaction Maps
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