Abstract / Description of output
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 language | English |
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Pages (from-to) | 8520-8525 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences (PNAS) |
Volume | 113 |
Issue number | 30 |
Early online date | 11 Jul 2016 |
DOIs | |
Publication status | Published - 26 Jul 2016 |
Keywords / Materials (for Non-textual outputs)
- 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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Blanca Diaz-Castro
- Deanery of Biomedical Sciences - UK DRI Programme Leader (Fellow)
- Centre for Discovery Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active , Academic: Research Active (Research Assistant)