Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub.
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.
['Blizinsky|Katherine D|KD|', 'Diaz-Castro|Blanca|B|', 'Forrest|Marc P|MP|', 'Schürmann|Britta|B|', 'Bach|Anthony P|AP|', 'Martin-de-Saavedra|Maria Dolores|MD|', 'Wang|Lei|L|', 'Csernansky|John G|JG|', 'Duan|Jubao|J|', 'Penzes|Peter|P|']
D000818:Animals D001321:Autistic Disorder D002478:Cells, Cultured D058674:Chromosome Duplication D033481:Chromosomes, Mammalian D056915:DNA Copy Number Variations D003712:Dendrites D004195:Disease Models, Animal D020869:Gene Expression Profiling D053263:Gene Regulatory Networks D006801:Humans D057507:Mice, 129 Strain D008810:Mice, Inbred C57BL D048052:Mitogen-Activated Protein Kinase 3 D010641:Phenotype D060066:Protein Interaction Maps D017966:Pyramidal Cells D012559:Schizophrenia
CNV schizophrenia autism MAPK3 ERK