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

Abstract

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.