A Frank Assessment of SHANK: Impacts of Pathogenic Variations in SHANK3 on Preclinical Models of Phelan McDermid Syndrome.

Abstract

Although there are as many as 40 preclinical models of the neurodevelopmental disorder Phelan McDermid syndrome (PMS, or 22q13.3 deletion syndrome), detailed phenotypic analyses to compare the effects of different pathogenic variants and inform treatment design are lacking. Here, we clarify behavioral traits (social, vocalization, repetitive and anxiety-like behavior), developmental trajectories, and motor activity in addition to changes in brain structure and function in 10 widely available Shank3 transgenic mouse models. Although behavioral deficits in Shank3B^-/- and Shank3^∆C/∆C mice were most extensively reported, each model reviewed here displayed autism-relevant behavioral traits. Most studies focused on assessing social, anxiety-like, and repetitive behavior, whereas few studies examined changes in vocalization, developmental milestones, motor function, or aggressive behavior. We did not identify any studies of gut function in the ten selected Shank3 models. Alterations in the gastrointestinal microbiome of Shank3-deficient mice are associated with changes in bacterial abundance and composition, which may impact social behavior and gastrointestinal function. Studying preclinical models can provide critical insights into molecular pathways contributing to PMS. Further research is needed to determine how various genetic variations in Shank3 impact the brain, behavior, and potentially the gastrointestinal system.