Shank3 mutant characterization in vivo
University of Texas Southwestern Medical Center, Dallas
Weatherstone Predoctoral Fellowship
Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Deletion and other loss-of-function mutations of shank3, an intracellular binding partner of neuroligins, have been strongly implicated in human autism. We hypothesize that creating a human autism-associated genetic mutation of shank3 in mouse models will lead to autism-relevant behavioral abnormalities and functional changes in excitatory synaptic transmission. We have a global shank3 truncation mutation knockin mouse as a novel genetic model of autism. Our initial goal is to establish how shank3 mutation affects autism-relevant behaviors. Behavioral testing will be performed on littermate, sex-matched progeny from shank3 mutation heterozygous by wild-type matings. Three core domains of autism related behaviors will be tested. In addition, we will examine input/output curves, long term potentiation, long term depression, and short term plasticity in the hippocampus of shank3 WT and mutation het mice. Linking abnormal behavior to underlying neuronal circuit changes is difficult, but defining the effect of an autism-linked genetic mutation in vivo is a critical first-step toward understanding the pathophysiology of autism.