Mutations in the SHANK3 gene have been implicated in a subset of patients with autism spectrum disorder (ASD) in a gene-dosage dependent manner. SHANK3, a putative scaffold molecule found at the post-synaptic density (PSD), binds multiple partners and has been termed the master scaffolding molecule of the PSD. One of the key interactors of SHANK3 is the Homer class of signaling and scaffold molecules. SHANK3 and Homer act in concert to regulate spine maturation. The study describes a novel Homer-dependent mechanism to stabilize SHANK3 at the PSD. Both genetic and pharmacological tools can modulate this pathway, thus having implications for ASD therapy. Finally, the study is making a novel mouse model of SHANK3 that mimics a reported deletion of the Homer-binding domain of SHANK3 in patients with ASD. This mouse model will be a useful tool to study the in vivo function of SHANK3. The study makes predictions on the stability of SHANK3 in this mouse model and proposes a repertoire of biochemical and behavioral tests to link its molecular model with ASD-like behavior.