Modeling Autism by SHANK Gene Mutations in Mice

Abstract

Summary Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene.

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

“…Therefore, since SHANK3 is a major scaffolding protein, one possible explanation is that SHANK3-containing scaffolds form distinct signaling complexes in D1 MSNs and D2 MSNs and that disruption of these complexes may lead to distinct synaptic defects. Alternatively, the Shank3 gene has multiple intragenic promoters and extensive alternative splicing, thereby producing multiple isoforms in the mouse brain (33,75,89). These different isoforms may be differentially expressed in D1 MSNs and D2 MSNs.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Shank mutations have very high penetrance at the phenotypic level, and any form of SHANK3 haploinsufficiency is sufficient to cause behavioral changes 187 . Given that the SHANK proteins are modulators of dendritic spine morphogenesis, it is plausible that related mutations or ACCEPTED MANUSCRIPT…”

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

“…The SHANK family proteins function as scaffolds at the PSD; they interact with NMDAR and AMPAR receptors through other synaptic proteins (1). We hypothesized that the disruption of SHANK2 in the PSD might alter NMDAR-or AMPAR-mediated synaptic function.…”

“…The SHANK (ProSAP) family, SHANK1-SHANK3, are scaffolding proteins enriched in the postsynaptic density (PSD) of excitatory synapses (1,2). Early genetic studies implicated SHANK family genes in both autism spectrum disorders (ASDs) and intellectual disability (3)(4)(5)(6).…”