Understanding the function of Shank2 and its role in autism

Project Leader: Dietmar Schmitz e-mail


Shank proteins are PDZ domain scaffolding proteins expressed at the post-synaptic density of glutamatergic synapses. The Shank family consists of three genes (Shanks 1, 2, and 3, also known as SSTRIP, ProSAP1, and ProSAP2, respectively). Both Shank2 and Shank3 mutations have recently been implicated in autism spectrum disorders, and behavioral abnormalities that partially overlap with autistic phenotypes have previously been described in both Shank1 and Shank3 knockout mice. Here we propose several strategies to broaden our understanding of Shank2 function and its role in autism. First of all, we will expand on our recently published (Schmeisser et al. 2012) electrophysiological characterization of the Shank2 KO mouse to include analysis of the effects of Shank2 on network oscillations. Secondly, we will explore in greater depth a potential mechanism underlying the altered glutamatergic transmission observed in the Shank2 KO autism model. Specifically, we will explore the possibility that the absence of Shank2 results in a synaptic maturation defect. We will focus initially on analysis of AMPA receptor properties in Shank2 KO neurons, using both electrophysiological and molecular methods. Thirdly, we will characterize a selected set of Shank2 mutants with regard to protein-protein interactions, synaptic targeting, and synaptic function. In parallel collaborative efforts, we will screen for novel mutations in Shank family genes in a local autism cohort, and we will further examine selected interaction partners for potential disease associations.