The mechanism through which deletion of Shank proteins leads to synaptic dysfunction is likely due to impaired interactions between glutamate receptors and postsynaptic density proteins leading to impaired signaling in dendritic spines. For instance, rescue of NMDA receptor hypofunction with an actin stabilizer after knockdown of Shank3 in cultured rat cortical neurons suggests that some of the synaptic defects are due to disrupted cytoskeleton signaling (Duffney et al., 2013). Similarly, treating Shank3 exon 21 deletion mice with an actin stabilizer rescues both behavioral phenotypes and synaptic deficits (Duffney et al., 2015).
