Mice with different Shank3 mutations have varying degrees of altered expression of receptors, synaptic proteins, and downstream signaling molecules. Deletion of exon 21 of Shank3 results in increased mGluR5 expression in hippocampal synaptosome and PSD fractions (Kouser et al., 2013) as well as decreased Rac1/PAK signaling, increased activated cofilin, and decreased expression of F-actin in synapses (Duffney et al., 2015). Deletion of exons 4–9 of Shank3 reduces Homer1b/c, GluA1, GluN2A, and SAPAP1 in hippocampal PSD fractions (Wang et al., 2011) as well as reduces Homer1b/c, PSD-95, GluA2, and GluA3 in striatal synaptosomes (Jaramillo et al., 2015). Finally, deletion of exons 13–16 results in reduced expression of SAPAP3, Homer, PSD-93, GluA2, GluN2A, and GluN2B in striatal PSD fractions (Peça et al., 2011) whereas deletion of exon 11 results in increased expression of GluN2B and Shank2 in striatal synaptosomal fractions (Schmeisser et al., 2012). It is currently unclear how these molecular changes lead to synaptic dysfunction and how synaptic dysfunction leads to changes in behavior.
