Ten different lines of Shank3 mutant mice have been reported, but due to the transcriptional complexity of Shank3 (Wang et al., 2014), none of the published lines disrupt all isoforms. Still, deletion of exons 4–7 (Peça et al., 2011), exons 4–9 (Bozdagi et al., 2010; Wang et al., 2011; Jaramillo et al., 2015), exon 9 (Lee et al., 2015), exon 11 (Schmeisser et al., 2012), exons 13–16 (Peça et al., 2011), or exon 21 (Kouser et al., 2013; Duffney et al., 2015), and an insertion mutation in exon 21 (Speed et al., 2015) all result in ASD-like behaviors to various degrees (reviewed in Bey and Jiang, 2014). Whereas humans with SHANK3-related ASDs are either haploinsufficient due to a large chromosomal deletion or have point mutations in one copy of their SHANK genes, many of the studies utilizing mouse models only report behavioral abnormalities in homozygous mutants. This, along with the fact that there currently is no model in which all Shank3 isoforms are disrupted, limits the construct validity of these models.
