Apparent Genetic Rescue of Adult Shank3 Exon 21 Insertion Mutation Mice Tempered by Appropriate Control Experiments

SHANK3 (ProSAP2) is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan–McDermid syndrome (PMS). We performed genetic rescue of Shank3 mutant phenotypes in adult mice expressing a Shank3 exon 21 insertion mutation (Shank3(G)). We used a tamoxifen-inducible Cre/loxP system (Cre(Tam)) to revert Shank3(G) to wild-type (WT) Shank3(+/+). We found that tamoxifen treatment in adult Shank3(G)Cre(Tam)+ mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared to Shank3(+/+)Cre(Tam)+ controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice (Shank3(+/+)Cre(Tam)− and Shank3(+/+)Cre(Tam)+) demonstrated clear effects of Cre(Tam) on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the Cre(Tam) tamoxifen-inducible system is a powerful tool that successfully rescues Shank3 expression in our Shank3(G/G) reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.