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

() 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 mutant phenotypes in adult mice expressing a exon 21 insertion mutation ( ). We used a tamoxifen-inducible Cre/loxP system ( ) to revert to wild-type (WT) We found that tamoxifen treatment in adult mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared to controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice ( and ) demonstrated clear effects of on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the tamoxifen-inducible system is a powerful tool that successfully rescues expression in our reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.