() is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan-McDermid Syndrome. 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 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, wild-type 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. Temporally and spatially controlled genetic reversal of mouse models of autism are used to determine critical windows in development for successful treatment. This study provides a clear example that any attempt at genetic reversal must be accompanied by all appropriate controls, including expression of the transgene in wild-type animals, for accurate interpretation of the genetic rescue result. In addition, this study provides two additional independent replications of behavioral and synaptic electrophysiologal abnormalities in exon 21 mutant mouse models in the -negative cohorts. Reproducibility is an important and often overlooked aspect of many mutant mouse behavioral and electrophysiological studies.