PT  - JOURNAL ARTICLE
AU  - Haley E. Speed
AU  - Mehreen Kouser
AU  - Zhong Xuan
AU  - Shunan Liu
AU  - Anne Duong
AU  - Craig M. Powell
TI  - Apparent Genetic Rescue of Adult <em>Shank3</em> Exon 21 Insertion Mutation Mice Tempered by Appropriate Control Experiments
AID  - 10.1523/ENEURO.0317-19.2019
DP  - 2019 Aug 26
TA  - eneuro
PG  - ENEURO.0317-19.2019
4099  - http://www.eneuro.org/content/early/2019/08/26/ENEURO.0317-19.2019.short
4100  - http://www.eneuro.org/content/early/2019/08/26/ENEURO.0317-19.2019.full
AB  - SHANK3 (ProSAP2) 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 Shank3 mutant phenotypes in adult mice expressing a Shank3 exon 21 insertion mutation (Shank3G). We used a tamoxifen-inducible Cre/loxP system (CreTam) to revert Shank3G to wild-type Shank3+/+. We found that tamoxifen treatment in adult Shank3GCreTam+ 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+/+CreTam+ controls. However, follow-up comparisons between vehicle-treated, wild-type Cre-negative mice (Shank3+/+CreTam− and Shank3+/+CreTam+) demonstrated clear effects of CreTam on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the CreTam tamoxifen-inducible system is a powerful tool that successfully rescues Shank3 expression in our Shank3G/G reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.SIGNIFICANCE STATEMENT 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 CreTam 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 Shank3 exon 21 mutant mouse models in the CreTam-negative cohorts. Reproducibility is an important and often overlooked aspect of many mutant mouse behavioral and electrophysiological studies.