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

eNeuro. 2019 Sep 27;6(5):ENEURO.0317-19.2019. doi: 10.1523/ENEURO.0317-19.2019. Print Sep/Oct 2019.


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 (Shank3G ). We used a tamoxifen-inducible Cre/loxP system (CreTam ) to revert Shank3G to wild-type (WT) 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, WT 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.

Keywords: Cre-recombinase; Shank3; autism; reversal; tamoxifen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Autism Spectrum Disorder / genetics
  • Exons / genetics*
  • Female
  • Locomotion / drug effects
  • Locomotion / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Mutagenesis, Insertional / drug effects*
  • Mutagenesis, Insertional / genetics*
  • Mutagenesis, Insertional / methods
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Tamoxifen / pharmacology*


  • Antineoplastic Agents, Hormonal
  • Nerve Tissue Proteins
  • Shank3 protein, mouse
  • Tamoxifen