Apparent genetic rescue of adult shank3 exon 21 insertion mutation mice tempered by appropriate control experiments

Haley E. Speed, Mehreen Kouser, Zhong Xuan, Shunan Liu, Anne Duong, Craig M. Powell

Research output: Contribution to journalArticle

Abstract

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 tamoxifeninducible 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.

Original languageEnglish (US)
Article numberENEURO.0317-19.2019
JournaleNeuro
Volume6
Issue number5
DOIs
StatePublished - Sep 1 2019
Externally publishedYes

Fingerprint

Insertional Mutagenesis
Exons
Tamoxifen
Synaptic Transmission
Genes
Phenotype
Brain
Proteins
Therapeutics

Keywords

  • Autism
  • Cre-recombinase
  • Reversal
  • Shank3
  • Tamoxifen

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Speed, H. E., Kouser, M., Xuan, Z., Liu, S., Duong, A., & Powell, C. M. (2019). Apparent genetic rescue of adult shank3 exon 21 insertion mutation mice tempered by appropriate control experiments. eNeuro, 6(5), [ENEURO.0317-19.2019]. https://doi.org/10.1523/ENEURO.0317-19.2019

Apparent genetic rescue of adult shank3 exon 21 insertion mutation mice tempered by appropriate control experiments. / Speed, Haley E.; Kouser, Mehreen; Xuan, Zhong; Liu, Shunan; Duong, Anne; Powell, Craig M.

In: eNeuro, Vol. 6, No. 5, ENEURO.0317-19.2019, 01.09.2019.

Research output: Contribution to journalArticle

Speed, Haley E. ; Kouser, Mehreen ; Xuan, Zhong ; Liu, Shunan ; Duong, Anne ; Powell, Craig M. / Apparent genetic rescue of adult shank3 exon 21 insertion mutation mice tempered by appropriate control experiments. In: eNeuro. 2019 ; Vol. 6, No. 5.
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