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

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

Author information

1
Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham 35294-2182, AL.
2
Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham 35294-2182, AL craigpow@uab.edu.
3
Civitan International Research Center at UAB, Birmingham 35294-2182, AL.

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 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

PMID:
31451607
DOI:
10.1523/ENEURO.0317-19.2019
Free PMC Article

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