title: Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.
abstract: Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid syndrome, symptoms of which can include absent or delayed speech, intellectual disability, neurological changes and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin-repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions, in Shank3 heterozygous mice. Changes in phenotype owing to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype owing to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3 heterozygous, knockout and wild-type mice, using C57BL/6, 129SVE and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain-independent.
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Elodie
authors.initials: E
authors.lastname: Drapeau
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nate P
authors.initials: NP
authors.lastname: Dorr
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Neurology Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Elder
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. joseph.buxbaum@mssm.edu.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D005091:Exons; D007858:Learning; D008568:Memory; D051379:Mice; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse
keywords: 22q13; Autism spectrum disorders; Behavior; Genetic modifier; Mouse strain; Phelan-McDermid syndrome; Shank3