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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Absence of strong strain effects in behavioral analyses of <italic>Shank3</italic>-deficient mice</title><author><name sortKey="Drapeau, Elodie" sort="Drapeau, Elodie" uniqKey="Drapeau E" first="Elodie" last="Drapeau">Elodie Drapeau</name><affiliation><nlm:aff id="af1-0070667">Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation></author><author><name sortKey="Dorr, Nate P" sort="Dorr, Nate P" uniqKey="Dorr N" first="Nate P." last="Dorr">Nate P. Dorr</name><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation></author><author><name sortKey="Elder, Gregory A" sort="Elder, Gregory A" uniqKey="Elder G" first="Gregory A." last="Elder">Gregory A. Elder</name><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af3-0070667">Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af4-0070667">Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af5-0070667">Neurology Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA.</nlm:aff></affiliation></author><author><name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name><affiliation><nlm:aff id="af1-0070667">Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af3-0070667">Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af6-0070667">Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af7-0070667">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af8-0070667">Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af9-0070667">Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24652766</idno><idno type="pmc">4036474</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036474</idno><idno type="RBID">PMC:4036474</idno><idno type="doi">10.1242/dmm.013821</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">003D86</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003D86</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Absence of strong strain effects in behavioral analyses of <italic>Shank3</italic>-deficient mice</title><author><name sortKey="Drapeau, Elodie" sort="Drapeau, Elodie" uniqKey="Drapeau E" first="Elodie" last="Drapeau">Elodie Drapeau</name><affiliation><nlm:aff id="af1-0070667">Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation></author><author><name sortKey="Dorr, Nate P" sort="Dorr, Nate P" uniqKey="Dorr N" first="Nate P." last="Dorr">Nate P. Dorr</name><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation></author><author><name sortKey="Elder, Gregory A" sort="Elder, Gregory A" uniqKey="Elder G" first="Gregory A." last="Elder">Gregory A. Elder</name><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af3-0070667">Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af4-0070667">Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af5-0070667">Neurology Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA.</nlm:aff></affiliation></author><author><name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name><affiliation><nlm:aff id="af1-0070667">Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af2-0070667">Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af3-0070667">Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af6-0070667">Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af7-0070667">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af8-0070667">Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="af9-0070667">Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</nlm:aff></affiliation></author></analytic><series><title level="j">Disease Models & Mechanisms</title><idno type="ISSN">1754-8403</idno><idno type="eISSN">1754-8411</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Haploinsufficiency of <italic>SHANK3</italic>, 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 <italic>Shank3</italic> 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 <italic>Shank3</italic> 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 <italic>Shank3</italic> 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 <italic>Shank3</italic> haploinsufficiency are largely strain-independent.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Arons, M H" uniqKey="Arons M">M. H. Arons</name></author><author><name sortKey="Thynne, C J" uniqKey="Thynne C">C. J. Thynne</name></author><author><name sortKey="Grabrucker, A M" uniqKey="Grabrucker A">A. M. Grabrucker</name></author><author><name sortKey="Li, D" uniqKey="Li D">D. Li</name></author><author><name sortKey="Schoen, M" uniqKey="Schoen M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Dis Model Mech</journal-id><journal-id journal-id-type="iso-abbrev">Dis Model Mech</journal-id><journal-id journal-id-type="hwp">dmm</journal-id><journal-id journal-id-type="publisher-id">DMM</journal-id><journal-title-group><journal-title>Disease Models & Mechanisms</journal-title></journal-title-group><issn pub-type="ppub">1754-8403</issn><issn pub-type="epub">1754-8411</issn><publisher><publisher-name>The Company of Biologists Limited</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24652766</article-id><article-id pub-id-type="pmc">4036474</article-id><article-id pub-id-type="doi">10.1242/dmm.013821</article-id><article-id pub-id-type="publisher-id">0070667</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Absence of strong strain effects in behavioral analyses of <italic>Shank3</italic>-deficient mice</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Drapeau</surname><given-names>Elodie</given-names></name><xref ref-type="aff" rid="af1-0070667"><sup>1</sup></xref><xref ref-type="aff" rid="af2-0070667"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dorr</surname><given-names>Nate P.</given-names></name><xref ref-type="aff" rid="af2-0070667"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Elder</surname><given-names>Gregory A.</given-names></name><xref ref-type="aff" rid="af2-0070667"><sup>2</sup></xref><xref ref-type="aff" rid="af3-0070667"><sup>3</sup></xref><xref ref-type="aff" rid="af4-0070667"><sup>4</sup></xref><xref ref-type="aff" rid="af5-0070667"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buxbaum</surname><given-names>Joseph D.</given-names></name><xref ref-type="aff" rid="af1-0070667"><sup>1</sup></xref><xref ref-type="aff" rid="af2-0070667"><sup>2</sup></xref><xref ref-type="aff" rid="af3-0070667"><sup>3</sup></xref><xref ref-type="aff" rid="af6-0070667"><sup>6</sup></xref><xref ref-type="aff" rid="af7-0070667"><sup>7</sup></xref><xref ref-type="aff" rid="af8-0070667"><sup>8</sup></xref><xref ref-type="aff" rid="af9-0070667"><sup>9</sup></xref><xref ref-type="corresp" rid="c1"><sup>*</sup></xref></contrib></contrib-group><aff id="af1-0070667"><label>1</label>Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><aff id="af2-0070667"><label>2</label>Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><aff id="af3-0070667"><label>3</label>Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><aff id="af4-0070667"><label>4</label>Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.</aff><aff id="af5-0070667"><label>5</label>Neurology Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA.</aff><aff id="af6-0070667"><label>6</label>Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><aff id="af7-0070667"><label>7</label>Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><aff id="af8-0070667"><label>8</label>Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><aff id="af9-0070667"><label>9</label>Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.</aff><author-notes><corresp id="c1"><label>*</label>Author for correspondence (<email>joseph.buxbaum@mssm.edu</email>)</corresp></author-notes><pub-date pub-type="ppub"><month>6</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>20</day><month>3</month><year>2014</year></pub-date><volume>7</volume><issue>6</issue><fpage>667</fpage><lpage>681</lpage><permissions><copyright-statement>© 2014. Published by The Company of Biologists Ltd</copyright-statement><copyright-year>2014</copyright-year><license license-type="open-access"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/3.0">http://creativecommons.org/licenses/by/3.0</ext-link>), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="667.pdf"></self-uri><abstract><p>Haploinsufficiency of <italic>SHANK3</italic>, 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 <italic>Shank3</italic> 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 <italic>Shank3</italic> 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 <italic>Shank3</italic> 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 <italic>Shank3</italic> haploinsufficiency are largely strain-independent.</p></abstract><kwd-group><title>KEY WORDS:</title><kwd>Shank3</kwd><kwd>Phelan-McDermid syndrome</kwd><kwd>Autism spectrum disorders</kwd><kwd>22q13</kwd><kwd>Mouse strain</kwd><kwd>Genetic modifier</kwd><kwd>Behavior</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>special-property</meta-name><meta-value>TIB</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec sec-type="intro"><title>INTRODUCTION</title><p>SHANK3 is a synaptic scaffolding protein that forms a key structural part of the post-synaptic density of excitatory synapses (<xref rid="b40-0070667" ref-type="bibr">Kreienkamp, 2008</xref>), where it interacts with numerous other post-synaptic proteins, including Homer, ionotropic and metabotropic glutamate receptors, neuroligin, and components of the actin cytoskeleton (<xref rid="b6-0070667" ref-type="bibr">Boeckers et al., 1999</xref>; <xref rid="b47-0070667" ref-type="bibr">Naisbitt et al., 1999</xref>; <xref rid="b69-0070667" ref-type="bibr">Tu et al., 1999</xref>; <xref rid="b65-0070667" ref-type="bibr">Sheng and Kim, 2000</xref>; <xref rid="b5-0070667" ref-type="bibr">Boeckers, 2006</xref>; <xref rid="b40-0070667" ref-type="bibr">Kreienkamp, 2008</xref>; <xref rid="b4-0070667" ref-type="bibr">Betancur et al., 2009</xref>; <xref rid="b1-0070667" ref-type="bibr">Arons et al., 2012</xref>). <italic>Shank3</italic> overexpression promotes the formation of new synapses and dendritic spines and regulates their shape and size (<xref rid="b60-0070667" ref-type="bibr">Sala et al., 2001</xref>; <xref rid="b59-0070667" ref-type="bibr">Roussignol et al., 2005</xref>; <xref rid="b30-0070667" ref-type="bibr">Grabrucker et al., 2011</xref>; <xref rid="b71-0070667" ref-type="bibr">Verpelli et al., 2011</xref>; <xref rid="b1-0070667" ref-type="bibr">Arons et al., 2012</xref>; <xref rid="b21-0070667" ref-type="bibr">Durand et al., 2012</xref>), whereas <italic>Shank3</italic> knockdown or autism-associated <italic>Shank3</italic> mutations specifically impair glutamate signaling at synapses (<xref rid="b71-0070667" ref-type="bibr">Verpelli et al., 2011</xref>; <xref rid="b1-0070667" ref-type="bibr">Arons et al., 2012</xref>). Similarly, a decrease in glutamatergic transmission and long-term potentiation (LTP), neuronal hypertrophy and a reduction in spine density are observed in animal models of <italic>Shank3</italic> haploinsufficiency (<xref rid="b12-0070667" ref-type="bibr">Bozdagi et al., 2010</xref>; <xref rid="b49-0070667" ref-type="bibr">Peça et al., 2011</xref>; <xref rid="b73-0070667" ref-type="bibr">Wang et al., 2011</xref>; <xref rid="b75-0070667" ref-type="bibr">Yang et al., 2012</xref>).</p><p>In humans, haploinsufficiency of <italic>SHANK3</italic>, caused either by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to Phelan-McDermid syndrome (PMS), a neurodevelopmental syndrome that is characterized by global developmental delay, intellectual disability, delayed or absent speech, and autism spectrum disorder (ASD), as well as hypotonia and other motor deficits, seizures, minor dysmorphic features and additional medical issues (<xref rid="b74-0070667" ref-type="bibr">Wilson et al., 2003</xref>; <xref rid="b8-0070667" ref-type="bibr">Bonaglia et al., 2006</xref>; <xref rid="b17-0070667" ref-type="bibr">Cusmano-Ozog et al., 2007</xref>; <xref rid="b20-0070667" ref-type="bibr">Durand et al., 2007</xref>; <xref rid="b43-0070667" ref-type="bibr">Moessner et al., 2007</xref>; <xref rid="b50-0070667" ref-type="bibr">Phelan, 2008</xref>; <xref rid="b34-0070667" ref-type="bibr">Herbert, 2011</xref>; <xref rid="b66-0070667" ref-type="bibr">Soorya et al., 2013</xref>). PMS is both one of the most penetrant and one of the most common monogenic causes of autism, and recent studies have shown <italic>SHANK3</italic> deletion or mutation in up to 1.7% of individuals with ASD (<xref rid="b43-0070667" ref-type="bibr">Moessner et al., 2007</xref>; <xref rid="b32-0070667" ref-type="bibr">Guilmatre et al., 2009</xref>; <xref rid="b56-0070667" ref-type="bibr">Qiao et al., 2009</xref>; <xref rid="b68-0070667" ref-type="bibr">Sykes et al., 2009</xref>; <xref rid="b54-0070667" ref-type="bibr">Pinto et al., 2010</xref>; <xref rid="b58-0070667" ref-type="bibr">Rosenfeld et al., 2010</xref>; <xref rid="b63-0070667" ref-type="bibr">Schaefer et al., 2010</xref>; <xref rid="b64-0070667" ref-type="bibr">Shen et al., 2010</xref>; <xref rid="b13-0070667" ref-type="bibr">Bremer et al., 2011</xref>; <xref rid="b72-0070667" ref-type="bibr">Waga et al., 2011</xref>; <xref rid="b29-0070667" ref-type="bibr">Gong et al., 2012</xref>; <xref rid="b3-0070667" ref-type="bibr">Betancur and Buxbaum, 2013</xref>). However, despite common features, there is a significant variability in the expression and severity of the phenotype observed in individuals with PMS (<xref rid="b28-0070667" ref-type="bibr">Goizet et al., 2000</xref>; <xref rid="b42-0070667" ref-type="bibr">Manning et al., 2004</xref>; <xref rid="b17-0070667" ref-type="bibr">Cusmano-Ozog et al., 2007</xref>; <xref rid="b18-0070667" ref-type="bibr">Dhar et al., 2010</xref>; <xref rid="b51-0070667" ref-type="bibr">Phelan and Betancur, 2011</xref>; <xref rid="b66-0070667" ref-type="bibr">Soorya et al., 2013</xref>).</p><p>The creation of mice with a <italic>Shank3</italic> gene deletion has helped define the role of the protein in synaptic function and in downstream behavioral changes. Bozdagi et al. have reported the generation of a <italic>Shank3</italic>-deficient mouse with a targeted disruption in one copy of <italic>Shank3</italic> in which exons 4–9 (coding for the ankyrin repeat domain) were deleted and expression of full-length Shank3 was disrupted (<xref rid="b12-0070667" ref-type="bibr">Bozdagi et al., 2010</xref>). These mice display reduced expression of glutamate receptor 1 and show deficits in synaptic function and plasticity, specifically in LTP, in hippocampal CA1 pyramidal neurons. Male heterozygotes also show less social sniffing and emit fewer ultrasonic vocalizations during interactions with estrus female mice (<xref rid="b12-0070667" ref-type="bibr">Bozdagi et al., 2010</xref>). In a follow-up study, similar, but more severe, deficits were observed in knockout mice (<xref rid="b75-0070667" ref-type="bibr">Yang et al., 2012</xref>).</p><boxed-text id="tib" position="float"><caption><title>TRANSLATIONAL IMPACT</title></caption><p><bold>Clinical issue</bold></p><p>Phelan-McDermid syndrome (PMS) is a rare genetic syndrome in which one copy of the q13 portion of chromosome 22 is missing or mutated, leading to a global developmental delay, delayed or absent speech, and autistic behaviors. Several genes map to the genomic region linked with the disease; however, there is overwhelming evidence that <italic>SHANK3</italic> –a gene encoding an essential protein for communication between neurons – causes the neurological and behavioral aspects of the syndrome. The effect of a gene on specific behaviors can be modified by other genes, and this effect can be dramatic when the entire genetic background is changed. Quantitative trait locus (QTL) analysis – a statistical method that links phenotypic data and genotypic data – can be used to identify genes that change the severity of a particular phenotype. The identification of modifier genes is a powerful means to dissect molecular pathophysiology, discover mechanisms underlying neurodevelopmental phenotypes and provide additional targets for drug development.</p><p><bold>Results</bold></p><p>To determine whether the broad range of impairments observed in PMS could be explained by modulation by other genetic loci, the authors generated <italic>Shank3</italic>-deficient mice using three different strains to provide distinct genetic backgrounds. They tested the animals using an extensive battery of behavioral tests designed to assess the main features of PMS. As in previous studies using similar or slightly different mouse models of <italic>Shank3</italic> deficiency, they observed altered phenotypes in different subcategories of behaviors. Surprisingly, however, there were very modest strain effects over a large battery of analysis: few tests revealed significant differences across the different strains or genetic backgrounds.</p><p><bold>Implications and future directions</bold></p><p>This study demonstrates that the genetic background is not a determining factor of the phenotype in <italic>Shank3</italic>-deficient mice and that quantitative trait locus analysis is unlikely to reveal the existence of genetic modifiers. Although this does not rule out the existence of a genetic modifier effect in humans, it suggests that variability observed between individuals is explained by a factor other than interactions with background genes. Recent studies have shown a correlation between the size of the deletion encompassing <italic>Shank3</italic> in individuals with PMS and the severity of the phenotype. Future analysis of the influence of the other genes affected by the deletion might contribute to our understanding of the molecular mechanisms involved in PMS.</p></boxed-text><p>In another mouse model with a similar deletion, knockout mice also display impaired LTP and altered dendritic spine morphology (<xref rid="b73-0070667" ref-type="bibr">Wang et al., 2011</xref>). These mice also show alterations in motor learning, vocalization, social behavior, repetitive behaviors, learning and memory. Peça et al. have generated <italic>Shank3</italic>-variant-deficient mice with a targeted disruption of the PDZ domain (<xref rid="b49-0070667" ref-type="bibr">Peça et al., 2011</xref>). They report altered cortico-striatal input-output functions, as well as changes in miniature excitatory post-synaptic current (mEPSC) frequency and amplitude in striatal medium spiny neurons. The behavioral characterization of these mice shows excessive grooming, along with altered responses in social approach and preference for social novelty paradigms (<xref rid="b49-0070667" ref-type="bibr">Peça et al., 2011</xref>).</p><p>Changes in synaptic plasticity and behavior caused by a mutation at a single locus are frequently modulated by other factors, including the prenatal and postnatal environment or by other genetic loci, which can be most easily demonstrated when the entire genetic background is changed. Each strain of laboratory mouse represents a distinct genetic background that is known to significantly alter baseline behaviors (<xref rid="b16-0070667" ref-type="bibr">Crawley et al., 1997</xref>; <xref rid="b35-0070667" ref-type="bibr">Holmes et al., 2002</xref>; <xref rid="b10-0070667" ref-type="bibr">Bothe et al., 2004</xref>; <xref rid="b45-0070667" ref-type="bibr">Moy et al., 2007</xref>), and several studies have demonstrated that the genetic background has a significant impact on multiple behavioral responses, including ASD-like traits, in mouse models of Fragile X syndrome, for example (<xref rid="b19-0070667" ref-type="bibr">Dobkin et al., 2000</xref>; <xref rid="b22-0070667" ref-type="bibr">Errijgers et al., 2008</xref>; <xref rid="b2-0070667" ref-type="bibr">Baker et al., 2010</xref>; <xref rid="b53-0070667" ref-type="bibr">Pietropaolo et al., 2011</xref>; <xref rid="b67-0070667" ref-type="bibr">Spencer et al., 2011</xref>). When such a change is identified, it can lead to identifying modifier loci that modulate phenotypes, as has recently been done in models for Rett syndrome (<xref rid="b14-0070667" ref-type="bibr">Buchovecky et al., 2013</xref>; <xref rid="b31-0070667" ref-type="bibr">Grillo et al., 2013</xref>), leading to a better understanding of pathophysiology and opportunities for therapeutics.</p><p>In PMS, there is some suggestion of genetic modifier loci. Mutation sizes are highly variable, ranging from point mutations to deletions covering tens of kilobases to over nine megabases. Several studies have shown correlations between the size of the deletion and the severity of some phenotypes (<xref rid="b74-0070667" ref-type="bibr">Wilson et al., 2003</xref>; <xref rid="b37-0070667" ref-type="bibr">Jeffries et al., 2005</xref>; <xref rid="b43-0070667" ref-type="bibr">Moessner et al., 2007</xref>; <xref rid="b50-0070667" ref-type="bibr">Phelan, 2008</xref>; <xref rid="b18-0070667" ref-type="bibr">Dhar et al., 2010</xref>; <xref rid="b9-0070667" ref-type="bibr">Bonaglia et al., 2011</xref>; <xref rid="b15-0070667" ref-type="bibr">Cooper et al., 2011</xref>; <xref rid="b61-0070667" ref-type="bibr">Sarasua et al., 2011</xref>; <xref rid="b66-0070667" ref-type="bibr">Soorya et al., 2013</xref>). In the current study, to investigate the role of genetic background on <italic>Shank3</italic>-deficient mice, animals that had been generated on the C57BL/6 (C57) background (<xref rid="b12-0070667" ref-type="bibr">Bozdagi et al., 2010</xref>; <xref rid="b75-0070667" ref-type="bibr">Yang et al., 2012</xref>) were backcrossed onto two additional genetic backgrounds, FVB/Ntac (FVB) and 129SVE. <italic>Shank3</italic> wild-type, heterozygous and knockout mice from the three genetic backgrounds were evaluated in a battery of tests that had been designed to assess the main features of PMS, including assays for neurodevelopment changes, sensory-motor defects, hyperactivity, emotionality and anxiety, as well as behaviors relevant to ASD.</p></sec><sec><title>RESULTS</title><sec><title>General health</title><p>Abnormal Mendelian ratios at the time of weaning were observed for the three strains, showing a significant deficit for <italic>Shank3</italic> knockout mice (<xref ref-type="fig" rid="f1-0070667">Fig. 1A</xref>). For the 129SVE strain, out of 777 animals, 53.54% were <italic>Shank3</italic> heterozygotes, 30.25% were wild type and 16.22% were <italic>Shank3</italic> knockout (<italic>P</italic>=3.26×10<sup>−8</sup>). For the C57 strain, out of 1248 animals, 51.20% were heterozygotes, 27.80% were wild type and 21.00% were knockout (<italic>P</italic>=0.02). For the FVB strain, out of 930 animals, 52.90% were heterozygous, 23.35% were wild type and 17.71% were knockout (<italic>P</italic>=7.45×10<sup>−7</sup>).</p><fig id="f1-0070667" position="float"><label>Fig. 1.</label><caption><p><bold>General health and sensory-motor performances in <italic>Shank3</italic>-deficient mice.</bold> (A) Distribution of genotype. A deficit in the number of knockout (KO) mice was observed in all strains. (B) Weight of mice. Knockout mice were significantly smaller than wild type (WT) and heterozygotes (Het) (the main effect of genotype across the three strains, <italic>P</italic>=0.001). 129, 129SVE. (C) Tail-flick assay. A higher tail-flick latency in response to a hot stimulus was observed during the first trial for the C57 strain knockout mice. (D) Beam walking. A significant decrease of the latency to the start of crossing the beam (left panel) and a shorter crossing time (middle panel) was observed in the C57 strain knockout mice. The distance traveled on the beam (right panel) was significantly shorter for 129SVE heterozygous mice, mainly because of an increase in the number of falls and freezing behavior; knockout animals on the 129SVE background performed similar to controls. (E) Spontaneous locomotion. The distance traveled over a 1-hour session in the open-field was similar for all genotypes; however, during the first ten minutes, a significant increase in locomotion was observed in 129SVE heterozygous and knockout animals. Data represents the means±s.e.m. *<italic>P</italic><0.05, **<italic>P</italic><0.01, ***<italic>P</italic><0.001. In C and E: * WT versus KO, <sup>o</sup> WT versus Het, <sup>+</sup> Het vs KO.</p></caption><graphic xlink:href="DMM013821F1"></graphic></fig><p>The body weight at 3 months of age was similar for the three strains (129SVE: <italic>n</italic>=54, 28.56±0.32 g; C57: <italic>n</italic>=50, 29.59±0.37 g; FVB: <italic>n</italic>=51, 28.72±0.37 g; F<sub>2,152</sub>=2.037, <italic>P</italic>=0.134). However, for the 129SVE strain, the body weight of knockout mice was slightly lower than that of their wild-type and heterozygous littermates [<xref ref-type="fig" rid="f1-0070667">Fig. 1B</xref>; wild type (WT): <italic>n</italic>=18, 29.50±0.54 g; heterozygote (Het): <italic>n</italic>=18, 28.89±0.58 g; knockout (KO): <italic>n</italic>=18, 27.28±0.46 g; F<sub>2,51</sub>=4.84, <italic>P</italic>=0.012; post-hoc: WT=Het, <italic>P</italic>=0.339; WT>KO, <italic>P</italic>=0.004; Het>KO, <italic>P</italic>=0.044]. A similar trend was observed for C57 mice (<xref ref-type="fig" rid="f1-0070667">Fig. 1B</xref>; WT: <italic>n</italic>=12, 30.00±0.76 g; Het, <italic>n</italic>=20, 30.37±0.63 g; KO, <italic>n</italic>=18, 28.44±0.49 g; F<sub>2,47</sub>=2.86, <italic>P</italic>=0.068) and FVB strains (<xref ref-type="fig" rid="f1-0070667">Fig. 1B</xref>; WT: <italic>n</italic>=17, 29.82±0.37 g; Het: <italic>n</italic>=16, 28.25±0.78 g; KO: <italic>n</italic>=18, 28.11±0.53 g; F<sub>2,48</sub>=2.34, <italic>P</italic>=0.107). A genotype and strain interaction showed an absence of strain effect (F<sub>2,145</sub>=2.30, <italic>P</italic>=0.104) or strain and genotype effect (F<sub>2,145</sub>=0.899, <italic>P</italic>=0.466), but there was a significant main effect of genotype across the three strains (F<sub>4,145</sub>=7.165, <italic>P</italic>=0.001). The body weight of knockout mice was significantly decreased compared with that of wild-type and heterozygous mice (WT: <italic>n</italic>=47, 29.74±0.34 g; Het: 29.25±0.39, KO: 27.97±0.29; post-hoc: WT=Het, <italic>P</italic>=0.236; WT>KO, <italic>P</italic><0.001; Het>KO, <italic>P</italic>=0.011).</p><p>Because PMS is often as associated with medical conditions such as craniofacial abnormalities, dysmorphic features (hands and feet), abnormal spine curvature, microcephaly, renal, cardiac or respiratory problems, or lymphedema, three 2-month-old male mice from each strain and genotype were submitted to a comprehensive anatomic phenotyping that included gross and microscopic examination of tissues and organs. Three mice in the 129SVE background group exhibited testicular degeneration that was characterized by partial to complete loss of germinal cells in the seminiferous tubules and few multinucleated giant cells (data not shown). Epididymides that were associated with the affected testes were empty, or contained few round nucleated cells. However, testicular degeneration has been reported to occur spontaneously in 129SVE mice, and lesions were present in all three genotypes; hence, these lesions were not associated with <italic>Shank3</italic> deficiency. All mice on the FVB background exhibited marked diffuse bilateral outer-retinal degeneration with loss of the outer plexiform layer, outer nuclear layer and photoreceptors (data not shown). Mice on the FVB background are known to have early-onset retinal degeneration that is associated with the <italic>rd</italic> mutation. For this reason, before behavioral experiments, the visual acuity of our mice was tested using the visual placing test. All of the mice, including those on the FVB background, exhibited a visual placing reflex (100% success, all strains and genotypes), indicating that there was no problem with vision in any of the strains. No other notable microscopic lesions were observed, and no anatomic phenotype attributable to the <italic>Shank3</italic> mutation was found. Complete blood counts and a blood chemistry screen were also performed; however, no differences were observed between genotypes (<ext-link ext-link-type="uri" xlink:href="http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.013821/-/DC1">supplementary material Table S1</ext-link>).</p></sec><sec><title>Sensory-motor function</title><p>For all sensory-motor function assays, detailed results are reported in <ext-link ext-link-type="uri" xlink:href="http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.013821/-/DC1">supplementary material Table S2</ext-link>. We first examined sensitivity to thermal stimulation using the tail-flick assay (<xref ref-type="fig" rid="f1-0070667">Fig. 1C</xref>). No significant differences between the genotypes were observed for the latency to respond to the stimulus in the 129SVE and FVB strains. Only C57 <italic>Shank3</italic> knockout mice had a longer tail-flick latency and, thus, lower pain sensitivity than their heterozygous and wild-type littermates on the first trial (F<sub>2,51</sub>=4.24, <italic>P</italic>=0.021; post-hoc: WT=Het, <italic>P</italic>=0.579; WT<italic>P</italic>=0.009; Het<italic>P</italic>=0.028), although this difference was not apparent in the following trials.</p><p>In the grip strength test, no significant differences were observed between the genotypes in any of the three strains studied, for both the mean of all trials and the best performance. However, there was a decreasing trend in the mean forelimb grip strength observed in the 129SVE knockout animals compared with their wild-type and heterozygous littermates (F<sub>2,51</sub>=2.71, <italic>P</italic>=0.097; mean grip strength: WT: 127.86±2.87 g; Het: 128.84±2.13 g; KO: 119.72±3.46 g).</p><p>Motor learning was evaluated with the accelerating Rotarod test. A learning effect, characterized by an improvement of the performances (latency to fall) over the three trials, was observed for both the 129SVE and C57 strains (trial effect: C57: F<sub>2,51</sub>=7.001, <italic>P</italic>=0.001; FVB: F<sub>2,51</sub>=6.083, <italic>P</italic>=0.005), but not for the 129SVE strain. However, there was no significant interaction between the trial and genotype for any of the strains, and latencies to fall were similar for all the genotypes.</p><p>The beam walking test (<xref ref-type="fig" rid="f1-0070667">Fig. 1D</xref>) was used to detect subtle deficits in fine motor coordination and balance that might not be detected by other motor tests. The C57 strain <italic>Shank3</italic> knockout mice had a shorter latency to start crossing than their wild-type and heterozygous littermates (WT, F<sub>2,51</sub>=3.37, <italic>P</italic>=0.036; post-hoc: WT=Het, <italic>P</italic>=0.178; WT>KO, <italic>P</italic>=0.003; Het>KO, <italic>P</italic>=0.059), as well as taking a shorter time to cross the beam (data not shown; F<sub>2,51</sub>=4.46, <italic>P</italic>=0.013; post-hoc: WT=Het, <italic>P</italic>=0.234; WT>KO, <italic>P</italic>=5.57×10<sup>−5</sup>; Het>KO, <italic>P</italic>=8.40×10<sup>−4</sup>), and, therefore, a faster speed (F<sub>2,51</sub>=9.62, <italic>P</italic>=0.0001; post-hoc: WT=Het, <italic>P</italic>=0.344; WT<italic>P</italic>=5.57×10<sup>−5</sup>; Het<italic>P</italic>=8.40×10<sup>−4</sup>) in the beam crossing test. In the 129SVE strain, fewer heterozygous animals were able to fully cross the beam (cross distance: F<sub>2,51</sub>=5.30, <italic>P</italic>=0.006; post-hoc: WT>Het, <italic>P</italic>=0.004; WT=KO, <italic>P</italic>=0.927; Het<italic>P</italic>=0.020), mainly because of an increased percentage of animals that stopped (froze) while crossing (F<sub>2,51</sub>=2.67, <italic>P</italic>=0.072; post-hoc: WT<italic>P</italic><italic>P</italic><italic>P</italic><sub>2,51</sub><italic>P</italic><italic>P</italic>
