Modeling Autism by SHANK Gene Mutations in Mice

In the paper

“Using the longest rat cDNA of Shank2 deposited in GenBank (NM_201350) as a reference, one can deduce that exons 6 and 7 in mouse Shank2a isoform correspond to exons 16 and 17 of predicted full length mouse Shank2 deduced from rat cDNA (NM_201350)”

What the sources say

• Not checked yetcites NM_201350

In the paper

“However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations.”

In the paper

“Remarkably little is known about the underlying pathophysiology or neurological basis of ASD (Amaral et al., 2008; Courchesne et al., 2007; Geschwind and Levitt, 2007; Rubenstein, 2010; Zoghbi, 2003).”

What the sources say

• Not checked yetcites Amaral et al., 2008 source
• Not checked yetcites Courchesne et al., 2007 source
• Not checked yetcites Geschwind and Levitt, 2007 source

In the paper

“Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses.”

What the sources say

• Not checked yetcites Grabrucker et al., 2011b
• Not checked yetcites Gundelfinger et al., 2006 source
• Not checked yetcites Kreienkamp, 2008 source

In the paper

“Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD).”

What the sources say

• Not checked yetcites Berkel et al., 2010 source
• Not checked yetcites Berkel et al., 2012 source
• Not checked yetcites Durand et al., 2007 source

In the paper

“Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD.”

In the paper

“SHANK/ProSAP family proteins (SHANK1, SHANK2, SHANK3) have emerged as promising candidates for modeling ASD in mice due to strong genetic evidence showing molecular defects of SHANK in patients with ASD (Berkel et al., 2010; Berkel et al., 2012; Durand et al., 2007; Gauthier et al., 2010; Marshall et al., 2008; Pinto et al., 2010; Sato et al., 2012).”

What the sources say

• Not checked yetcites Berkel et al., 2010 source
• Not checked yetcites Berkel et al., 2012 source
• Not checked yetcites Durand et al., 2007 source

In the paper

“By comparison, for point mutations such as missense mutation and small intragenic deletions identified in SHANK2 and SHANK3, the pathogenic mechanism is less clear (Bonaglia et al., 2011; Durand et al., 2011; Moessner et al., 2007).”

What the sources say

• Not checked yetcites Bonaglia et al., 2011 source
• Not checked yetcites Durand et al., 2011
• Not checked yetcites Moessner et al., 2007 source

In the paper

“Recently, mutations in SHANK1 and SHANK2 have also been associated with ASD (Berkel et al., 2010; Berkel et al., 2012; Sato et al., 2012), supporting a general function for this gene family in common molecular pathways associated with ASD.”

What the sources say

• Not checked yetcites Berkel et al., 2010 source
• Not checked yetcites Berkel et al., 2012 source
• Not checked yetcites Sato et al., 2012 source

In the paper

“Pathological point mutations have not yet been reported in ASD so far (Sato et al., 2012)”

What the sources say

• Not checked yetcites Sato et al., 2012 source

In the paper

“In the cases of SHANK1 and SHANK2 mutations associated with ASD, no studies relating genotype and phenotype have been reported.”

In the paper

“Interestingly, point mutations, including a nonsense mutation in exon 21 (p.R1117X) of SHANK3 have been reported in families with schizophrenia and mild intellectual disability (Gauthier et al., 2010).”

What the sources say

• Not checked yetcites Gauthier et al., 2010 source

In the paper

“The genetic association of ASD with SHANK family genes provided an immediate link between synaptic dysfunction and the pathophysiology of ASD.”

In the paper

“The penetrance of SHANK2 mutations in ASD is not complete in some cases (Leblond et al., 2012).”

What the sources say

• Not checked yetcites Leblond et al., 2012 source

In the paper

“Deletions involving entire SHANK family genes in ASD predict that haploinsufficiency is the primary mechanism underlying ASD pathogenesis (Wilson et al., 2003).”

What the sources say

• Not checked yetcites Wilson et al., 2003 source

In the paper

“Because the clinical data are not complete in most cases, it is difficult to draw firm conclusions about the relationship between specific SHANK3 variants and clinical features related to ASD.”

In the paper

“and the degree to which SHANK3 mutations contribute to the population attributable risk of ASD is small (Betancur, 2011; Buxbaum, 2009; State, 2010b).”

What the sources say

• Not checked yetcites Betancur, 2011 source
• Not checked yetcites Buxbaum, 2009 source
• Not checked yetcites State, 2010b

In the paper

“Similarly, in other cases with almost identical small microdeletions (<100 kb) including SHANK3, neurobehavioral phenotypes were quite variable (Boccuto et al., 2013; Bonaglia et al., 2011; Dhar et al., 2010).”

What the sources say

• Not checked yetcites Boccuto et al., 2013 source
• Not checked yetcites Bonaglia et al., 2011 source
• Not checked yetcites Dhar et al., 2010 source

In the paper

“In the case of SHANK1, microdeletions including SHANK1 and two other adjacent genes were reported in five ASD individuals in two families with mild ASD (Figure 1C).”

What the sources say

• Not checked yetcites Sato et al., 2012 source

In the paper

“A nonsense mutation in SHANK2 exon 24 encoding the proline-rich homer-binding domain has also been found in an ASD proband (Figure 1B) (Berkel et al., 2010).”

What the sources say

• Not checked yetcites Berkel et al., 2010 source

In the paper

“This challenge is best illustrated in three cases with very similar mutations (p.A1227fs, p.E1311fs, and p.R1117X) in exon 21 encoding Homer binding site of SHANK3 (Figure 1A).”

In the paper

“However, the frequency of putatively pathological mutations in SHANK3 appears to be rare in ASD (< 0.75%) (Moessner et al., 2007)”

What the sources say

• Not checked yetcites Moessner et al., 2007 source

In the paper

“Subsequently, point mutations and microdeletions of SHANK3 have been identified in idiopathic ASD cases (Boccuto et al., 2012; Dhar et al., 2010; Durand et al., 2007; Gauthier et al., 2010; Gong et al., 2012; Marshall et al., 2008; Moessner et al., 2007; Waga et al., 2011).”

What the sources say

• Not checked yetcites Boccuto et al., 2012
• Not checked yetcites Dhar et al., 2010 source
• Not checked yetcites Durand et al., 2007 source

In the paper

“De novo sequence changes in SHANK3 including missense, frame shift, and splice site mutations have been reported in ASD patients (Boccuto et al., 2012; Durand et al., 2007; Gauthier et al., 2010; Gauthier et al., 2009; Gong et al., 2012; Hamdan et al., 2011; Moessner et al., 2007; Schaaf et al., 2011; Waga et al., 2011).”

What the sources say

• Not checked yetcites Boccuto et al., 2012
• Not checked yetcites Durand et al., 2007 source
• Not checked yetcites Gauthier et al., 2010 source

In the paper

“Microduplications of SHANK3 have also been reported in children with developmental delay and dysmorphic features (Okamoto et al., 2007)”

What the sources say

• Not checked yetcites Okamoto et al., 2007 source

In the paper

“Interestingly, microdeletion of SHANK1 is only penetrant in males with mild ASD in families studied (Sato et al., 2012).”

What the sources say

• Not checked yetcites Sato et al., 2012 source

In the paper

“Shank family proteins are scaffolding proteins that organize a cytoskeleton-associated signaling complex at the postsynaptic density (PSD) of nearly all excitatory glutamatergic synapses in the mammalian brain (Grabrucker et al., 2011b; Gundelfinger et al., 2006; Kreienkamp, 2008; Sheng and Kim, 2000).”

What the sources say

• Not checked yetcites Grabrucker et al., 2011b
• Not checked yetcites Gundelfinger et al., 2006 source
• Not checked yetcites Kreienkamp, 2008 source

In the paper

“All microdeletions found in ASD are intragenic deletions that disrupt the SHANK2 protein.”

In the paper

“the clinical features from these cases reports suggest a genotype-phenotype correlation related to the autism diagnosis.”

In the paper

“deletions of SHANK3 have been reported in all cases except in one report of two children who have deletions proximal to SHANK3 (Wilson et al., 2008)”

What the sources say

• Not checked yetcites Wilson et al., 2008 source

In the paper

“suggesting that SHANK3 gene dosage affects brain function.”

In the paper

“These observations have led to the conclusion that haploinsufficiency of SHANK3 is a major contributor to the neurobehavioral features in 22q13.3 deletion patients.”

In the paper

“SHANK3 maps to the critical region of 22q13.3 deletion syndrome (Phelan-McDermid syndrome, PMS) (Figure 1A) (Wilson et al., 2003).”

What the sources say

• Not checked yetcites Wilson et al., 2003 source

In the paper

“In all, six types of molecular defects have been identified in SHANK3 in more than 1000 human patients.”

In the paper

“RNA in situ hybridization in rat brain using a single probe from exon 21 encoding the proline-rich domain showed that Shank3 is widely expressed in all brain regions at a low level at birth but increases after 2 weeks of age in the striatum, hippocampus, cerebellum, and in layers 1 and 2 of the neocortex (Bockers et al., 2001; Bockers et al., 2004).”

What the sources say

• Not checked yetcites Bockers et al., 2001 source
• Not checked yetcites Bockers et al., 2004 source

In the paper

“For example, Shank3e and Shank3f mRNAs lack exons encoding the PDZ domain that is responsible for the interaction with NMDA and AMPA receptors (Naisbitt et al., 1999).”

What the sources say

• Not checked yetcites Naisbitt et al., 1999 source

In the paper

“Shank3b lacks the proline-rich and SAM domains that are critical for Homer binding and multimerization (Tu et al., 1999).”

What the sources say

• Not checked yetcites Tu et al., 1999

In the paper

“More than 30 synaptic proteins have been reported to interact with Shank family proteins (Figure 2 and Table 2).”

In the paper

“Expression of Shank3 with deletions of various domains in cultured mouse neurons has demonstrated distinct roles for each domain in dendritic spine development (Roussignol et al., 2005).”

What the sources say

• Not checked yetcites Roussignol et al., 2005 source

In the paper

“For example, the intron 5 splicing mutations in the exon encoding the ANK domain is only predicted to affect two long isoforms of SHANK3 initiated from promoters 1 and 2 (SHANK3a and SHANK3b) (Figures 1A and 2B).”

In the paper

“Therefore, the molecular consequences at the RNA and protein levels for each SHANK3 mutation are almost certainly different.”

In the paper

“Concentrated at glutamatergic synapses, Shanks interact directly or indirectly with all major types of glutamate receptors – NMDA receptors, AMPA receptors, and mGluRs – via different domains (Ehlers, 1999; Naisbitt et al., 1999; Tu et al., 1999; Uchino et al., 2006; Verpelli et al., 2011).”

What the sources say

• Not checked yetcites Ehlers, 1999 source
• Not checked yetcites Naisbitt et al., 1999 source
• Not checked yetcites Tu et al., 1999

In the paper

“Because each protein domain mediates a unique complement of protein-protein interactions (Hayashi et al., 2009; Roussignol et al., 2005), it is likely that each Shank3 isoform has a distinct set of functions.”

What the sources say

• Not checked yetcites Hayashi et al., 2009 source
• Not checked yetcites Roussignol et al., 2005 source

In the paper

“The exact number of protein isoforms has not been determined, but selected mRNA isoforms analyzed in silico indicate that each Shank3 isoform (Shank3a-f) has a unique combination of different protein domains as illustrated in Figure 2B (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“In contrast, microdeletions or large cytogenetic deletions will disrupt all SHANK3 isoforms.”

In the paper

“Shank3-interacting proteins include receptors, ion channels, cytoskeletal proteins, scaffolding proteins, enzymes, and signaling molecules (Grabrucker et al., 2011b; Kreienkamp, 2008).”

What the sources say

• Not checked yetcites Grabrucker et al., 2011b
• Not checked yetcites Kreienkamp, 2008 source

In the paper

“SHANK genes display a complex transcriptional regulation with multiple intragenic promoters and extensive alternatively spliced exons both in humans and mice (Leblond et al., 2012; Lim et al., 1999; Maunakea et al., 2010; McWilliams et al., 2004; Redecker et al., 2006; Wang et al., 2011; Wilson et al., 2003).”

What the sources say

• Not checked yetcites Leblond et al., 2012 source
• Not checked yetcites Lim et al., 1999 source
• Not checked yetcites Maunakea et al., 2010 source

In the paper

“However, to date, we have little information on the molecular mechanisms by which more subtle mutations in SHANK3 alter protein function at synapses (Durand et al., 2007; Durand et al., 2011).”

What the sources say

• Not checked yetcites Durand et al., 2007 source
• Not checked yetcites Durand et al., 2011

In the paper

“The alternatively spliced exons of Shank3 encode the SH3, proline-rich, and SAM domains (Figure 1A).”

In the paper

“Mutations in exon 21 are expected to have no effect on mRNAs lacking exon 21 or other short SHANK3 mRNAs truncated before exon 21.”

In the paper

“Due to the similarity of protein domains among Shank family proteins, in vitro binding experiments have shown a significant overlap in protein-protein interactions involving Shank1-3.”

In the paper

“The complexity of SHANK3 transcript structure indicates that point mutations, translocations, and intragenic deletions of SHANK3 found in ASD patients are isoform-specific.”

In the paper

“Shanks are scaffolding proteins that interact with many synaptic proteins in the PSD (Ehlers, 1999; Gundelfinger et al., 2006; Kreienkamp, 2008; Sheng and Kim, 2000).”

What the sources say

• Not checked yetcites Ehlers, 1999 source
• Not checked yetcites Gundelfinger et al., 2006 source
• Not checked yetcites Kreienkamp, 2008 source

In the paper

“Thus, in addition to alternate promoter use and mRNA splicing, epigenetic mechanisms such as DNA methylation and histone acetylation regulate the expression of the Shank3 gene in an isoform-specific manner.”

In the paper

“Two different lines of Shank2 mutant mice have been recently reported (Schmeisser et al., 2012; Won et al., 2012).”

What the sources say

• Not checked yetcites Schmeisser et al., 2012 source
• Not checked yetcites Won et al., 2012 source

In the paper

“SHANK2 exhibits transcriptional regulation similar to SHANK3 (Leblond et al., 2012).”

What the sources say

• Not checked yetcites Leblond et al., 2012 source

In the paper

“Therefore, the molecular nature of these two targeted mutations is predicted to be very similar at protein level.”

In the paper

“In Shank2 Δex 6-7−/− mice, reduction of phosphorylated CaMKIIα/β (T286), ERK1/2, p38, and GluA1 (Ser831/S845) was observed in hippocampus (Won et al., 2012).”

What the sources say

• Not checked yetcites Won et al., 2012 source

In the paper

“Both DNA methylation and histone deacetylase inhibitors have been shown to modulate the isoform specific gene expression of Shank3 in cultured neurons (Beri et al., 2007; Maunakea et al., 2010).”

What the sources say

• Not checked yetcites Beri et al., 2007 source
• Not checked yetcites Maunakea et al., 2010 source

In the paper

“Won et al. described mice with both exons 6 and 7 deleted (Shank2 Δex6-7).”

What the sources say

• Not checked yetcites Won et al., 2012 source

In the paper

“The difference in exon numbering for SHANK2 in different organisms in other reports is likely due to the pattern of uncharacterized exons or alternative splicing (Leblond et al., 2012; Lim et al., 1999; McWilliams et al., 2004).”

What the sources say

• Not checked yetcites Leblond et al., 2012 source
• Not checked yetcites Lim et al., 1999 source
• Not checked yetcites McWilliams et al., 2004 source

In the paper

“Similar to Shank2 Δex7−/− mice (Schmeisser et al., 2012), GluN1 is increased in the hippocampus of Shank2 Δex6-7−/− mice (Won et al., 2012).”

What the sources say

• Not checked yetcites Won et al., 2012 source

In the paper

“Together, the available evidence indicates that the overall transcriptional structure of SHANK family genes is conserved in mice (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“Schmeisser et al. reported Shank2 exon 7 deletion mutant mice (Shank2 Δex7)”

What the sources say

• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“Peak expression of Shank3 occurs at an important developmental stage of synaptic plasticity and experience-dependent circuit maturation (Bockers et al., 2004).”

What the sources say

• Not checked yetcites Bockers et al., 2004 source

In the paper

“However, the complexity of transcriptional regulation poses a significant technical challenge to adequately model human SHANK mutations in mice.”

In the paper

“Mutant mice for all Shank family genes have now been produced and characterized (Figure 3).”

In the paper

“Interestingly, Shank3 was up-regulated in striatum of Shank2 Δex7−/− mice.”

• Also stated in: § Synaptic Proteins in Shank3-Deficient Mouse Brain · plain

  “while Shank3 was found to be increased in Shank2 Δex7−/− mutant mice (Schmeisser et al., 2012).”

What the sources say

• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“Specifically, SHANK2 has several isoforms driven by multiple promoters and alternative splicing of coding exons (Figure 1B).”

In the paper

“Intriguingly, spatial learning and memory was enhanced in Shank1−/− mice (Hung et al., 2010).”

What the sources say

• Not checked yetcites Hung et al., 2010

In the paper

“The synaptic proteins GKAP/SAPAP and Homer are reduced in the PSD of Shank1−/− mouse brain.”

What the sources say

• Not checked yetcites Hung et al., 2008 source

In the paper

“Decreased PSD thickness and length were observed at corticostriatal synapses in Δex13-16−/− mice (Peca et al., 2011)”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“In contrast, GluN2B was increased in synaptosomal fractions from Δex11−/− hippocampus (Schmeisser et al., 2012).”

What the sources say

• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“The totality of ultrastructural and morphological analysis in Shank3 mutant mice indicates complex regulation of glutamatergic synapse size, shape, and structure.”

In the paper

“Dendritic branching and spine area was increased in medium spiny neurons (MSNs) of the striatum of Δex13-16−/− mice (Peca et al., 2011)”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“Intriguingly, this cryptic splicing from exon 2 to 10 occurred only in brain but not in kidney of Δex4-9J−/− mice.”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“PSD proteins were altered in different brain regions of all Shank3 mutant mice but to varying degrees”

In the paper

“Spine length was increased in CA1 hippocampus of Δex4-9J−/− mice (Wang et al., 2011)”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“The AMPA receptor subunit GluA1 was reduced in hippocampal neurons examined in culture and hippocampal tissues from Δex4-9J−/− (Wang et al., 2011) and Δex4-9B+/− mice (Bozdagi et al., 2010)”

What the sources say

• Not checked yetcites Wang et al., 2011 source
• Not checked yetcites Bozdagi et al., 2010 source

In the paper

“In nearly all mouse lines and brain areas examined, changes in the level of these synaptic proteins and receptors was relatively modest”

In the paper

“The corresponding changes of Homer1 and Shank3 in several mouse lines and several brain regions are consistent with the known multimeric network formed between these two proteins (Hayashi et al., 2009; Tu et al., 1999).”

What the sources say

• Not checked yetcites Hayashi et al., 2009 source
• Not checked yetcites Tu et al., 1999

In the paper

“Mutations of Shank3 altered the levels of synaptic glutamate receptors.”

In the paper

“Phenotypic analyses at the biochemical, synaptic, and behavioral levels were performed extensively on either heterozygotes or homozygotes at different ages for Shank3 Δex4-7, Δex4-9J, Δex4-9B, and Δex13-16 but to a lesser degree in Δex11 mutant mice”

What the sources say

• Not checked yetcites Bozdagi et al., 2010 source
• Not checked yetcites Peca et al., 2011 source
• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“Activity-induced spine growth by theta burst stimulation in cultured brain slices was attenuated at CA1 synapses of Δex4-9B+/− mice (Bozdagi et al., 2010).”

What the sources say

• Not checked yetcites Bozdagi et al., 2010 source

In the paper

“Based on current knowledge of Shank3 promoters and alternative splicing, each of these mice is expected to have disruption of different Shank3 isoforms (Wang et al., 2011)”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“Both GluN2A and GluN2B subunits were reduced in the striatum of Δex13-16−/− mice (Peca et al., 2011)”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“Homer1, GKAP/SAPAP, and PSD-93 were reduced in PSD fractions isolated from the striatum of Δex13-16−/− mice (Peca et al., 2011)”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“Homer1b/c and GKAP1/SAPAP1 were reduced in the PSD fraction but not in the cytosolic fraction of Δex4-9J−/− hippocampus (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“Isoform-specific disruption of Shank3 was evident in Δex4-7, Δex4-9J, Δex11, and Δex13-16 mice (Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011).”

What the sources say

• Not checked yetcites Peca et al., 2011 source
• Not checked yetcites Schmeisser et al., 2012 source
• Not checked yetcites Wang et al., 2011 source

In the paper

“In the case of NMDA receptors, GluN2A subunit was reduced in the hippocampus of Δex4-9J−/− mice (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“The reduction of spine density visualized by Golgi impregnation was developmental stage-specific in Δex4-9J−/− mice, with significant spine loss observed at 4 weeks but not at 10 weeks of age (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“while the Δex13-16 mutation (Peca et al., 2011) is predicted to disrupt transcripts from promoter 1 to 4 (Shank3a-d) but not from promoter 5 to 6 (Shank3e-f)”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“This observation adds to the complexity of predicting the molecular consequence of different mutations in Shank3 mutant mice, and perhaps in human SHANK3 mutations, and suggests that otherwise similar mutations such as Δex4-9B, Δex4-9J, and Δex4-7 may have different molecular consequences for Shank3 at the mRNA and protein level.”

In the paper

“The specific patterns of altered synaptic proteins varied among different mutant mice lines with similar mutations.”

In the paper

“This compensatory mechanism may contribute to the reciprocal changes in Shank2 Δex7−/− and Shank3 Δex11−/− mice.”

In the paper

“and GluA2 was reduced in the striatum of Δex13-16−/− mice (Peca et al., 2011).”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“One unexpected finding from RNA expression analysis of Δex4-9J mice was the presence of an mRNA splice isoform from exon 2 to exon 10, in addition to the expected splicing isoform from exon 3 to exon 10 due to the deletion of exons 4-9 (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“These effects, together with spine elongation, suggests a phenotype of reduced or delayed synapse maturation that is reminiscent of the phenotypes observed in mouse models of fragile X syndrome (Comery et al., 1997; Irwin et al., 2001), Rett syndrome (Armstrong, 2005; Belichenko et al., 2009; Chao et al., 2007), and Angelman syndrome (Dindot et al., 2008; Sato and Stryker, 2010; Yashiro et al., 2”

What the sources say

• Not checked yetcites Comery et al., 1997 source
• Not checked yetcites Irwin et al., 2001 source
• Not checked yetcites Armstrong, 2005 source

In the paper

“Interestingly, Shank2 was increased in the synaptosomal fraction of Δex11−/− striatum”

What the sources say

• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“The Δex4-9J deletion disrupted mRNA transcripts from promoters 1 and 2 (Shank3a and Shank3b) but not Shank3c-f as confirmed by isoform-specific RT-PCR analysis (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“Five lines of Shank3 mutant mice carrying different mutations in Shank3 have been reported (Bozdagi et al., 2010; Peca et al., 2011; Schmeisser et al., 2012; Wang et al., 2011)”

What the sources say

• Not checked yetcites Bozdagi et al., 2010 source
• Not checked yetcites Peca et al., 2011 source
• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“but GKAP/SAPAP was not reduced in striatum of Δex11−/− mice (Schmeisser et al., 2012).”

What the sources say

• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“Synaptic dysfunction and abnormal behaviors have been documented in mice harboring Disc1 mutations (Clapcote et al., 2007; Kim et al., 2009)”

What the sources say

• Not checked yetcites Clapcote et al., 2007 source
• Not checked yetcites Kim et al., 2009 source

In the paper

“but were not apparent in Δex4-7−/− mice (Peca et al., 2011).”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“Firm conclusions in this regard are complicated by the fact that the different Shank3 isoforms are probably expressed in various Shank3 mutant mice, which were analyzed at different ages using slightly different protocols.”

In the paper

“There is currently no reliable biomarker, pathology, anatomical finding, or functional neuroimaging change that can be considered pathognomonic or predictive for ASD (Anagnostou and Taylor, 2011; Bauman and Kemper, 2005; Courchesne et al., 2007; Lord et al., 2000a).”

What the sources say

• Not checked yetcites Anagnostou and Taylor, 2011
• Not checked yetcites Bauman and Kemper, 2005 source
• Not checked yetcites Courchesne et al., 2007 source

In the paper

“Prepulse inhibition (PPI) is not affected in Δex4-9J−/− (Wang et al., 2011) and Δex4-9B−/− (Yang et al., 2012) mice”

What the sources say

• Not checked yetcites Wang et al., 2011 source
• Not checked yetcites Yang et al., 2012 source

In the paper

“Reduced ultrasonic vocalizations adult were also reported in Δex4-9B (Bozdagi et al., 2010; Yang et al., 2012).”

What the sources say

• Not checked yetcites Bozdagi et al., 2010 source
• Not checked yetcites Yang et al., 2012 source

In the paper

“The Δex4-9 (Bozdagi et al., 2010) and Δex4-7 mutations in mouse (Peca et al., 2011) are closest to patients with intragenic exon 1-9 deletion and splice mutation of intron 5 in SHANK3 (Bonaglia et al., 2011; Hamdan et al., 2011)”

What the sources say

• Not checked yetcites Bonaglia et al., 2011 source
• Not checked yetcites Hamdan et al., 2011 source

In the paper

“suggesting differences in effects of Shank3 on mGluR1/5 signaling over development”

In the paper

“Since different mutations affect different isoforms of Shank3, some of the observed phenotypes may arise from isoform-specific effects on synaptic transmission.”

In the paper

“Collectively, these data support circuit defects mediated by glutamate receptors in Shank3 mutant mice that appear to be both synapse- and mutation-specific.”

In the paper

“The different degree of synaptic transmission defects in mice with specific Shank3 mutations supports the notion of an isoform-specific contribution to synaptic function.”

In the paper

“and this may present a confounding factor for phenotypic analysis.”

In the paper

“Hippocampal LTP was reduced at CA1 synapses of Δex4-9J−/− and Δex4-9B but not examined in Δex11−/− and Δex13-16−/− animals”

What the sources say

• Not checked yetcites Bozdagi et al., 2010 source
• Not checked yetcites Wang et al., 2011 source
• Not checked yetcites Yang et al., 2012 source

In the paper

“but the phenotypic heterogeneity itself appears consistent with the clinical heterogeneity of patients harboring SHANK3 mutations.”

In the paper

“Moreover, acute knockdown of Shank3 in cultured neurons decreases mGluR-dependent plasticity (Verpelli et al., 2011)”

What the sources say

• Not checked yetcites Verpelli et al., 2011 source

In the paper

“Different severity of similar behaviors with different mutations may reflect Shank3 isoform-specific contributions to specific behaviors.”

In the paper

“Presynaptic responses measured by paired pulse ratio and input/output curves were not altered at corticostriatal synapses in Δex13-16−/− or Δex4-7−/− mice (Peca et al., 2011).”

What the sources say

• Not checked yetcites Peca et al., 2011 source

In the paper

“Variable performances were noted in different cohorts of Δe4-9B−/− mice (Yang et al., 2012).”

What the sources say

• Not checked yetcites Yang et al., 2012 source

In the paper

“Repetitive behaviors measured by increased self-grooming in the home cage and behavioral inflexibility in the reverse Morris water maze were observed in Δex4-9J−/− (Wang et al., 2011) and Δex4-9B−/− mice”

What the sources say

• Not checked yetcites Wang et al., 2011 source
• Not checked yetcites Bozdagi et al., 2010 source
• Not checked yetcites Yang et al., 2012 source

In the paper

“A more marked increase in self-grooming and self-injurious behaviors was observed in Δex11−/− and Δex13-16−/− mice”

What the sources say

• Not checked yetcites Peca et al., 2011 source
• Not checked yetcites Schmeisser et al., 2012 source

In the paper

“The number, frequency, and duration of ultrasonic vocalizations were altered in a sex-specific manner in Δex4-9J−/− mice (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“In a strict sense, none of these Shank3 mouse mutations are equivalent to SHANK3 mutations found in human ASD patients.”

In the paper

“The most notable and consistent observation was reduced social interaction and affiliation behaviors using different testing methods”

What the sources say

• Not checked yetcites Bozdagi et al., 2010 source
• Not checked yetcites Peca et al., 2011 source
• Not checked yetcites Wang et al., 2011 source

In the paper

“suggesting an alteration in the set-point for bidirectional Hebbian synaptic plasticity (Cho and Bear, 2010).”

What the sources say

• Not checked yetcites Cho and Bear, 2010

In the paper

“Because of the molecular and clinical heterogeneity documented in ASD, the challenge of interpreting any human data from heterogeneous patient populations is obvious.”

In the paper

“In fact, there are few clinical tools available to evaluate behavioral features quantitatively in humans that could guide more basic neurobiological studies in model systems (Lord et al., 2001; Lord et al., 2000b; Lord et al., 1994).”

What the sources say

• Not checked yetcites Lord et al., 2001 source
• Not checked yetcites Lord et al., 2000b
• Not checked yetcites Lord et al., 1994 source

In the paper

“However, to date none of the various social and communication behaviors have been validated as robustly translatable from rodents to humans (Silverman et al., 2010).”

What the sources say

• Not checked yetcites Silverman et al., 2010 source

In the paper

“Analyses of the Shanks mutant mice indicate that subtle differences in mutations within a given ASD risk gene can produce overlapping but non-identical cellular, synaptic, and behavioral phenotypes.”

In the paper

“the diverse and often non-congruent phenotypes in various Shank mutant mice highlight the fact that most of the current mouse models do not carry the human mutations.”

In the paper

“This may be due to the high degree of specialization and diverse strategies for ethologically relevant social behaviors in mammals, particularly primates (Bucan and Abel, 2002; Flint and Mott, 2008; Kas et al., 2007).”

What the sources say

• Not checked yetcites Bucan and Abel, 2002
• Not checked yetcites Flint and Mott, 2008
• Not checked yetcites Kas et al., 2007 source

In the paper

“Interventions that improve cognitive performance, behaviors, or neuropathology in rodents have frequently not led to accelerated therapeutic development, most notably in Alzheimer’s disease where reports abound of cured mouse models despite repeated clinical failures (Cisse et al., 2011; Gandy and DeKosky, 2013; Malenka and Malinow, 2011; Vaillend et al., 2002).”

What the sources say

• Not checked yetcites Cisse et al., 2011 source
• Not checked yetcites Gandy and DeKosky, 2013
• Not checked yetcites Malenka and Malinow, 2011

In the paper

“Recently, whole genome sequencing technology has successfully identified a list of candidate genes in ASD (Bi et al., 2012; Chahrour et al., 2012; Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2012a; Sanders et al., 2012)”

What the sources say

• Not checked yetcites Bi et al., 2012
• Not checked yetcites Chahrour et al., 2012 source
• Not checked yetcites Iossifov et al., 2012 source