Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism

El-Kordi, Ahmed; Winkler, Daniela; Hammerschmidt, Kurt; Kästner, Anne; Krueger, Dilja D.; Ronnenberg, Anja; Ritter, Caroline; Jatho, Jasmin; Radyushkin, Konstantin; Bourgeron, Thomas; Fischer, Julia; Brose, Nils; Ehrenreich, Hannelore

doi:10.1016/j.bbr.2012.11.016

Cited by 110 publications

(85 citation statements)

References 48 publications

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“…Employing our 3-chambered social approach task, a simple yes-or-no assay for sociability [13], absence of sociability was reported in mice with mutations in genes including Shank3 [15,16], Cntnap2 [17], Pten [18], Tsc1 [19], En2 [20], Gabrb3 [21], Ube3a triplication [22], and oxytocin receptor knockouts [23]. Normal 3-chambered social approach appeared in mice with mutations in genes including oxytocin [24], Shank1 [25], Nlgn2 [26], Ephrin-A [27] and 16p11.2 deletion [28] Variable findings on social approach across laboratories and in mouse lines generated on different genetic backgrounds have been reported for mutations including Fmr1 [29,30], Nlgn3 [31][32][33][34], and Nlgn4 [35,36]. Social deficits on the 3-chambered sociability have been wellreplicated in 2 inbred strains of mice, BTBR [10,12,[37][38][39][40][41][42][43][44] and Balb/cJ [45,46].…”

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

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In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on highresolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery.

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Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

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“…Recently Nlgn4 null mice have been extensively phenotyped with the aim to develop an 'Autism Severity Score' [El-Kordi et al, 2012]. Interestingly, male and female monogenic mutant mice exhibited a similar pattern of coordinated behavioral impairments, albeit females were less severely affected than males.…”

Section: Clinical Implications and Novel Clues For The Study And Treamentioning

confidence: 99%

Towards Identification of Individual Etiologies by Resolving Genomic and Biological Conundrums in Patients with Autism Spectrum Disorders

Poot¹

2013

Mol Syndromol

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Recent genomic research into autism spectrum disorders (ASD) has revealed a remarkably complex genetic architecture. Large numbers of common variants, copy number variations and single nucleotide variants have been identified, yet each of them individually afforded only a small phenotypic impact. A polygenic model in which multiple genes interact either in an additive or a synergistic way appears the most plausible for the majority of ASD patients. Based on recently identified ASD candidate genes, transgenic mouse models for neuroligins/neurorexins and genes such as Cntnap2,Cntn5, Tsc1, Tsc2, Akt3, Cyfip1, Scn1a, En2, Slc6a4, and Bckdk have been generated and studied with respect to behavioral and neuroanatomical phenotypes and sensitivity to drug treatments. From these models, a few clues for potential pharmacologic intervention emerged. The Fmr1,Shank2 and Cntn5 knockout mice exhibited alterations of glutamate receptors, which may become a target for pharmacologic modulation. Some of the phenotypes of Mecp2 knockout mice can be ameliorated by administering IGF1. In the near future, comprehensive genotyping of individual patients and siblings combined with the novel insights generated from the transgenic animal studies may provide us with personalized treatment options. Eventually, autism may indeed turn out to be a phenotypically heterogeneous group of disorders (‘autisms') caused by combinations of changes in multiple possible candidate genes, being different in each patient and requiring for each combination of mutations a distinct, individually tailored treatment.

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“…Mice lacking Cntnap2 (Peñagarikano et al, 2011) or Cntnap4 (Karayannis et al, 2014) also have phenotypes which resemble ASD. Likewise, mice lacking Nlgn1 (Blundell et al, 2010), Nlgn2 (Blundell et al, 2009; Wöhr et al, 2013), Nlgn3 (Radyushkin et al, 2009; Rothwell et al, 2014), or Nlgn4 (Jamain et al, 2008; El-Kordi et al, 2013; Ju et al, 2014) all have ASD-like behaviors to various degrees. Mice with a knock-in mutation of NLGN3 (R451C) found in human populations have also been generated and recapitulate some ASD-like features (Tabuchi et al, 2007; Jaramillo et al, 2014; Rothwell et al, 2014).…”

Section: Overview Of Monogenic Mouse Models Of Asdsmentioning

confidence: 99%

Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links

Hulbert

Jiang

2016

Neuroscience

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Autism Spectrum Disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral analysis with circuit-level analysis in genetically modified models with strong construct validity.

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Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism

Cited by 110 publications

References 48 publications

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

Towards Identification of Individual Etiologies by Resolving Genomic and Biological Conundrums in Patients with Autism Spectrum Disorders

Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links

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