Top

Published in:

Open Access 01-12-2016 | Research

Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice

Authors: Remco T. Molenhuis, Hilgo Bruining, Esther Remmelink, Leonie de Visser, Maarten Loos, J. Peter H. Burbach, Martien J. H. Kas

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2016

Abstract

Background

Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages.

Methods

C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors.

Results

Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice.

Conclusions

Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance.

Available only for authorised users

Am. Psychiatr. Assoc.: Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC; 2013.

Chen JA, Peñagarikano O, Belgard TG, Swarup V, Geschwind DH. The emerging picture of autism spectrum disorder: genetics and pathology. Annu Rev Pathol: Mech Dis. 2015;10:111–44.CrossRef

Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–94.CrossRefPubMedPubMedCentral

De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15.CrossRefPubMedPubMedCentral

Abrahams BS, Arking DE, Campbell DB, Mefford HC, Morrow EM, Weiss LA, et al. SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism. 2013;4:36.CrossRefPubMedPubMedCentral

Molenhuis RT, de Visser L, Bruining H, Kas MJ. Enhancing the value of psychiatric mouse models; differential expression of developmental behavioral and cognitive profiles in four inbred strains of mice. Eur Neuropsychopharmacol. 2014;24:945–54.CrossRefPubMed

Zuko A, Kleijer KTE, Oguro-Ando A, Kas MJH, Van Daalen E, Van Der Zwaag B, et al. Contactins in the neurobiology of autism. Eur J Pharmacol. 2013;719:63–74.CrossRefPubMed

Kaneko-Goto T, Yoshihara S-I, Miyazaki H, Yoshihara Y. BIG-2 mediates olfactory axon convergence to target glomeruli. Neuron. 2008;57:834–46.CrossRefPubMed

Osterhout JA, Stafford BK, Nguyen PL, Yoshihara Y, Huberman AD. Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron. 2015;86:985–99.CrossRefPubMed

10.

Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A, et al. Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet. 2004;74:1286–93.CrossRefPubMedPubMedCentral

11.

Roohi J, Montagna C, Tegay DH, Palmer LE, DeVincent C, Pomeroy JC, et al. Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet. 2009;46:176–82.CrossRefPubMedPubMedCentral

12.

Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72.CrossRefPubMedPubMedCentral

13.

Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–73.CrossRefPubMedPubMedCentral

14.

Guo H, Xun G, Peng Y, Xiang X, Xiong Z, Zhang L, et al. Disruption of contactin 4 in two subjects with autism in Chinese population. Gene. 2012;505:201–5.CrossRefPubMed

15.

Cottrell CE, Bir N, Varga E, Alvarez CE, Bouyain S, Zernzach R, et al. Contactin 4 as an autism susceptibility locus. Autism Res. 2011;4:189–99.CrossRefPubMedPubMedCentral

16.

Murdoch JD, Gupta AR, Sanders SJ, Walker MF, Keaney J, Fernandez TV, et al. No evidence for association of autism with rare heterozygous point mutations in contactin-associated protein-like 2 (CNTNAP2), or in other contactin-associated proteins or contactins. PLoS Genet. 2015;11:e1004852.CrossRefPubMedPubMedCentral

17.

Rogers DC, Jones DNC, Nelson PR, Jones CM, Quilter CA, Robinson TL, et al. Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behav Brain Res. 1999;105:207–17.CrossRefPubMed

18.

Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci. 2010;11:490–502.CrossRefPubMedPubMedCentral

19.

Bruining H, Matsui A, Oguro-Ando A, Kahn RS, Spijker HM V’t, Akkermans G, et al. Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition, and sensorimotor development. Biol Psychiatry. 2015;78:485–95.CrossRefPubMed

20.

Pearson BL, Pobbe RLH, Defensor EB, Oasay L, Bolivar VJ, Blanchard DC, et al. Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism. Genes Brain Behav. 2011;10:228–35.CrossRefPubMedPubMedCentral

21.

Seigers R, Loos M, Van Tellingen O, Boogerd W, Smit AB, Schagen SB. Cognitive impact of cytotoxic agents in mice. Psychopharmacology (Berl). 2015;232(1):17–37.

22.

Green S, Hernandez L, Tottenham N, Krasileva K, Bookheimer S, Dapretto M: Neurobiology of sensory overresponsivity in youth with autism spectrum disorders. JAMA Psychiatry. 2015;72(8):778-786.

23.

Chen L, Toth M. Fragile X mice develop sensory hyperreactivity to auditory stimuli. Neuroscience. 2001;103:1043–50.CrossRefPubMed

24.

Takahashi H, Nakahachi T, Komatsu S, Ogino K, Iida Y, Kamio Y. Hyperreactivity to weak acoustic stimuli and prolonged acoustic startle latency in children with autism spectrum disorders. Mol Autism. 2014;5:23.CrossRefPubMedPubMedCentral

25.

Blanchard DC, Griebel G, Blanchard RJ. Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic. Eur J Pharmacol. 2003;463:97–116.CrossRefPubMed

26.

Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472:437–42.CrossRefPubMedPubMedCentral

27.

Jiang YH, Ehlers MD. Modeling autism by SHANK gene mutations in mice. Neuron. 2013;78:8–27.CrossRefPubMedPubMedCentral

28.

Ey E, Leblond CS, Bourgeron T. Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 2011;4:5–16.CrossRefPubMed

29.

Parker JDA, Majeski SA, Collin VT. ADHD symptoms and personality: relationships with the five-factor model. Pers Individ Dif. 2004;36:977–87.CrossRef

30.

Dalgleish T, Moradi AR, Taghavi MR, Neshat-Doost HT, Yule W. An experimental investigation of hypervigilance for threat in children and adolescents with post-traumatic stress disorder. Psychol Med. 2001;31:541–7.CrossRefPubMed

31.

Freedman R, Waldo M, Bickford-Wimer P, Nagamoto H. Elementary neuronal dysfunctions in schizophrenia. Schizophr Res. 1991;4:233–43.CrossRefPubMed

32.

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.CrossRefPubMedCentral

Title: Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice
Authors: Remco T. Molenhuis
Hilgo Bruining
Esther Remmelink
Leonie de Visser
Maarten Loos
J. Peter H. Burbach
Martien J. H. Kas
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neurodevelopmental Disorders / Issue 1/2016
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI: https://doi.org/10.1186/s11689-016-9140-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus

A developmental, longitudinal investigation of autism phenotypic profiles in fragile X syndrome

Verbal labels increase the salience of novel objects for preschoolers with typical development and Williams syndrome, but not in autism

Postural orientation and equilibrium processes associated with increased postural sway in autism spectrum disorder (ASD)

The NIH Toolbox Cognitive Battery for intellectual disabilities: three preliminary studies and future directions

Methods for acquiring MRI data in children with autism spectrum disorder and intellectual impairment without the use of sedation