Abstract
Animal studies provide a unique opportunity to study the consequences of genetic variants at the behavioural level. Human studies have identified hundreds of risk genes for autism spectrum disorder (ASD) that can lead to understanding on how genetic variation contributes to individual differences in social interaction and stereotyped behaviour in people with ASD. To develop rational therapeutic interventions, systematic animal model studies are needed to understand the relationships between genetic variation, pathogenic processes and the expression of autistic behaviours. Genetic and non-genetic animal model strategies are here reviewed in their propensity to study the underpinnings of behavioural trait variation. We conclude that an integration of reverse and forward genetic approaches may be essential to unravel the neurobiological mechanisms underlying ASD.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Abrahams BS, Arking DE, Campbell DB et al (2013) SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism 4:36. doi:10.1186/2040-2392-4-36
Amir RE, Van den Veyver IB, Wan M et al (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188. doi:10.1038/13810
Aylor DL, Valdar W, Foulds-Mathes W et al (2011) Genetic analysis of complex traits in the emerging collaborative cross. Genome Res 21:1213–1222. doi:10.1101/gr.111310.110
Bachevalier J (1994) Medial temporal lobe structures and autism: a review of clinical and experimental findings. Neuropsychologia 32:627–648
Bachevalier J (1996) Brief report: medial temporal lobe and autism: a putative animal model in primates. J Autism Dev Disord 26:217–220
Baron-Cohen S, Scott FJ, Allison C et al (2009) Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry 194:500–509. doi:10.1192/bjp.bp.108.059345
Baudouin SJ, Gaudias J, Gerharz S et al (2012) Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 338:128–132. doi:10.1126/science.1224159
Bernardet M, Crusio WE (2006) Fmr1 KO mice as a possible model of autistic features. ScientificWorldJournal 6:1164–1176. doi:10.1100/tsw.2006.220
Bissonette GB, Powell EM (2012) Reversal learning and attentional set-shifting in mice. Neuropharmacology 62:1168–1174. doi:10.1016/j.neuropharm.2011.03.011
Blumberg SJ, Bramlett MD, Kogan MD et al (2013) Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011–2012. Natl Health Stat Report 1–12
Bolivar VJ, Walters SR, Phoenix JL (2007) Assessing autism-like behavior in mice: variations in social interactions among inbred strains. Behav Brain Res 176:21–26. doi:10.1016/j.bbr.2006.09.007
Bonasera SJ, Schenk AK, Luxenberg EJ, Tecott LH (2008) A novel method for automatic quantification of psychostimulant-evoked route-tracing stereotypy: application to Mus musculus. Psychopharmacology (Berl) 196:591–602. doi:10.1007/s00213-007-0994-6
Brigman JL, Daut RA, Wright T et al (2013) GluN2B in corticostriatal circuits governs choice learning and choice shifting. Nat Neurosci 16:1101–1110. doi:10.1038/nn.3457
Bruining H, Matsui A, Oguro-Ando A et al (2015) Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development. Biol Psychiatry 78:485–495. doi:10.1016/j.biopsych.2015.01.017
Bruining H, Passtoors L, Goriounova N, Jansen F, Hakvoort B (2015) Paradoxical benzodiazepine response: a rationale for bumetanide in neurodevelopmental disorders? Pediatrics 136(2). doi:10.1542/peds.2014-4133
Brunner D, Kabitzke P, He D et al (2015) Comprehensive analysis of the 16p11.2 deletion and Null Cntnap2 mouse models of autism spectrum disorder. PLoS One 10:e0134572. doi:10.1371/journal.pone.0134572
Canetta S, Sourander A, Surcel H-M et al (2014) Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. Am J Psychiatry 171:960–968. doi:10.1176/appi.ajp.2014.13121579
Chadman KK, Gong S, Scattoni ML et al (2008) Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res 1:147–158. doi:10.1002/aur.22
Chalfin L, Dayan M, Levy DR et al (2014) Mapping ecologically relevant social behaviours by gene knockout in wild mice. Nat Commun 5:4569. doi:10.1038/ncomms5569
Chesler EJ (2014) Out of the bottleneck: the Diversity Outcross and Collaborative Cross mouse populations in behavioral genetics research. Mamm Genome 25:3–11. doi:10.1007/s00335-013-9492-9
Christensen J, Gronborg TK, Sorensen MJ et al (2013) Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309:1696–1703. doi:10.1001/jama.2013.2270
Christianson AL, Chesler N, Kromberg JG (1994) Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol 36:361–369
Churchill GA, Airey DC, Allayee H et al (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137. doi:10.1038/ng1104-1133
de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH (2016) Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22:345–361. doi:10.1038/nm.4071
De Rubeis S, He X, Goldberg AP et al (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–215. doi:10.1038/nature13772
Delorme R, Ey E, Toro R et al (2013) Progress toward treatments for synaptic defects in autism. Nat Med 19:685–694. doi:10.1038/nm.3193
den Ouden HEM, Daw ND, Fernandez G et al (2013) Dissociable effects of dopamine and serotonin on reversal learning. Neuron 80:1090–1100. doi:10.1016/j.neuron.2013.08.030
Durrant C, Tayem H, Yalcin B et al (2011) Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection. Genome Res 21:1239–1248. doi:10.1101/gr.118786.110
European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315. 0092-8674(93)90618-Z
Ey E, Torquet N, Le Sourd AM et al (2013) The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations. Behav Brain Res 256:677–689. doi:10.1016/j.bbr.2013.08.031
Fountain C, Winter AS, Bearman PS (2012) Six developmental trajectories characterize children with autism. Pediatrics 129:e1112–e1120. doi:10.1542/peds.2011-1601
Gardener H, Spiegelman D, Buka SL (2009) Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry 195:7–14. doi:10.1192/bjp.bp.108.051672
Gardener H, Spiegelman D, Buka SL (2011) Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics 128:344–355. doi:10.1542/peds.2010-1036d
Gaugler T, Klei L, Sanders SJ et al (2014) Most genetic risk for autism resides with common variation. Nat Genet 46:881–885. doi:10.1038/ng.3039
Geschwind DH, State MW (2015) Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol 14:1109–1120. doi:10.1016/S1474-4422(15)00044-7
Gralinski LE, Ferris MT, Aylor DL et al (2015) Genome wide identification of SARS-CoV susceptibility Loci using the Collaborative Cross. PLoS Genet 11:e1005504. doi:10.1371/journal.pgen.1005504
Guy J, Gan J, Selfridge J et al (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–1147. doi:10.1126/science.1138389
Hagerman RJ (2006) Lessons from fragile X regarding neurobiology, autism, and neurodegeneration. J Dev Behav Pediatr 27:63–74. doi:10.1097/00004703-200602000-00012
Hall M, Manship G, Morahan G et al (2012) The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 190:389–401. doi:10.1534/genetics.111.132639
Huber KM, Gallagher SM, Warren ST, Bear MF (2002) Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 99:7746–7750. doi:10.1073/pnas.122205699
Hultman CM, Sandin S, Levine SZ et al (2011) Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry 16:1203–1212. doi:10.1038/mp.2010.121
Hyman SE (2014) How far can mice carry autism research? Cell 158:13–14. doi:10.1016/j.cell.2014.06.032
Insel TR, Cuthbert BN (2015) Brain disorders? Precisely. Science 348:499–500. doi:10.1126/science.aab2358
Jeste SS, Frohlich J, Loo SK (2015) Electrophysiological biomarkers of diagnosis and outcome in neurodevelopmental disorders. Curr Opin Neurol 28:110–116. doi:10.1097/WCO.0000000000000181
Jones W, Klin A (2013) Attention to eyes is present but in decline in 2-6-month-old infants later diagnosed with autism. Nature 504:427–431. doi:10.1038/nature12715
Jones BC, Tarantino LM, Rodriguez LA et al (1999) Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry. Pharmacogenetics 9:607–617
Jones-Davis DM, Yang M, Rider E et al (2013) Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T(+) tf/J mouse model of autism. PLoS One 8:e61829. doi:10.1371/journal.pone.0061829
Kalueff AV, Stewart AM, Song C et al (2016) Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci 17:45–59. doi:10.1038/nrn.2015.8
Karvat G, Kimchi T (2012) Systematic autistic-like behavioral phenotyping of 4 mouse strains using a novel wheel-running assay. Behav Brain Res 233:405–414. doi:10.1016/j.bbr.2012.05.028
Kas MJH, Fernandes C, Schalkwyk LC, Collier DA (2007) Genetics of behavioural domains across the neuropsychiatric spectrum; of mice and men. Mol Psychiatry 12:324–330. doi:10.1038/sj.mp.4001979
Kas MJH, Gelegen C, Schalkwyk LC, Collier DA (2009) Interspecies comparisons of functional genetic variations and their implications in neuropsychiatry. Am J Med Genet B Neuropsychiatr Genet 150B:309–317. doi:10.1002/ajmg.b.30815
Kas MJ, Glennon JC, Buitelaar J et al (2014) Assessing behavioural and cognitive domains of autism spectrum disorders in rodents: current status and future perspectives. Psychopharmacology (Berl) 231:1125–1146. doi:10.1007/s00213-013-3268-5
Kasari C, Shire S, Factor R, McCracken C (2014) Psychosocial treatments for individuals with autism spectrum disorder across the lifespan: new developments and underlying mechanisms. Curr Psychiatry Rep 16:512. doi:10.1007/s11920-014-0512-6
Kazdoba TM, Leach PT, Silverman JL, Crawley JN (2014) Modeling fragile X syndrome in the Fmr1 knockout mouse. Intractable Rare Dis Res 3:118–133. doi:10.5582/irdr.2014.01024
Kazdoba TM, Leach PT, Crawley JN (2015) Behavioral phenotypes of genetic mouse models of autism. Genes Brain Behav:7–26. doi:10.1111/gbb.12256
Keane TM, Goodstadt L, Danecek P et al (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477:289–294. doi:10.1038/nature10413
Keverne EB (2002) Mammalian pheromones: from genes to behaviour. Curr Biol 12:R807–R809. doi:10.1016/S0960-9822(02)01314-3
Kim YS, Leventhal BL, Koh Y-J et al (2011) Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry 168:904–912. doi:10.1176/appi.ajp.2011.10101532
Klanker M, Feenstra M, Denys D (2013) Dopaminergic control of cognitive flexibility in humans and animals. Front Neurosci 7:201. doi:10.3389/fnins.2013.00201
Klei L, Sanders SJ, Murtha MT et al (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3:9. doi:10.1186/2040-2392-3-9
Langen M, Durston S, Kas MJH et al (2011a) The neurobiology of repetitive behavior: …and men. Neurosci Biobehav Rev 35:356–365. doi:10.1016/j.neubiorev.2010.02.005
Langen M, Kas MJH, Staal WG, et al (2011b) The neurobiology of repetitive behavior: of mice.... Neurosci Biobehav Rev 35:345–355. doi:10.1016/j.neubiorev.2010.02.004
Laughlin RE, Grant TL, Williams RW, Jentsch JD (2011) Genetic dissection of behavioral flexibility: reversal learning in mice. Biol Psychiatry 69:1109–1116. doi:10.1016/j.biopsych.2011.01.014
Lemonnier E et al (2012) A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2:e202–e208. doi:10.1038/tp.2012.124
Liu Z, Li X, Zhang J-T et al (2016) Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2. Nature 530:98–102. doi:10.1038/nature16533
Lorenz KZ (1958) The evolution of behavior. Sci Am 199:67–74
Lotter V (1966) Epidemiology of autistic conditions in young children. Soc Psychiatry 1:124–135. doi:10.1007/BF00584048
Mattila ML, Kielinen M, Linna SL et al (2011) Autism spectrum disorders according to DSM-IV-TR and comparison with DSM-5 draft criteria: an epidemiological study. J Am Acad Child Adolesc Psychiatry 50:583–592. doi:10.1016/j.jaac.2011.04.001
McDougle CJ, Stigler KA, Erickson CA, Posey DJ (2008) Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry 69(Suppl 4):15–20
Mei Y, Monteiro P, Zhou Y et al (2016) Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530:481–484. doi:10.1038/nature16971
Molenhuis RT, de Visser L, Bruining H, Kas MJ (2014) Enhancing the value of psychiatric mouse models; differential expression of developmental behavioral and cognitive profiles in four inbred strains of mice. Eur Neuropsychopharmacol 24:945–954. doi:10.1016/j.euroneuro.2014.01.013
Moy SS, Nadler JJ, Magnuson TR, Crawley JN (2006) Mouse models of autism spectrum disorders: the challenge for behavioral genetics. Am J Med Genet C Semin Med Genet 142C:40–51. doi:10.1002/ajmg.c
Moy SS, Nadler JJ, Young NB et al (2007) Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 176:4–20. doi:10.1016/j.bbr.2006.07.030
Moy SS, Nadler JJ, Young NB et al (2008) Social approach and repetitive behavior in eleven inbred mouse strains. Behav Brain Res 191:118–129. doi:10.1016/j.bbr.2008.03.015
Nadler JJ, Moy SS, Dold G et al (2004) Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav 3:303–314. doi:10.1111/j.1601-183X.2004.00071.x
Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169. doi:10.1146/annurev-clinpsy-032210-104454
Pearson BL, Defensor EB, Blanchard DC, Blanchard RJ (2010) C57BL/6J mice fail to exhibit preference for social novelty in the three-chamber apparatus. Behav Brain Res 213:189–194. doi:10.1016/j.bbr.2010.04.054
Pearson BL, Pobbe RLH, Defensor EB et al (2011) Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism. Genes Brain Behav 10:228–235. doi:10.1111/j.1601-183X.2010.00659.x
Peca J, Feliciano C, Ting JT et al (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–442. doi:10.1038/nature09965
Peirce JL, Lu L, Gu J et al (2004) A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 5:7. doi:10.1186/1471-2156-5-7
Penagarikano O, Abrahams BS, Herman EI et al (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147:235–246. doi:10.1016/j.cell.2011.08.040
Penagarikano O, Lazaro MT, Lu X-H et al (2015) Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med 7:271ra8. doi:10.1126/scitranslmed.3010257
Pietropaolo S, Guilleminot A, Martin B et al (2011) Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice. PLoS One 6:1–11. doi:10.1371/journal.pone.0017073
Robinson EB, St Pourcain B, Anttila V et al (2016) Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat Genet 48:552–555. doi:10.1038/ng.3529
Roelfsema MT, Hoekstra RA, Allison C et al (2012) Are autism spectrum conditions more prevalent in an information-technology region? A school-based study of three regions in the Netherlands. J Autism Dev Disord 42:734–739. doi:10.1007/s10803-011-1302-1
Rogers SJ, Vismara L, Wagner AL et al (2014) Autism treatment in the first year of life: a pilot study of infant start, a parent-implemented intervention for symptomatic infants. J Autism Dev Disord 44:2981–2995. doi:10.1007/s10803-014-2202-y
Ronald A, Hoekstra RA (2011) Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet 156B:255–274. doi:10.1002/ajmg.b.31159
Roullet FI, Lai JKY, Foster JA (2013) In utero exposure to valproic acid and autism—A current review of clinical and animal studies. Neurotoxicol Teratol 36:47–56. doi:10.1016/j.ntt.2013.01.004
Sandin S, Hultman CM, Kolevzon A et al (2012) Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry 51:477–486.e1. doi:10.1016/j.jaac.2012.02.018
Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30:80–89. doi:10.1038/sj.npp.1300518
Schughart K, Libert C, Kas MJ (2013) Controlling complexity: the clinical relevance of mouse complex genetics. Eur J Hum Genet 21:1191–1196. doi:10.1038/ejhg.2013.79
Silverman JL, Yang M, Lord C, Crawley JN (2010) Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11:490–502. doi:10.1038/nrn2851
Sittig LJ, Carbonetto P, Engel KA et al (2016) Genetic background limits generalizability of genotype-phenotype relationships. Neuron 91:1253–1259. doi:10.1016/j.neuron.2016.08.013
Spencer CM, Alekseyenko O, Hamilton SM et al (2011) Modifying behavioral phenotypes in Fmr1KO mice: genetic background differences reveal autistic-like responses. Autism Res 4:40–56. doi:10.1002/aur.168
Tabuchi K, Blundell J, Etherton MR et al (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76. doi:10.1126/science.1146221
Tanimura Y, Yang MC, Lewis MH (2008) Procedural learning and cognitive flexibility in a mouse model of restricted, repetitive behaviour. Behav Brain Res 189:250–256. doi:10.1016/j.bbr.2008.01.001
Tanimura Y, King MA, Williams DK, Lewis MH (2011) Development of repetitive behavior in a mouse model: roles of indirect and striosomal basal ganglia pathways. Int J Dev Neurosci 29:461–467. doi:10.1016/j.ijdevneu.2011.02.004
Thomas A, Burant A, Bui N et al (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl) 204:361–373. doi:10.1007/s00213-009-1466-y
Turner M (1999) Annotation: repetitive behaviour in autism: a review of psychological research. J Child Psychol Psychiatry 40:839–849
van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808. doi:10.1126/science.277.5327.805
Verkerk AJMH, Pieretti M, Sutcliffe JS et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914
Volk HE, Lurmann F, Penfold B et al (2013) Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry 70:71–77. doi:10.1001/jamapsychiatry.2013.266
Weber JN, Peterson BK, Hoekstra HE (2013) Discrete genetic modules are responsible for complex burrow evolution in Peromyscus mice. Nature 493:402–405. doi:10.1038/nature11816
Weintraub K (2011) The prevalence puzzle: Autism counts. Nature 479:22–24
Weissbrod A, Shapiro A, Vasserman G et al (2013) Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment. Nat Commun 4:2018. doi:10.1038/ncomms3018
Williams EGG, Auwerx J (2015) The convergence of systems and reductionist approaches in complex trait analysis. Cell 162:23–32. doi:10.1016/j.cell.2015.06.024
Acknowledgements
This work was supported by EU-AIMS, which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no.115300, resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (P7/2007–2013), from EFPIA companies in kind contribution and from Autism Speaks.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Molenhuis, R.T., Bruining, H., Kas, M.J. (2017). Modelling Autistic Features in Mice Using Quantitative Genetic Approaches. In: Schmeisser, M., Boeckers, T. (eds) Translational Anatomy and Cell Biology of Autism Spectrum Disorder. Advances in Anatomy, Embryology and Cell Biology, vol 224. Springer, Cham. https://doi.org/10.1007/978-3-319-52498-6_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-52498-6_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-52496-2
Online ISBN: 978-3-319-52498-6
eBook Packages: MedicineMedicine (R0)