Mouse Models of Autism: Testing Hypotheses About Molecular Mechanisms
Abstract
Autism is a neurodevelopmental disorder that is currently diagnosed by the presence of three behavioral criteria (1) qualitative impairments in reciprocal social interactions, (2) deficits in communication, including delayed language and noninteractive conversation, and (3) motor stereotypies, repetitive behaviors, insistence on sameness, and restricted interests. This chapter describes analogous behavioral assays that have been developed for mice, including tests for social approach, reciprocal social interactions, olfactory communication, ultrasonic vocalizations, repetitive and perseverative behaviors, and motor stereotypies. Examples of assay applications to genetic mouse models of autism are provided. Robust endophenotypes that are highly relevant to the core symptoms of autism are enabling the search for the genetic and environmental causes of autism, and the discovery of effective treatments.
Keywords
Autism Behavior Candidate genes Communication Genetics Mice Mouse models Olfactory Repetitive Social VocalizationAbbreviations
- 5Htt
Serotonin transporter mutant line of mice
- Avpr1b
Arginine vasopressin receptor 1b null mutant line of mice
- B6
C57BL/6J inbred strain of mice
- BTBR
BTBR T+tf/J inbred strain of mice
- Fmr1
Fragile X Fmr1 null mutant line of mice
- Nlgn2
Neuroligin 2 mutant line of mice
- VPA
Valproic acid [Di-n-dipropylacetic acid]
References
- Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355PubMedGoogle Scholar
- Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159PubMedGoogle Scholar
- Amaral DG, Schumann CM, Nordahl CW (2008) Neuroanatomy of autism. Trends Neurosci 31:137–145PubMedGoogle Scholar
- American Psychiatric Association WDC (1994) Diagnostic and Statistical Manual of Mentral Disorders (DSM-IV). APA, Washington DCGoogle Scholar
- Anderson GM (2002) Genetics of childhood disorders: XLV. Autism, part 4: serotonin in autism. J Am Acad Child Adolesc Psychiatry 41:1513–1516PubMedGoogle Scholar
- Arakawa H, Arakawa K, Blanchard DC, Blanchard RJ (2007) Scent marking behavior in male C57BL/6J mice: sexual and developmental determination. Behav Brain Res 182:73–79PubMedGoogle Scholar
- Arakawa H, Blanchard DC, Arakawa K, Dunlap C, Blanchard RJ (2008) Scent marking behavior as an odorant communication in mice. Neurosci Biobehav Rev 32:1236–1248PubMedGoogle Scholar
- Arakawa H, Arakawa K, Blanchard DC, Blanchard RJ (2009) Social features of scent-donor mice modulate scent marking of C57BL/6J recipient males. Behav Brain Res 205:138–145PubMedGoogle Scholar
- Ardinger HH, Atkin JF, Blackston RD, Elsas LJ, Clarren SK, Livingstone S, Flannery DB, Pellock JM, Harrod MJ, Lammer EJ et al (1988) Verification of the fetal valproate syndrome phenotype. Am J Med Genet 29:171–185PubMedGoogle Scholar
- Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH, Chakravarti A (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160–164PubMedGoogle Scholar
- Arpino C, Brescianini S, Robert E, Castilla EE, Cocchi G, Cornel MC, de Vigan C, Lancaster PA, Merlob P, Sumiyoshi Y, Zampino G, Renzi C, Rosano A, Mastroiacovo P (2000) Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure (MADRE). Epilepsia 41:1436–1443PubMedGoogle Scholar
- Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Roge B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bolte S, Feineis-Matthews S, Herbrecht E, Schmotzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F et al (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328PubMedGoogle Scholar
- Bakker CE (1994) Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. Cell 78:23–33Google Scholar
- Baron-Cohen S (2009) Autism: the empathizing-systemizing (E-S) theory. Ann NY Acad Sci 1156:68–80PubMedGoogle Scholar
- Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:201–214PubMedGoogle Scholar
- Beckel-Mitchener A, Greenough WT (2004) Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome. Ment Retard Dev Disabil Res Rev 10:53–59PubMedGoogle Scholar
- Bielsky IF, Young LJ (2004) Oxytocin, vasopressin, and social recognition in mammals. Peptides 25:1565–1574PubMedGoogle Scholar
- Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ (2004) Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 29:483–493PubMedGoogle Scholar
- Bielsky IF, Hu SB, Ren X, Terwilliger EF, Young LJ (2005) The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron 47:503–513PubMedGoogle Scholar
- Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM (2009) Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 46:94–102PubMedGoogle Scholar
- Blundell J, Tabuchi K, Bolliger MF, Blaiss CA, Brose N, Liu X, Sudhof TC, Powell CM (2009) Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav 8:114–126PubMedGoogle Scholar
- Bodfish JW, Symons FJ, Parker DE, Lewis MH (2000) Varieties of repetitive behavior in autism: comparisons to mental retardation. J Autism Dev Disord 30:237–243PubMedGoogle Scholar
- Bolivar VJ, Walters SR, Phoenix JL (2007) Assessing autism-like behavior in mice: variations in social interactions among inbred strains. Behav Brain Res 176:21–26PubMedGoogle Scholar
- Bowers JM, Alexander BK (1967) Mice: individual recognition by olfactory cues. Science 158:1208–1210PubMedGoogle Scholar
- Branchi I, Santucci D, Alleva E (2001) Ultrasonic vocalisation emitted by infant rodents: a tool for assessment of neurobehavioural development. Behav Brain Res 125:49–56PubMedGoogle Scholar
- Brennan PA, Keverne EB (2004) Something in the air? New insights into mammalian pheromones. Curr Biol 14:R81–R89PubMedGoogle Scholar
- Brigman JL, Padukiewicz KE, Sutherland ML, Rothblat LA (2006) Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav Neurosci 120:984–988PubMedGoogle Scholar
- Brodkin ES (2007) BALB/c mice: low sociability and other phenotypes that may be relevant to autism. Behav Brain Res 176:53–65PubMedGoogle Scholar
- Carter CS, Williams JR, Witt DM, Insel TR (1992) Oxytocin and social bonding. Ann N Y Acad Sci Jun 12;652:204–211PubMedGoogle Scholar
- Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU, Heintz N, Crawley JN (2008) Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res 1:147–158PubMedGoogle Scholar
- Cheetham SA, Thom MD, Jury F, Ollier WE, Beynon RJ, Hurst JL (2007) The genetic basis of individual-recognition signals in the mouse. Curr Biol 17:1771–1777PubMedGoogle Scholar
- Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, Kamdar S, Wagner GC (2006) En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res 1116:166–176PubMedGoogle Scholar
- Chen G, Chen KS, Kobayashi D, Barbour R, Motter R, Games D, Martin SJ, Morris RG (2007) Active beta-amyloid immunization restores spatial learning in PDAPP mice displaying very low levels of beta-amyloid. J Neurosci 27:2654–2662PubMedGoogle Scholar
- Christianson AL, Chesler N, Kromberg JG (1994) Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol 36:361–369PubMedGoogle Scholar
- Cook EH Jr, Scherer SW (2008) Copy-number variations associated with neuropsychiatric conditions. Nature 455:919–923PubMedGoogle Scholar
- Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 60:928–934PubMedGoogle Scholar
- Crawley JN (2004) Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 10:248–258PubMedGoogle Scholar
- Crawley JN (2007a) Medicine. Testing hypotheses about autism. Science 318:56–57PubMedGoogle Scholar
- Crawley JN (2007b) Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol 17:448–459PubMedGoogle Scholar
- Crawley JN, Chen T, Puri A, Washburn R, Sullivan TL, Hill JM, Young NB, Nadler JJ, Moy SS, Young LJ, Caldwell HK, Young WS (2007) Social approach behaviors in oxytocin knockout mice: comparison of two independent lines tested in different laboratory environments. Neuropeptides 41:145–163PubMedGoogle Scholar
- Creese I, Iversen SD (1975) The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res 83:419–436PubMedGoogle Scholar
- Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790PubMedGoogle Scholar
- Cuccaro ML, Shao Y, Grubber J, Slifer M, Wolpert CM, Donnelly SL, Abramson RK, Ravan SA, Wright HH, DeLong GR, Pericak-Vance MA (2003) Factor analysis of restricted and repetitive behaviors in autism using the autism diagnostic interview-R. Child Psychiatry Hum Dev 34:3–17PubMedGoogle Scholar
- Dawson G, Webb S, Schellenberg GD, Dager S, Friedman S, Aylward E, Richards T (2002) Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives. Dev Psychopathol 14:581–611PubMedGoogle Scholar
- D’Amato FR, Moles A (2001) Ultrasonic vocalizations as an index of social memory in female mice. Behav Neurosci 115:834–840PubMedGoogle Scholar
- D’Hooge R, Nagels G, Franck F, Bakker CE, Reyniers E, Storm K, Kooy RF, Oostra BA, Willems PJ, De Deyn PP (1997) Mildly impaired water maze performance in male Fmr1 knockout mice. Neuroscience 76:367–376PubMedGoogle Scholar
- DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A, Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW (1998) Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 18:8505–8514PubMedGoogle Scholar
- DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (2008) Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res 187:207–220PubMedGoogle Scholar
- Diaz-Meco MT, Abu-Baker S (2009) The Par-4/PTEN connection in tumor suppression. Cell Cycle 8:2518–2522PubMedGoogle Scholar
- DiLiberti JH, Farndon PA, Dennis NR, Curry CJ (1984) The fetal valproate syndrome. Am J Med Genet 19:473–481PubMedGoogle Scholar
- Dolen G, Bear MF (2008) Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J Physiol 586:1503–1508PubMedGoogle Scholar
- Dolen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56:955–962PubMedGoogle Scholar
- Doty RL (1986) Odor-guided behavior in mammals. Experientia 42:257–271PubMedGoogle Scholar
- Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39:25–27PubMedGoogle Scholar
- Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ (2008a) Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med 14:843–848PubMedGoogle Scholar
- Ehninger D, Li W, Fox K, Stryker MP, Silva AJ (2008b) Reversing neurodevelopmental disorders in adults. Neuron 60(6):950–960PubMedGoogle Scholar
- Enard W, Gehre S, Hammerschmidt K, Holter SM, Blass T, Somel M, Bruckner MK, Schreiweis C, Winter C, Sohr R, Becker L, Wiebe V, Nickel B, Giger T, Muller U, Groszer M, Adler T, Aguilar A, Bolle I, Calzada-Wack J, Dalke C, Ehrhardt N, Favor J, Fuchs H, Gailus-Durner V, Hans W, Holzlwimmer G, Javaheri A, Kalaydjiev S, Kallnik M, Kling E, Kunder S, Mossbrugger I, Naton B, Racz I, Rathkolb B, Rozman J, Schrewe A, Busch DH, Graw J, Ivandic B, Klingenspor M, Klopstock T, Ollert M, Quintanilla-Martinez L, Schulz H, Wolf E, Wurst W, Zimmer A, Fisher SE, Morgenstern R, Arendt T, de Angelis MH, Fischer J, Schwarz J, Paabo S (2009) A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell 137:961–971PubMedGoogle Scholar
- Errijgers V, Fransen E, D'Hooge R, De Deyn PP, Kooy RF (2008) Effect of genetic background on acoustic startle response in fragile X knockout mice. Genet Res 90:341–345Google Scholar
- Fombonne E (2009) Epidemiology of pervasive developmental disorders. Pediatr Res 65:591–598PubMedGoogle Scholar
- Frith U (2003) Autism: explaining the Enigma. Wiley-Blackwell, Oxford, UKGoogle Scholar
- Fujita E, Tanabe Y, Shiota A, Ueda M, Suwa K, Momoi MY, Momoi T (2008) Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells. Proc Natl Acad Sci USA 105:3117–3122PubMedGoogle Scholar
- Garber K (2007) Neuroscience. Autism’s cause may reside in abnormalities at the synapse. Science 317:190–191PubMedGoogle Scholar
- Gondo Y, Murata T, Makino S, Fukumura R, Ishitsuka Y (2011) Mouse mutagenesis and disease models for neuropsychiatric disorders. Curr Topics Behav Neurosci. doi: 10.1007/7854_2010_106
- Gourbal BE, Barthelemy M, Petit G, Gabrion C (2004) Spectrographic analysis of the ultrasonic vocalisations of adult male and female BALB/c mice. Naturwissenschaften 91:381–385PubMedGoogle Scholar
- Grant EC, MacIntosh JH (1963) A comparison of the social postures of some common laboratory rodents. Behaviour 21:246–259Google Scholar
- Greer JM, Capecchi MR (2002) Hoxb8 is required for normal grooming behavior in mice. Neuron 33:23–34PubMedGoogle Scholar
- Halladay AK, Amaral D, Aschner M, Bolivar VJ, Bowman A, DiCicco-Bloom E, Hyman SL, Keller F, Lein P, Pessah I, Restifo L, Threadgill DW (2009) Animal models of autism spectrum disorders: information for neurotoxicologists. Neurotoxicology 30:811–821PubMedGoogle Scholar
- Happe F, Ronald A (2008) The ‘fractionable autism triad’: a review of evidence from behavioural, genetic, cognitive and neural research. Neuropsychol Rev 18:287–304PubMedGoogle Scholar
- Herbert MR, Ziegler DA, Deutsch CK, O’Brien LM, Lange N, Bakardjiev A, Hodgson J, Adrien KT, Steele S, Makris N, Kennedy D, Harris GJ, Caviness VS Jr (2003) Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys. Brain 126:1182–1192PubMedGoogle Scholar
- Hertz-Picciotto I, Delwiche L (2009) The rise in autism and the role of age at diagnosis. Epidemiology 20:84–90PubMedGoogle Scholar
- Hofer MA, Shair HN, Masmela JR, Brunelli SA (2001) Developmental effects of selective breeding for an infantile trait: the rat pup ultrasonic isolation call. Dev Psychobiol 39:231–246PubMedGoogle Scholar
- Holmes A, Murphy DL, Crawley JN (2003) Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 54:953–959PubMedGoogle Scholar
- Humphries RE, Robertson DH, Beynon RJ, Hurst JL (1999) Unravelling the chemical basis of competitive scent marking in house mice. Anim Behav 58:1177–1190PubMedGoogle Scholar
- Hurst JL, Beynon RJ (2004) Scent wars: the chemobiology of competitive signalling in mice. Bioessays 26:1288–1298PubMedGoogle Scholar
- Hurst JL, Payne CE, Nevison CM, Marie AD, Humphries RE, Robertson DH, Cavaggioni A, Beynon RJ (2001) Individual recognition in mice mediated by major urinary proteins. Nature 414:631–634PubMedGoogle Scholar
- Hurst JL, Thom MD, Nevison CM, Humphries RE, Beynon RJ (2005) MHC odours are not required or sufficient for recognition of individual scent owners. Proc Biol Sci 272:715–724PubMedGoogle Scholar
- Ingram JL, Peckham SM, Tisdale B, Rodier PM (2000) Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22:319–324PubMedGoogle Scholar
- Isles AR, Baum MJ, Ma D, Keverne EB, Allen ND (2001) Urinary odour preferences in mice. Nature 409:783–784PubMedGoogle Scholar
- Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34:27–29PubMedGoogle Scholar
- Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J, Ronnenberg A, Winter D, Frahm J, Fischer J, Bourgeron T, Ehrenreich H, Brose N (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA 105:1710–1715PubMedGoogle Scholar
- Jeffries AR, Curran S, Elmslie F, Sharma A, Wenger S, Hummel M, Powell J (2005) Molecular and phenotypic characterization of ring chromosome 22. Am J Med Genet A 137:139–147PubMedGoogle Scholar
- Kanner L (1943) Autistic disturbances of affective contact. Nerv Child 2:217–250Google Scholar
- Kavaliers M, Choleris E, Pfaff DW (2005) Recognition and avoidance of the odors of parasitized conspecifics and predators: differential genomic correlates. Neurosci Biobehav Rev 29:1347–1359PubMedGoogle Scholar
- Keller M, Douhard Q, Baum MJ, Bakker J (2006) Sexual experience does not compensate for the disruptive effects of zinc sulfate–lesioning of the main olfactory epithelium on sexual behavior in male mice. Chem Senses 31:753–762PubMedGoogle Scholar
- Keverne EB (2004) Importance of olfactory and vomeronasal systems for male sexual function. Physiol Behav 83:177–187PubMedGoogle Scholar
- Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y, Lally E, Weiss LA, Najm J, Kutsche K, Descartes M, Holt L, Braddock S, Troxell R, Kaplan L, Volkmar F, Klin A, Tsatsanis K, Harris DJ, Noens I, Pauls DL, Daly MJ, MacDonald ME, Morton CC, Quade BJ, Gusella JF (2008) Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82:199–207PubMedGoogle Scholar
- King M, Bearman P (2009) Diagnostic change and the increased prevalence of autism. Int J Epidemiol 38:1224–1234PubMedGoogle Scholar
- Kolozsi E, Mackenzie RN, Roullet FI, deCatanzaro D, Foster JA (2009) Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Neuroscience 163:1201–1210PubMedGoogle Scholar
- Korff S, Harvey BH (2006) Animal models of obsessive-compulsive disorder: rationale to understanding psychobiology and pharmacology. Psychiatr Clin North Am 29:371–390PubMedGoogle Scholar
- Kwasnicka-Crawford DA, Roberts W, Scherer SW (2007) Characterization of an autism-associated segmental maternal heterodisomy of the chromosome 15q11-13 region. J Autism Dev Disord 37:694–702PubMedGoogle Scholar
- Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377–388PubMedGoogle Scholar
- Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH, Hamel BC, Andres C, Barthelemy C, Moraine C, Briault S (2004) X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 74:552–557PubMedGoogle Scholar
- Lauterborn JC, Rex CS, Kramar E, Chen LY, Pandyarajan V, Lynch G, Gall CM (2007) Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 27:10685–10694PubMedGoogle Scholar
- Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008) Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 16:614–618PubMedGoogle Scholar
- Lee JW, Ryoo ZY, Lee EJ, Hong SH, Chung WH, Lee HT, Chung KS, Kim TY, Oh YS, Suh JG (2002) Circling mouse, a spontaneous mutant in the inner ear. Exp Anim 51:167–171PubMedGoogle Scholar
- Levitt P, Campbell DB (2009) The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest 119:747–754PubMedGoogle Scholar
- Lewis MH, Tanimura Y, Lee LW, Bodfish JW (2007) Animal models of restricted repetitive behavior in autism. Behav Brain Res 176:66–74PubMedGoogle Scholar
- Lintas C, Persico AM (2009) Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet 46:1–8PubMedGoogle Scholar
- Lise MF, El-Husseini A (2006) The neuroligin and neurexin families: from structure to function at the synapse. Cell Mol Life Sci 63:1833–1849PubMedGoogle Scholar
- London E (2007) The role of the neurobiologist in redefining the diagnosis of autism. Brain Pathol 17:408–411PubMedGoogle Scholar
- Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30:205–223PubMedGoogle Scholar
- Maggio JC, Whitney G (1985) Ultrasonic vocalizing by adult female mice (Mus musculus). J Comp Psychol 99:420–436PubMedGoogle Scholar
- McAlonan GM, Suckling J, Wong N, Cheung V, Lienenkaemper N, Cheung C, Chua SE (2008) Distinct patterns of grey matter abnormality in high-functioning autism and Asperger’s syndrome. J Child Psychol Psychiatry 49:1287–1295PubMedGoogle Scholar
- McDougle CJ, Erickson CA, Stigler KA, Posey DJ (2005) Neurochemistry in the pathophysiology of autism. J Clin Psychiatry 66(Suppl 10):9–18PubMedGoogle Scholar
- McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN (2008) Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 7:152–163PubMedGoogle Scholar
- Miczek KA, Maxson SC, Fish EW, Faccidomo S (2001) Aggressive behavioral phenotypes in mice. Behav Brain Res 125:167–181PubMedGoogle Scholar
- Mineur YS, Huynh LX, Crusio WE (2006) Social behavior deficits in the Fmr1 mutant mouse. Behav Brain Res 168:172–175PubMedGoogle Scholar
- Minshew NJ, Williams DL (2007) The new neurobiology of autism: cortex, connectivity, and neuronal organization. Arch Neurol 64:945–950PubMedGoogle Scholar
- Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297PubMedGoogle Scholar
- Moon J, Beaudin AE, Verosky S, Driscoll LL, Weiskopf M, Levitsky DA, Crnic LS, Strupp BJ (2006) Attentional dysfunction, impulsivity, and resistance to change in a mouse model of fragile X syndrome. Behav Neurosci 120:1367–1379PubMedGoogle Scholar
- Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC (2000) A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 37:489–497PubMedGoogle Scholar
- Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, Piven J, Crawley JN (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3:287–302PubMedGoogle Scholar
- Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, Barbaro JR, Wilson LM, Threadgill DW, Lauder JM, Magnuson TR, Crawley JN (2007) Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 176:4–20PubMedGoogle Scholar
- Moy SS, Nadler JJ, Poe MD, Nonneman RJ, Young NB, Koller BH, Crawley JN, Duncan GE, Bodfish JW (2008a) Development of a mouse test for repetitive, restricted behaviors: relevance to autism. Behav Brain Res 188:178–194PubMedGoogle Scholar
- Moy SS, Nadler JJ, Young NB, Nonneman RJ, Segall SK, Andrade GM, Crawley JN, Magnuson TR (2008b) Social approach and repetitive behavior in eleven inbred mouse strains. Behav Brain Res 191:118–129PubMedGoogle Scholar
- Moy SS, Nadler JJ, Young NB, Nonneman RJ, Grossman AW, Murphy DL, D’Ercole AJ, Crawley JN, Magnuson TR, Lauder JM (2009) Social approach in genetically engineered mouse lines relevant to autism. Genes Brain Behav 8:129–142PubMedGoogle Scholar
- Nadler JJ, Moy SS, Dold G, Trang D, Simmons N, Perez A, Young NB, Barbaro RP, Piven J, Magnuson TR, Crawley JN (2004) Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav 3:303–314PubMedGoogle Scholar
- Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y, Chung YJ, Banerjee R, Iwamoto K, Kato T, Okazawa M, Yamauchi K, Tanda K, Takao K, Miyakawa T, Bradley A, Takumi T (2009) Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137:1235–1246PubMedGoogle Scholar
- Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N (2002) Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Pediatr Res 52(4):576–579PubMedGoogle Scholar
- Ornoy A (2009) Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol 28:1–10PubMedGoogle Scholar
- Page DT, Kuti OJ, Prestia C, Sur M (2009) Haploinsufficiency for Pten and serotonin transporter cooperatively influences brain size and social behavior. Proc Natl Acad Sci USA 106:1989–1994PubMedGoogle Scholar
- Panksepp JB, Jochman KA, Kim JU, Koy JJ, Wilson ED, Chen Q, Wilson CR, Lahvis GP (2007) Affiliative behavior, ultrasonic communication and social reward are influenced by genetic variation in adolescent mice. PLoS One 2:e351PubMedGoogle Scholar
- Paylor R, Yuva-Paylor LA, Nelson DL, Spencer CM (2008) Reversal of sensorimotor gating abnormalities in Fmr1 knockout mice carrying a human Fmr1 transgene. Behav Neurosci 122:1371–1377PubMedGoogle Scholar
- Peier AM, McIlwain KL, Kenneson A, Warren ST, Paylor R, Nelson DL (2000) (Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features. Hum Mol Genet 9:1145–1159PubMedGoogle Scholar
- Pelphrey KA, Sasson NJ, Reznick JS, Paul G, Goldman BD, Piven J (2002) Visual scanning of faces in autism. J Autism Dev Disord 32:249–261PubMedGoogle Scholar
- Piven J, Palmer P, Jacobi D, Childress D, Arndt S (1997) Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry 154:185–190PubMedGoogle Scholar
- Pogorelov VM, Rodriguiz RM, Insco ML, Caron MG, Wetsel WC (2005) Novelty seeking and stereotypic activation of behavior in mice with disruption of the Dat1 gene. Neuropsychopharmacology 30:1818–1831PubMedGoogle Scholar
- Radyushkin K, Hammerschmidt K, Boretius S, Varoqueaux F, El-Kordi A, Ronnenberg A, Winter D, Frahm J, Fischer J, Brose N, Ehrenreich H (2009) Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav 8:416–425PubMedGoogle Scholar
- Ralph RJ, Paulus MP, Fumagalli F, Caron MG, Geyer MA (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21:305–313PubMedGoogle Scholar
- Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC (2005) Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 47:551–555PubMedGoogle Scholar
- Restrepo D, Doucette W, Whitesell JD, McTavish TS, Salcedo E (2009) From the top down: flexible reading of a fragmented odor map. Trends Neurosci 32:525–531PubMedGoogle Scholar
- Richter K, Wolf G, Engelmann M (2005) Social recognition memory requires two stages of protein synthesis in mice. Learn Mem 12(4):407–413PubMedGoogle Scholar
- Rinaldi T, Kulangara K, Antoniello K, Markram H (2007) Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci USA 104:13501–13506PubMedGoogle Scholar
- Rinaldi T, Silberberg G, Markram H (2008) Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex 18:763–770PubMedGoogle Scholar
- Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370:247–261PubMedGoogle Scholar
- Roullet FI, Wöhr M, Crawley JN (2011) Female urine-induced male mice ultrasonic vocalizations, but not scent-marking, is modulated by social experience. Behav Brain Res 216(1):19–28Google Scholar
- Ryan BC, Young NB, Moy SS, Crawley JN (2008) Olfactory cues are sufficient to elicit social approach behaviors but not social transmission of food preference in C57BL/6J mice. Behav Brain Res 193:235–242PubMedGoogle Scholar
- Sanchez-Andrade G, James BM, Kendrick KM (2005) Neural encoding of olfactory recognition memory. J Reprod Dev 51:547–558PubMedGoogle Scholar
- Scattoni ML, Gandhy SU, Ricceri L, Crawley JN (2008a) Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS One 3:e3067PubMedGoogle Scholar
- Scattoni ML, McFarlane HG, Zhodzishsky V, Caldwell HK, Young WS, Ricceri L, Crawley JN (2008b) Reduced ultrasonic vocalizations in vasopressin 1b knockout mice. Behav Brain Res 187:371–378PubMedGoogle Scholar
- Scattoni ML, Crawley J, Ricceri L (2009) Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci Biobehav Rev 33:508–515PubMedGoogle Scholar
- Schellinck HM, Smyth C, Brown R, Wilkinson M (1993) Odor-induced sexual maturation and expression of c-fos in the olfactory system of juvenile female mice. Brain Res Dev Brain Res 74:138–141PubMedGoogle Scholar
- Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30:80–89PubMedGoogle Scholar
- Schneider T, Turczak J, Przewlocki R (2006) Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology 31:36–46PubMedGoogle Scholar
- Schneider T, Roman A, Basta-Kaim A, Kubera M, Budziszewska B, Schneider K, Przewlocki R (2008) Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology 33:728–740PubMedGoogle Scholar
- Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449PubMedGoogle Scholar
- Sheinkopf SJ, Mundy P, Oller DK, Steffens M (2000) Vocal atypicalities of preverbal autistic children. J Autism Dev Disord 30:345–354PubMedGoogle Scholar
- Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD (2005) Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci USA 102:9643–9648PubMedGoogle Scholar
- Silverman JL, Tolu SS, Barkan CL, CrawleyJN (2010) Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35(4):976–989Google Scholar
- Snow WM, Hartle K, Ivanco TL (2008) Altered morphology of motor cortex neurons in the VPA rat model of autism. Dev Psychobiol 50:633–639PubMedGoogle Scholar
- South M, Ozonoff S, McMahon WM (2005) Repetitive behavior profiles in Asperger syndrome and high-functioning autism. J Autism Dev Disord 35:145–158PubMedGoogle Scholar
- Spencer CM, Alekseyenko O, Serysheva E, Yuva-Paylor LA, Paylor R (2005) Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Genes Brain Behav 4:420–430PubMedGoogle Scholar
- Spencer CM, Graham DF, Yuva-Paylor LA, Nelson DL, Paylor R (2008) Social behavior in Fmr1 knockout mice carrying a human FMR1 transgene. Behav Neurosci 122:710–715PubMedGoogle Scholar
- Spezio ML, Adolphs R, Hurley RS, Piven J (2007) Abnormal use of facial information in high-functioning autism. J Autism Dev Disord 37:929–939PubMedGoogle Scholar
- Stack CM, Lim MA, Cuasay K, Stone MM, Seibert KM, Spivak-Pohis I, Crawley JN, Waschek JA, Hill JM (2008) Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice. Exp Neurol 211:67–84PubMedGoogle Scholar
- Stanton ME, Peloso E, Brown KL, Rodier P (2007) Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism. Behav Brain Res 176:133–140PubMedGoogle Scholar
- Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455:903–911PubMedGoogle Scholar
- Tager-Flusberg H, Caronna E (2007) Language disorders: autism and other pervasive developmental disorders. Pediatr Clin North Am 54:469–481, viPubMedGoogle Scholar
- Terranova ML, Laviola G (2005) Scoring of social interactions and play in mice during adolescence. Curr Protocols Toxicol 13:10.1–10.10Google Scholar
- Tsujino N, Nakatani Y, Seki Y, Nakasato A, Nakamura M, Sugawara M, Arita H (2007) Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res 57:289–295PubMedGoogle Scholar
- Turner CA, Presti MF, Newman HA, Bugenhagen P, Crnic L, Lewis MH (2001) Spontaneous stereotypy in an animal model of Down syndrome: Ts65Dn mice. Behav Genet 31:393–400PubMedGoogle Scholar
- Varga EA, Pastore M, Prior T, Herman GE, McBride KL (2009) The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med 11:111–117PubMedGoogle Scholar
- Volkmar FR, Pauls D (2003) Autism. Lancet 362:1133–1141PubMedGoogle Scholar
- Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK (2006) A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J Autism Dev Disord 36(6):779–793PubMedGoogle Scholar
- Wanisch K, Wotjak CT, Engelmann M (2008) Long-lasting second stage of recognition memory consolidation in mice. Behav Brain Res 186(2):191–196PubMedGoogle Scholar
- Wang H, Liang S, Burgdorf J, Wess J, Yeomans J (2008) Ultrasonic vocalizations induced by sex and amphetamine in M2, M4, M5 muscarinic and D2 dopamine receptor knockout mice. PLoS One 3:e1893PubMedGoogle Scholar
- Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, Feliciano C, Chen M, Adams JP, Luo J, Dudek SM, Weinberg RJ, Calakos N, Wetsel WC, Feng G (2007) Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448:894–900PubMedGoogle Scholar
- Wersinger SR, Ginns EI, O’Carroll AM, Lolait SJ, Young WS 3rd (2002) Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry 7:975–984PubMedGoogle Scholar
- Wersinger SR, Caldwell HK, Martinez L, Gold P, Hu SB, Young WS 3rd (2007) Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression. Genes Brain Behav 6:540–551PubMedGoogle Scholar
- White NR, Prasad M, Barfield RJ, Nyby JG (1998) 40- and 70-kHz vocalizations of mice (Mus musculus) during copulation. Physiol Behav 63:467–473PubMedGoogle Scholar
- Wide K, Winbladh B, Kallen B (2004) Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 93:174–176PubMedGoogle Scholar
- Williams PG, Hersh JH (1997) A male with fetal valproate syndrome and autism. Dev Med Child Neurol 39:632–634PubMedGoogle Scholar
- Williams DL, Minshew NJ (2007) Understanding autism and related disorders: what has imaging taught us? Neuroimaging Clin N Am 17:495–509, ixPubMedGoogle Scholar
- Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH (2001) Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 43:202–206PubMedGoogle Scholar
- Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, van de Water J (2009) Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun 23:64–74Google Scholar
- Winslow JT (2003) Mouse social recognition and preference. Curr Protoc Neurosci Chapter 8, Unit 8.16Google Scholar
- Winslow JT, Insel TR (2002) The social deficits of the oxytocin knockout mouse. Neuropeptides 36:221–229PubMedGoogle Scholar
- Wöhr M, Roullet FI, Crawley JN (2010) Reduced scent marking and ultrasonic vocalizations in the BTBR T+tf/J mouse model of autism. Genes Brain Behav. doi: 10.1111/j.1601-183X.2010.00582.xGoogle Scholar
- Yang M, Crawley JN (2009) Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci Chapter 8, Unit 8.24Google Scholar
- Yang M, Scattoni ML, Zhodzishsky V, Chen T, Caldwell HK, Young WS, McFarlane HG, Crawley JN (2007a) Similar social approach behaviors in BTBR T+tf/J, C57BL/6J, and vasopressine receptor 1B knockout mice tested on conventional versus reverse light cycles, and in replications across cohorts. Front Behav Neurosci 1:9Google Scholar
- Yang M, Zhodzishsky V, Crawley JN (2007b) Social deficits in BTBR T+tf/J mice are unchanged by cross-fostering with C57BL/6J mothers. Int J Dev Neurosci 25:515–521PubMedGoogle Scholar
- Yang M, Clarke AM, Crawley JN (2009) Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability. Eur J Neurosci 29:1663–1677PubMedGoogle Scholar
- Young LJ, Pitkow LJ, Ferguson JN (2002) Neuropeptides and social behavior: animal models relevant to autism. Mol Psychiatry 7(suppl 2):S38–S39PubMedGoogle Scholar
- Zecavati N, Spence SJ (2009) Neurometabolic disorders and dysfunction in autism spectrum disorders. Curr Neurol Neurosci Rep 9:129–136PubMedGoogle Scholar
- Zhou J, Blundell J, Ogawa S, Kwon CH, Zhang W, Sinton C, Powell CM, Parada LF (2009) Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci 29:1773–1783PubMedGoogle Scholar
- Zippelius HM, Schleidt WM (1956) Ultraschall-aute bei jungen Mausen. Naturwissenschaften 43:502–503Google Scholar
- Zwaigenbaum L, Bryson S, Rogers T, Roberts W, Brian J, Szatmari P (2005) Behavioral manifestations of autism in the first year of life. Int J Dev Neurosci 23:143–152PubMedGoogle Scholar