Abstract
Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Folstein SE, Rosen-Sheidley B . Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943–955.
Lord C, Risi S, Lambrecht L, Cook Jr EH, Leventhal BL, DiLavore PC et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000; 30: 205–223.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). American Psychiatric Association: Washington, DC, 2000.
Fombonne E . Epidemiological trends in rates of autism. Mol Psychiatry 2002; 7(Suppl 2): S4–S6.
Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007; 28: 235–258.
Tuchman R, Rapin I . Epilepsy in autism. Lancet Neurol 2002; 1: 352–358.
Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG et al. Autism and environmental genomics. Neurotoxicology 2006; 27: 671–684.
Newschaffer CJ, Fallin D, Lee NL . Heritable and nonheritable risk factors for autism spectrum disorders. Epidemiol Rev 2002; 24: 137–153.
Persico AM, Bourgeron T . Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006; 29: 349–358.
Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65: 493–507.
Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P . The search for autism disease genes. Ment Retard Dev Disabil Res Rev 2004; 10: 272–283.
Insel TR . Mouse models for autism: report from a meeting. Mamm Genome 2001; 12: 755–757.
Lewis MH, Tanimura Y, Lee LW, Bodfish JW . Animal models of restricted repetitive behavior in autism. Behav Brain Res 2007; 176: 66–74.
Moy SS, Nadler JJ, Magnuson TR, Crawley JN . Mouse models of autism spectrum disorders: the challenge for behavioral genetics. Am J Med Genet C Semin Med Genet 2006; 142: 40–51.
Murcia CL, Gulden F, Herrup K . A question of balance: a proposal for new mouse models of autism. Int J Dev Neurosci 2005; 23: 265–275.
Rodier PM, Ingram JL, Tisdale B, Croog VJ . Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 1997; 11: 417–422.
Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 2007; 176: 4–20.
Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 2004; 3: 287–302.
Nadler JJ, Moy SS, Dold G, Trang D, Simmons N, Perez A et al. Automated apparatus for rapid quantitation of autism-like social deficits in mice. Genes Brain Behav 2004; 3: 303–314.
Brodkin ES, Hagemann A, Nemetski SM, Silver LM . Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice. Brain Res 2004; 1002: 151–157.
Sankoorikal GM, Kaercher KA, Boon CJ, Lee JK, Brodkin ES . A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains. Biol Psychiatry 2006; 59: 415–423.
Bolivar VJ, Walters SR, Phoenix JL . Assessing autism-like behavior in mice: variations in social interactions among inbred strains. Behav Brain Res 2007; 176: 21–26.
Bodfish JW, Symons FJ, Parker DE, Lewis MH . Varieties of repetitive behavior in autism: comparisons to mental retardation. J Autism Dev Disord 2000; 30: 237–243.
Turner M . Annotation: repetitive behaviour in autism: a review of psychological research. J Child Psychol Psychiatry 1999; 40: 839–849.
Carcani-Rathwell I, Rabe-Hasketh S, Santosh PJ . Repetitive and stereotyped behaviours in pervasive developmental disorders. J Child Psychol Psychiatry 2006; 47: 573–581.
Mooney EL, Gray KM, Tonge BJ . Early features of autism: repetitive behaviours in young children. Eur Child Adolesc Psychiatry 2006; 15: 12–18.
South M, Ozonoff S, McMahon WM . Repetitive behavior profiles in Asperger syndrome and high-functioning autism. J Autism Dev Disord 2005; 35: 145–158.
Ronald A, Happe F, Bolton P, Butcher LM, Price TS, Wheelwright S et al. Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry 2006; 45: 691–699.
Ronald A, Happe F, Plomin R . The genetic relationship between individual differences in social and nonsocial behaviours characteristic of autism. Dev Sci 2005; 8: 444–458.
Coldren JT, Halloran C . Spatial reversal as a measure of executive functioning in children with autism. J Genet Psychol 2003; 164: 29–41.
Branchi I, Ricceri L . Transgenic and knock-out mouse pups: the growing need for behavioral analysis. Genes Brain Behav 2002; 1: 135–141.
Branchi I, Bichler Z, Berger-Sweeney J, Ricceri L . Animal models of mental retardation: from gene to cognitive function. Neurosci Biobehav Rev 2003; 27: 141–153.
Ricceri L, Moles A, Crawley J . Behavioral phenotyping of mouse models of neurodevelopmental disorders: relevant social behavior patterns across the life span. Behav Brain Res 2007; 176: 40–52.
Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, Kamdar S et al. En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res 2006; 1116: 166–176.
Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK . A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J Autism Dev Disord 2006; 36: 779–793.
Picker JD, Yang R, Ricceri L, Berger-Sweeney J . An altered neonatal behavioral phenotype in Mecp2 mutant mice. NeuroReport 2006; 17: 541–544.
Moles A, Kieffer BL, D’Amato FR . Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science 2004; 304: 1983–1986.
Ognibene E, Adriani W, Macri S, Laviola G . Neurobehavioural disorders in the infant reeler mouse model: interaction of genetic vulnerability and consequences of maternal separation. Behav Brain Res 2007; 177: 142–149.
Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA et al. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci USA 2005; 102: 9643–9648.
Long JM, LaPorte P, Paylor R, Wynshaw-Boris A . Expanded characterization of the social interaction abnormalities in mice lacking Dvl1. Genes Brain Behav 2004; 3: 51–62.
Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci USA 2005; 102: 16096–16101.
El-Khodor BF, Dimmler MH, Amara DA, Hofer M, Hen R, Brunner D . Juvenile 5HT(1B) receptor knockout mice exhibit reduced pharmacological sensitivity to 5HT(1A) receptor activation. Int J Dev Neurosci 2004; 22: 405–413.
Weller A, Leguisamo AC, Towns L, Ramboz S, Bagiella E, Hofer M et al. Maternal effects in infant and adult phenotypes of 5HT1A and 5HT1B receptor knockout mice. Dev Psychobiol 2003; 42: 194–205.
Brunner D, Buhot MC, Hen R, Hofer M . Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav Neurosci 1999; 113: 587–601.
Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE et al. Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA 1996; 93: 13333–13338.
Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR . Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 2000; 37: 145–155.
Hahn ME, Lavooy MJ . A review of the methods of studies on infant ultrasound production and maternal retrieval in small rodents. Behav Genet 2005; 35: 31–52.
Hagerman RJ, Jackson III AW, Levitas A, Rimland B, Braden M . An analysis of autism in fifty males with the fragile X syndrome. Am J Med Genet 1986; 23: 359–374.
Chen L, Toth M . Fragile X mice develop sensory hyperreactivity to auditory stimuli. Neuroscience 2001; 103: 1043–1050.
Musumeci SA, Bosco P, Calabrese G, Bakker C, De Sarro GB, Elia M et al. Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome. Epilepsia 2000; 41: 19–23.
Yan QJ, Asafo-Adjei PK, Arnold HM, Brown RE, Bauchwitz RP . A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouse. Genes Brain Behav 2004; 3: 337–359.
Bakker CE, Verheij C, Willemsen R, van der Helm R, Oerlemans F, Vermey M et al. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 1994; 78: 23–33.
Kooy RF, D’Hooge R, Reyniers E, Bakker CE, Nagels G, De Boulle K et al. Transgenic mouse model for the fragile X syndrome. Am J Med Genet 1996; 64: 241–245.
Willems PJ, Reyniers E, Oostra BA . An animal model for fragile X syndrome. Ment Retard Dev Disabil Res Rev 1995; 1: 298–302.
Spencer CM, Alekseyenko O, Serysheva E, Yuva-Paylor LA, Paylor R . Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Genes Brain Behav 2005; 4: 420–430.
Mineur YS, Huynh LX, Crusio WE . Social behavior deficits in the Fmr1 mutant mouse. Behav Brain Res 2006; 168: 172–175.
Mineur YS, Sluyter F, de Wit S, Oostra BA, Crusio WE . Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse. Hippocampus 2002; 12: 39–46.
Peier AM, McIlwain KL, Kenneson A, Warren ST, Paylor R, Nelson DL . Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features. Hum Mol Genet 2000; 9: 1145–1159.
Restivo L, Ferrari F, Passino E, Sgobio C, Bock J, Oostra BA et al. Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc Natl Acad Sci USA 2005; 102: 11557–11562.
Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY et al. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci USA 2007; 104: 11489–11494.
Paradee W, Melikian HE, Rasmussen DL, Kenneson A, Conn PJ, Warren ST . Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function. Neuroscience 1999; 94: 185–192.
Van Dam D, D’Hooge R, Hauben E, Reyniers E, Gantois I, Bakker CE et al. Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice. Behav Brain Res 2000; 117: 127–136.
Nielsen DM, Derber WJ, McClellan DA, Crnic LS . Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome. Brain Res 2002; 927: 8–17.
Spencer CM, Serysheva E, Yuva-Paylor LA, Oostra BA, Nelson DL, Paylor R . Exaggerated behavioral phenotypes in Fmr1/Fxr2 double knockout mice reveal a functional genetic interaction between fragile X-related proteins. Hum Mol Genet 2006; 15: 1984–1994.
Dobkin C, Rabe A, Dumas R, El Idrissi A, Haubenstock H, Brown WT . Fmr1 knockout mouse has a distinctive strain-specific learning impairment. Neuroscience 2000; 100: 423–429.
Frankland PW, Wang Y, Rosner B, Shimizu T, Balleine BW, Dykens EM et al. Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice. Mol Psychiatry 2004; 9: 417–425.
Perry W, Minassian A, Lopez B, Maron L, Lincoln A . Sensorimotor gating deficits in adults with autism. Biol Psychiatry 2007; 61: 482–486.
McAlonan GM, Daly E, Kumari V, Critchley HD, van Amelsvoort T, Suckling J et al. Brain anatomy and sensorimotor gating in Asperger's syndrome. Brain 2002; 125: 1594–1606.
Fisch GS, Hao HK, Bakker C, Oostra BA . Learning and memory in the FMR1 knockout mouse. Am J Med Genet 1999; 84: 277–282.
Gould TD, Gottesman II . Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav 2006; 5: 113–119.
Glaze DG . Rett syndrome: of girls and mice—lessons for regression in autism. Ment Retard Dev Disabil Res Rev 2004; 10: 154–158.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY . Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23: 185–188.
Shahbazian MD, Zoghbi HY . Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr Opin Neurol 2001; 14: 171–176.
Moretti P, Zoghbi HY . MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006; 16: 276–281.
Chen RZ, Akbarian S, Tudor M, Jaenisch R . Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 2001; 27: 327–331.
Guy J, Hendrich B, Holmes M, Martin JE, Bird A . A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 2001; 27: 322–326.
Santos M, Silva-Fernandes A, Oliveira P, Sousa N, Maciel P . Evidence for abnormal early development in a mouse model of Rett syndrome. Genes Brain Behav 2007; 6: 277–286.
Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 2002; 35: 243–254.
Moretti P, Bouwknecht JA, Teague R, Paylor R, Zoghbi HY . Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 2005; 14: 205–220.
Gemelli T, Berton O, Nelson ED, Perrotti LI, Jaenisch R, Monteggia LM . Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol Psychiatry 2006; 59: 468–476.
Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, Antalffy B et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci 2006; 26: 319–327.
McGill BE, Bundle SF, Yaylaoglu MB, Carson JP, Thaller C, Zoghbi HY . Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc Natl Acad Sci USA 2006; 103: 18267–18272.
Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, Steinhoff C et al. Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet 2005; 14: 2247–2256.
Dykens EM, Sutcliffe JS, Levitt P . Autism and 15q11–q13 disorders: behavioral, genetic, and pathophysiological issues. Ment Retard Dev Disabil Res Rev 2004; 10: 284–291.
Veltman MW, Craig EE, Bolton PF . Autism spectrum disorders in Prader–Willi and Angelman syndromes: a systematic review. Psychiatr Genet 2005; 15: 243–254.
Williams CA . Neurological aspects of the Angelman syndrome. Brain Dev 2005; 27: 88–94.
Samaco RC, Hogart A, LaSalle JM . Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 2005; 14: 483–492.
van Woerden GM, Harris KD, Hojjati MR, Gustin RM, Qiu S, de Avila Freire R et al. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation. Nat Neurosci 2007; 10: 280–282.
Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 1998; 21: 799–811.
Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes GL et al. Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol Dis 2002; 9: 149–159.
Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL et al. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci USA 1997; 94: 4143–4148.
DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A et al. Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 1998; 18: 8505–8514.
Greaves N, Prince E, Evans DW, Charman T . Repetitive and ritualistic behaviour in children with Prader–Willi syndrome and children with autism. J Intellect Disabil Res 2006; 50: 92–100.
Ding F, Prints Y, Dhar MS, Johnson DK, Garnacho-Montero C, Nicholls RD et al. Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader–Willi syndrome mouse models. Mamm Genome 2005; 16: 424–431.
Yang T, Adamson TE, Resnick JL, Leff S, Wevrick R, Francke U et al. A mouse model for Prader–Willi syndrome imprinting-centre mutations. Nat Genet 1998; 19: 25–31.
Gerard M, Hernandez L, Wevrick R, Stewart CL . Disruption of the mouse necdin gene results in early post-natal lethality. Nat Genet 1999; 23: 199–202.
Muscatelli F, Abrous DN, Massacrier A, Boccaccio I, Le Moal M, Cau P et al. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader–Willi syndrome. Hum Mol Genet 2000; 9: 3101–3110.
Bartak L, Rutter M . Differences between mentally retarded and normally intelligent autistic children. J Autism Child Schizophr 1976; 6: 109–120.
Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C et al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998; 43: 270–277.
de Jonge MV, Kemner C, van Engeland H . Superior disembedding performance of high-functioning individuals with autism spectrum disorders and their parents: the need for subtle measures. J Autism Dev Disord 2006; 36: 677–683.
Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci USA 1997; 94: 5401–5404.
McKinney BC, Grossman AW, Elisseou NM, Greenough WT . Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am J Med Genet B Neuropsychiatr Genet 2005; 136: 98–102.
Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E . Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 2006; 51: 441–454.
Huber KM, Gallagher SM, Warren ST, Bear MF . Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 2002; 99: 7746–7750.
Nosyreva ED, Huber KM . Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J Neurophysiol 2006; 95: 3291–3295.
Li J, Pelletier MR, Perez Velazquez JL, Carlen PL . Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol Cell Neurosci 2002; 19: 138–151.
Wilson BM, Cox CL . Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice. Proc Natl Acad Sci USA 2007; 104: 2454–2459.
Bagni C, Greenough WT . From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci 2005; 6: 376–387.
Zalfa F, Achsel T, Bagni C . mRNPs, polysomes or granules: FMRP in neuronal protein synthesis. Curr Opin Neurobiol 2006; 16: 265–269.
Garber K, Smith KT, Reines D, Warren ST . Transcription, translation and fragile X syndrome. Curr Opin Genet Dev 2006; 16: 270–275.
Grossman AW, Aldridge GM, Weiler IJ, Greenough WT . Local protein synthesis and spine morphogenesis: fragile X syndrome and beyond. J Neurosci 2006; 26: 7151–7155.
Bear MF . Therapeutic implications of the mGluR theory of fragile X mental retardation. Genes Brain Behav 2005; 4: 393–398.
Bear MF, Huber KM, Warren ST . The mGluR theory of fragile X mental retardation. Trends Neurosci 2004; 27: 370–377.
Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM . Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 2006; 21: 217–227.
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393: 386–389.
Weeber EJ, Jiang YH, Elgersma Y, Varga AW, Carrasquillo Y, Brown SE et al. Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci 2003; 23: 2634–2644.
Cline H . Synaptogenesis: a balancing act between excitation and inhibition. Curr Biol 2005; 15: R203–R205.
Hussman JP . Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J Autism Dev Disord 2001; 31: 247–248.
Rubenstein JL, Merzenich MM . Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003; 2: 255–267.
D’Hulst C, De Geest N, Reeve SP, Van Dam D, De Deyn PP, Hassan BA et al. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res 2006; 1121: 238–245.
Gantois I, Vandesompele J, Speleman F, Reyniers E, D’Hooge R, Severijnen LA et al. Expression profiling suggests underexpression of the GABA(A) receptor subunit delta in the fragile X knockout mouse model. Neurobiol Dis 2006; 21: 346–357.
El Idrissi A, Ding XH, Scalia J, Trenkner E, Brown WT, Dobkin C . Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse. Neurosci Lett 2005; 377: 141–146.
Selby L, Zhang C, Sun QQ . Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci Lett 2007; 412: 227–232.
Kuwajima T, Nishimura I, Yoshikawa K . Necdin promotes GABAergic neuron differentiation in cooperation with Dlx homeodomain proteins. J Neurosci 2006; 26: 5383–5392.
Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R, Nelson SB . Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci USA 2005; 102: 12560–12565.
Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, Nicoll RA . Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc Natl Acad Sci USA 1995; 92: 11175–11179.
Waxham MN, Malenka RC, Kelly PT, Mauk MD . Calcium/calmodulin-dependent protein kinase II regulates hippocampal synaptic transmission. Brain Res 1993; 609: 1–8.
Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA et al. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 1989; 340: 554–557.
Kawaguchi SY, Hirano T . Signaling cascade regulating long-term potentiation of GABA(A) receptor responsiveness in cerebellar Purkinje neurons. J Neurosci 2002; 22: 3969–3976.
Silva AJ, Stevens CF, Tonegawa S, Wang Y . Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 1992; 257: 201–206.
Hansel C, de Jeu M, Belmeguenai A, Houtman SH, Buitendijk GH, Andreev D et al. alphaCaMKII Is essential for cerebellar LTD and motor learning. Neuron 2006; 51: 835–843.
Sanhueza M, McIntyre CC, Lisman JE . Reversal of synaptic memory by Ca2+/calmodulin-dependent protein kinase II inhibitor. J Neurosci 2007; 27: 5190–5199.
Muddashetty RS, Kelic S, Gross C, Xu M, Bassell GJ . Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J Neurosci 2007; 27: 5338–5348.
Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006; 52: 255–269.
Belmonte MK, Bourgeron T . Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci 2006; 9: 1221–1225.
Jiang YH, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD et al. A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am J Med Genet A 2004; 131: 1–10.
Freitag CM . The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 2007; 12: 2–22.
Polleux F, Lauder JM . Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev 2004; 10: 303–317.
Dean C, Dresbach T . Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function. Trends Neurosci 2006; 29: 21–29.
Lise MF, El-Husseini A . The neuroligin and neurexin families: from structure to function at the synapse. Cell Mol Life Sci 2006; 63: 1833–1849.
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003; 34: 27–29.
Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328.
Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M, Gottmann K et al. Neuroligins determine synapse maturation and function. Neuron 2006; 51: 741–754.
Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer RE, Gottmann K et al. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 2003; 423: 939–948.
Beglopoulos V, Montag-Sallaz M, Rohlmann A, Piechotta K, Ahmad M, Montag D et al. Neurexophilin 3 is highly localized in cortical and cerebellar regions and is functionally important for sensorimotor gating and motor coordination. Mol Cell Biol 2005; 25: 7278–7288.
Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 2001; 6: 150–159.
Serajee FJ, Zhong H, Mahbubul Huq AH . Association of Reelin gene polymorphisms with autism. Genomics 2006; 87: 75–83.
Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 2005; 10: 563–571.
Zhang H, Liu X, Zhang C, Mundo E, Macciardi F, Grayson DR et al. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry 2002; 7: 1012–1017.
Devlin B, Bennett P, Dawson G, Figlewicz DA, Grigorenko EL, McMahon W et al. Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Am J Med Genet B Neuropsychiatr Genet 2004; 126: 46–50.
Li J, Nguyen L, Gleason C, Lotspeich L, Spiker D, Risch N et al. Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. Am J Med Genet B Neuropsychiatr Genet 2004; 126: 51–57.
Bonora E, Beyer KS, Lamb JA, Parr JR, Klauck SM, Benner A et al. Analysis of reelin as a candidate gene for autism. Mol Psychiatry 2003; 8: 885–892.
Fatemi SH . Reelin glycoprotein in autism and schizophrenia. Int Rev Neurobiol 2005; 71: 179–187.
Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Reutiman TJ, Lee S et al. Reelin signaling is impaired in autism. Biol Psychiatry 2005; 57: 777–787.
Fatemi SH . Reelin glycoprotein: structure, biology and roles in health and disease. Mol Psychiatry 2005; 10: 251–257.
Pappas GD, Kriho V, Pesold C . Reelin in the extracellular matrix and dendritic spines of the cortex and hippocampus: a comparison between wild type and heterozygous reeler mice by immunoelectron microscopy. J Neurocytol 2001; 30: 413–425.
Salinger WL, Ladrow P, Wheeler C . Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation. Behav Neurosci 2003; 117: 1257–1275.
Badea A, Nicholls PJ, Johnson GA, Wetsel WC . Neuroanatomical phenotypes in the reeler mouse. Neuroimage 2007; 34: 1363–1374.
Marrone MC, Marinelli S, Biamonte F, Keller F, Sgobio CA, Ammassari-Teule M et al. Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. Eur J Neurosci 2006; 24: 2061–2070.
Lalonde R, Hayzoun K, Derer M, Mariani J, Strazielle C . Neurobehavioral evaluation of Reln-rl-orl mutant mice and correlations with cytochrome oxidase activity. Neurosci Res 2004; 49: 297–305.
Qiu S, Weeber EJ . Reelin signaling facilitates maturation of CA1 glutamatergic synapses. J Neurophysiol 2007; 97: 2312–2321.
Beffert U, Durudas A, Weeber EJ, Stolt PC, Giehl KM, Sweatt JD et al. Functional dissection of Reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J Neurosci 2006; 26: 2041–2052.
Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem 2002; 277: 39944–39952.
Brigman JL, Padukiewicz KE, Sutherland ML, Rothblat LA . Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav Neurosci 2006; 120: 984–988.
Tueting P, Costa E, Dwivedi Y, Guidotti A, Impagnatiello F, Manev R et al. The phenotypic characteristics of heterozygous reeler mouse. NeuroReport 1999; 10: 1329–1334.
Larson J, Hoffman JS, Guidotti A, Costa E . Olfactory discrimination learning deficit in heterozygous reeler mice. Brain Res 2003; 971: 40–46.
Qiu S, Korwek KM, Pratt-Davis AR, Peters M, Bergman MY, Weeber EJ . Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. Neurobiol Learn Mem 2006; 85: 228–242.
Krueger DD, Howell JL, Hebert BF, Olausson P, Taylor JR, Nairn AC . Assessment of cognitive function in the heterozygous reeler mouse. Psychopharmacology (Berl) 2006; 189: 95–104.
Podhorna J, Didriksen M . The heterozygous reeler mouse: behavioural phenotype. Behav Brain Res 2004; 153: 43–54.
Liu WS, Pesold C, Rodriguez MA, Carboni G, Auta J, Lacor P et al. Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc Natl Acad Sci USA 2001; 98: 3477–3482.
Liu W, Pappas GD, Carter CS . Oxytocin receptors in brain cortical regions are reduced in haploinsufficient (+/−) reeler mice. Neurol Res 2005; 27: 339–345.
Carter CS . Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 2007; 176: 170–186.
Hranilovic D, Bujas-Petkovic Z, Vragovic R, Vuk T, Hock K, Jernej B . Hyperserotonemia in adults with autistic disorder. J Autism Dev Disord 2006 (e-pub ahead of print, doi:10.1007/S1080300603246).
Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E . Central serotonin2C receptor: from physiology to pathology. Curr Top Med Chem 2006; 6: 1909–1925.
Bockaert J, Claeysen S, Becamel C, Dumuis A, Marin P . Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 2006; 326: 553–572.
Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry 2005; 62: 1366–1376.
Boylan CB, Blue ME, Hohmann CF . Modeling early cortical serotonergic deficits in autism. Behav Brain Res 2007; 176: 94–108.
Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 2002; 416: 396–400.
Gaspar P, Cases O, Maroteaux L . The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003; 4: 1002–1012.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.
Hillion J, Catelon J, Raid M, Hamon M, De Vitry F . Neuronal localization of 5-HT1A receptor mRNA and protein in rat embryonic brain stem cultures. Brain Res Dev Brain Res 1994; 79: 195–202.
Yan W, Wilson CC, Haring JH . 5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells. Brain Res Dev Brain Res 1997; 98: 185–190.
Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 1995; 268: 1763–1766.
Cases O, Vitalis T, Seif I, De Maeyer E, Sotelo C, Gaspar P . Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 1996; 16: 297–307.
Rebsam A, Seif I, Gaspar P . Refinement of thalamocortical arbors and emergence of barrel domains in the primary somatosensory cortex: a study of normal and monoamine oxidase a knock-out mice. J Neurosci 2002; 22: 8541–8552.
Persico AM, Mengual E, Moessner R, Hall FS, Revay RS, Sora I et al. Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J Neurosci 2001; 21: 6862–6873.
Persico AM, Baldi A, Dell’Acqua ML, Moessner R, Murphy DL, Lesch KP et al. Reduced programmed cell death in brains of serotonin transporter knockout mice. NeuroReport 2003; 14: 341–344.
Altamura C, Dell’acqua ML, Moessner R, Murphy DL, Lesch KP, Persico AM . Altered neocortical cell density and layer thickness in serotonin transporter knockout mice: a quantitation study. Cereb Cortex 2007; 17: 1394–1401.
Kalueff AV, Fox MA, Gallagher PS, Murphy DL . Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav 2007; 6: 389–400.
Zhao S, Edwards J, Carroll J, Wiedholz L, Millstein RA, Jaing C et al. Insertion mutation at the C-terminus of the serotonin transporter disrupts brain serotonin function and emotion-related behaviors in mice. Neuroscience 2006; 140: 321–334.
Holmes A, Lit Q, Murphy DL, Gold E, Crawley JN . Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2003; 2: 365–380.
Kaplan DR, Miller FD . Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 2000; 10: 381–391.
Amaral MD, Chapleau CA, Pozzo-Miller L . Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: potential implications for Rett syndrome. Pharmacol Ther 2007; 113: 394–409.
Luikart BW, Parada LF . Receptor tyrosine kinase B-mediated excitatory synaptogenesis. Prog Brain Res 2006; 157: 15–24.
Daws LC, Munn JL, Valdez MF, Frosto-Burke T, Hensler JG . Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in BDNF-deficient mice. J Neurochem 2007; 101: 641–651.
Chan JP, Unger TJ, Byrnes J, Rios M . Examination of behavioral deficits triggered by targeting Bdnf in fetal or postnatal brains of mice. Neuroscience 2006; 142: 49–58.
Guiard BP, David DJ, Deltheil T, Chenu F, Le Maitre E, Renoir T et al. Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype. Int J Neuropsychopharmacol 2007; 1–14 (e-pub ahead of print, doi:10.1017/S1461145707007857).
Hensler JG, Advani T, Monteggia LM . Regulation of serotonin-1A receptor function in inducible brain-derived neurotrophic factor knockout mice after administration of corticosterone. Biol Psychiatry 2007; 62: 521–529.
Rios M, Lambe EK, Liu R, Teillon S, Liu J, Akbarian S et al. Severe deficits in 5-HT2A -mediated neurotransmission in BDNF conditional mutant mice. J Neurobiol 2006; 66: 408–420.
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 1999; 96: 15239–15244.
Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003; 302: 890–893.
Wang H, Chan SA, Ogier M, Hellard D, Wang Q, Smith C et al. Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice. J Neurosci 2006; 26: 10911–10915.
Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 2001; 15: 1748–1757.
Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry 2007; 61: 187–197.
Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA 2004; 101: 10827–10832.
Hill JJ, Kolluri N, Hashimoto T, Wu Q, Sampson AR, Monteggia LM et al. Analysis of pyramidal neuron morphology in an inducible knockout of brain-derived neurotrophic factor. Biol Psychiatry 2005; 57: 932–934.
Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN et al. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 2005; 25: 372–383.
Murphy DL, Uhl GR, Holmes A, Ren-Patterson R, Hall FS, Sora I et al. Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes Brain Behav 2003; 2: 350–364.
Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang SJ, Tolliver T et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J Neurosci Res 2005; 79: 756–771.
Ren-Patterson RF, Cochran LW, Holmes A, Lesch KP, Lu B, Murphy DL . Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies. Cell Mol Neurobiol 2006; 26: 755–780.
Buxbaum JD, Cai G, Chaste P, Nygren G, Goldsmith J, Reichert J et al. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 484–491.
Curatolo P, Porfirio MC, Manzi B, Seri S . Autism in tuberous sclerosis. Eur J Paediatr Neurol 2004; 8: 327–332.
Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 2006; 50: 377–388.
Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP . Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19: 348–355.
Cully M, You H, Levine AJ, Mak TW . Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006; 6: 184–192.
Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS et al. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol 2005; 25: 1869–1878.
Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T et al. Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 2005; 132: 2943–2954.
Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL . Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 2005; 8: 1727–1734.
Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC . Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol 2007; 61: 139–152.
Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 2007; 27: 5546–5558.
Lenz G, Avruch J . Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. J Biol Chem 2005; 280: 38121–38124.
Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L et al. Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. Nat Med 2006; 12: 324–329.
Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG . An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005; 122: 261–273.
Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 2004; 24: 9760–9769.
De Sarno P, Li X, Jope RS . Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology 2002; 43: 1158–1164.
Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000; 37: 489–497.
Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 2005; 47: 551–555.
Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH . Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001; 43: 202–206.
Maestro S, Muratori F, Cavallaro MC, Pei F, Stern D, Golse B et al. Attentional skills during the first 6 months of age in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2002; 41: 1239–1245.
Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol 2001; 49: 597–606.
Nelson PG, Kuddo T, Song EY, Dambrosia JM, Kohler S, Satyanarayana G et al. Selected neurotrophins, neuropeptides, and cytokines: developmental trajectory and concentrations in neonatal blood of children with autism or Down syndrome. Int J Dev Neurosci 2006; 24: 73–80.
Arndt TL, Stodgell CJ, Rodier PM . The teratology of autism. Int J Dev Neurosci 2005; 23: 189–199.
Wilkerson DS, Volpe AG, Dean RS, Titus JB . Perinatal complications as predictors of infantile autism. Int J Neurosci 2002; 112: 1085–1098.
Beversdorf DQ, Manning SE, Hillier A, Anderson SL, Nordgren RE, Walters SE et al. Timing of prenatal stressors and autism. J Autism Dev Disord 2005; 35: 471–478.
Miles JH, Hillman RE . Value of a clinical morphology examination in autism. Am J Med Genet 2000; 91: 245–253.
Rodier PM, Bryson SE, Welch JP . Minor malformations and physical measurements in autism: data from Nova Scotia. Teratology 1997; 55: 319–325.
Miller MT, Stromland K, Ventura L, Johansson M, Bandim JM, Gillberg C . Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci 2005; 23: 201–219.
Miles JH, Takahashi TN, Bagby S, Sahota PK, Vaslow DF, Wang CH et al. Essential versus complex autism: definition of fundamental prognostic subtypes. Am J Med Genet A 2005; 135: 171–180.
Hrdlicka M, Dudova I, Beranova I, Lisy J, Belsan T, Neuwirth J et al. Subtypes of autism by cluster analysis based on structural MRI data. Eur Child Adolesc Psychiatry 2005; 14: 138–144.
Dean JC, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J . Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002; 39: 251–259.
Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C . Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 1994; 36: 351–356.
Bandim JM, Ventura LO, Miller MT, Almeida HC, Costa AE . Autism and Mobius sequence: an exploratory study of children in northeastern Brazil. Arq Neuropsiquiatr 2003; 61: 181–185.
Libbey JE, Sweeten TL, McMahon WM, Fujinami RS . Autistic disorder and viral infections. J Neurovirol 2005; 11: 1–10.
Hava G, Vered L, Yael M, Mordechai H, Mahoud H . Alterations in behavior in adult offspring mice following maternal inflammation during pregnancy. Dev Psychobiol 2006; 48: 162–168.
Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M . Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry 2006; 59: 546–554.
Shi L, Fatemi SH, Sidwell RW, Patterson PH . Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003; 23: 297–302.
Fatemi SH, Pearce DA, Brooks AI, Sidwell RW . Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. Synapse 2005; 57: 91–99.
Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I et al. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci 2006; 26: 4752–4762.
Liverman CS, Kaftan HA, Cui L, Hersperger SG, Taboada E, Klein RM et al. Altered expression of pro-inflammatory and developmental genes in the fetal brain in a mouse model of maternal infection. Neurosci Lett 2006; 399: 220–225.
Ingram JL, Peckham SM, Tisdale B, Rodier PM . Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 2000; 22: 319–324.
Rodier PM . Animal model of autism based on developmental data. Ment Retard Dev Disabil Res Rev 1996; 2: 249–256.
Miyazaki K, Narita N, Narita M . Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci 2005; 23: 287–297.
Schneider T, Przewlocki R . Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005; 30: 80–89.
Stodgell CJ, Ingram JL, O’Bara M, Tisdale BK, Nau H, Rodier PM . Induction of the homeotic gene Hoxa1 through valproic acid's teratogenic mechanism of action. Neurotoxicol Teratol 2006; 28: 617–624.
Barrow JR, Stadler HS, Capecchi MR . Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse. Development 2000; 127: 933–944.
Chisaka O, Musci TS, Capecchi MR . Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1. Nature 1992; 355: 516–520.
Gavalas A, Ruhrberg C, Livet J, Henderson CE, Krumlauf R . Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes. Development 2003; 130: 5663–5679.
Rossel M, Capecchi MR . Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 1999; 126: 5027–5040.
Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J . Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 1996; 370: 247–261.
Rodier PM . Converging evidence for brain stem injury in autism. Dev Psychopathol 2002; 14: 537–557.
Conciatori M, Stodgell CJ, Hyman SL, O’Bara M, Militerni R, Bravaccio C et al. Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism. Biol Psychiatry 2004; 55: 413–419.
Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM . Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 2000; 62: 393–405.
Devlin B, Bennett P, Cook Jr EH, Dawson G, Gonen D, Grigorenko EL et al. No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network. Am J Med Genet 2002; 114: 667–672.
Gallagher L, Hawi Z, Kearney G, Fitzgerald M, Gill M . No association between allelic variants of HOXA1/HOXB1 and autism. Am J Med Genet B Neuropsychiatr Genet 2004; 124: 64–67.
Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 2005; 37: 1035–1037.
Martinez-Ceballos E, Chambon P, Gudas LJ . Differences in gene expression between wild type and Hoxa1 knockout embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal. J Biol Chem 2005; 280: 16484–16498.
Eikel D, Lampen A, Nau H . Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem Res Toxicol 2006; 19: 272–278.
Wiltse J . Mode of action: inhibition of histone deacetylase, altering WNT-dependent gene expression, and regulation of beta-catenin—developmental effects of valproic acid. Crit Rev Toxicol 2005; 35: 727–738.
Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J et al. Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001; 105: 406–413.
Mak BC, Kenerson HL, Aicher LD, Barnes EA, Yeung RS . Aberrant beta-catenin signaling in tuberous sclerosis. Am J Pathol 2005; 167: 107–116.
Jozwiak J, Wlodarski P . Hamartin and tuberin modulate gene transcription via beta-catenin. J Neurooncol 2006; 79: 229–234.
Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K et al. Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell 1997; 90: 895–905.
Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC . Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci 2005; 8: 34–42.
Ahmad-Annuar A, Ciani L, Simeonidis I, Herreros J, Fredj NB, Rosso SB et al. Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release. J Cell Biol 2006; 174: 127–139.
Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C . Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas. Health Place 2006; 12: 203–209.
Windham GC, Zhang L, Gunier R, Croen LA, Grether JK . Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco bay area. Environ Health Perspect 2006; 114: 1438–1444.
D’Amelio M, Ricci I, Sacco R, Liu X, D’Agruma L, Muscarella LA et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions. Mol Psychiatry 2005; 10: 1006–1016.
Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL et al. An autosomal genomic screen for autism. Collaborative linkage study of autism. Am J Med Genet 1999; 88: 609–615.
Blaess S, Corrales JD, Joyner AL . Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region. Development 2006; 133: 1799–1809.
Corrales JD, Blaess S, Mahoney EM, Joyner AL . The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 2006; 133: 1811–1821.
Fu JR, Liu WL, Zhou JF, Sun HY, Xu HZ, Luo L et al. Sonic hedgehog protein promotes bone marrow-derived endothelial progenitor cell proliferation, migration and VEGF production via PI 3-kinase/Akt signaling pathways. Acta Pharmacol Sin 2006; 27: 685–693.
Koide T, Hayata T, Cho KW . Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase. Development 2006; 133: 2395–2405.
Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 2003; 33: 508–513.
Digilio MC, Marino B, Giannotti A, Dallapiccola B, Opitz JM . Specific congenital heart defects in RSH/Smith–Lemli–Opitz syndrome: postulated involvement of the sonic hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia. Birth Defects Res A Clin Mol Teratol 2003; 67: 149–153.
Sikora DM, Pettit-Kekel K, Penfield J, Merkens LS, Steiner RD . The near universal presence of autism spectrum disorders in children with Smith–Lemli–Opitz syndrome. Am J Med Genet A 2006; 140: 1511–1518.
Tierney E, Nwokoro NA, Porter FD, Freund LS, Ghuman JK, Kelley RI . Behavior phenotype in the RSH/Smith–Lemli–Opitz syndrome. Am J Med Genet 2001; 98: 191–200.
Fitzky BU, Witsch-Baumgartner M, Erdel M, Lee JN, Paik YK, Glossmann H et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome. Proc Natl Acad Sci USA 1998; 95: 8181–8186.
Solca C, Pandit B, Yu H, Tint GS, Patel SB . Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith–Lemli–Opitz syndrome mouse. Mol Genet Metab 2007; 91: 7–14.
Fitzky BU, Moebius FF, Asaoka H, Waage-Baudet H, Xu L, Xu G et al. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith–Lemli–Opitz/RSH syndrome. J Clin Invest 2001; 108: 905–915.
Wassif CA, Zhu P, Kratz L, Krakowiak PA, Battaile KP, Weight FF et al. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome. Hum Mol Genet 2001; 10: 555–564.
Yu H, Wessels A, Tint GS, Patel SB . Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression. Brain Res Dev Brain Res 2005; 156: 46–60.
Waage-Baudet H, Lauder JM, Dehart DB, Kluckman K, Hiller S, Tint GS et al. Abnormal serotonergic development in a mouse model for the Smith–Lemli–Opitz syndrome: implications for autism. Int J Dev Neurosci 2003; 21: 451–459.
Correa-Cerro LS, Wassif CA, Kratz L, Miller GF, Munasinghe JP, Grinberg A et al. Development and characterization of a hypomorphic Smith–Lemli–Opitz syndrome mouse model and efficacy of simvastatin therapy. Hum Mol Genet 2006; 15: 839–851.
Tierney E, Bukelis I, Thompson RE, Ahmed K, Aneja A, Kratz L et al. Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 666–668.
Simon HH, Scholz C, O’Leary DD . Engrailed genes control developmental fate of serotonergic and noradrenergic neurons in mid- and hindbrain in a gene dose-dependent manner. Mol Cell Neurosci 2005; 28: 96–105.
Sgado P, Alberi L, Gherbassi D, Galasso SL, Ramakers GM, Alavian KN et al. Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice. Proc Natl Acad Sci USA 2006; 103: 15242–15247.
Alberi L, Sgado P, Simon HH . Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons. Development 2004; 131: 3229–3236.
Simon HH, Thuret S, Alberi L . Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors. Cell Tissue Res 2004; 318: 53–61.
Kuemerle B, Gulden F, Cherosky N, Williams E, Herrup K . The mouse Engrailed genes: a window into autism. Behav Brain Res 2007; 176: 121–132.
Gerlai R, Millen KJ, Herrup K, Fabien K, Joyner AL, Roder J . Impaired motor learning performance in cerebellar En-2 mutant mice. Behav Neurosci 1996; 110: 126–133.
Kuemerle B, Zanjani H, Joyner A, Herrup K . Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. J Neurosci 1997; 17: 7881–7889.
Joyner AL, Herrup K, Auerbach BA, Davis CA, Rossant J . Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science 1991; 251: 1239–1243.
Millen KJ, Wurst W, Herrup K, Joyner AL . Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants. Development 1994; 120: 695–706.
MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC et al. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 2005; 76: 1074–1080.
Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP . A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001; 413: 519–523.
Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA 2006; 103: 16834–16839.
Segarra J, Balenci L, Drenth T, Maina F, Lamballe F . Combined signaling through ERK, PI3K/AKT, and RAC1/p38 is required for met-triggered cortical neuron migration. J Biol Chem 2006; 281: 4771–4778.
Powell EM, Campbell DB, Stanwood GD, Davis C, Noebels JL, Levitt P . Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. J Neurosci 2003; 23: 622–631.
Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM . 15q11–13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet 2007; 16: 691–703.
Hu VW, Frank BC, Heine S, Lee NH, Quackenbush J . Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics 2006; 7: 118.
Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tueting P et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci USA 2002; 99: 17095–17100.
Tremolizzo L, Doueiri MS, Dong E, Grayson DR, Davis J, Pinna G et al. Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biol Psychiatry 2005; 57: 500–509.
Dong E, Guidotti A, Grayson DR, Costa E . Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proc Natl Acad Sci USA 2007; 104: 4676–4681.
Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A . Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc Natl Acad Sci USA 2005; 102: 12578–12583.
Kundakovic M, Chen Y, Costa E, Grayson DR . DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol 2007; 71: 644–653.
Tueting P, Doueiri MS, Guidotti A, Davis JM, Costa E . Reelin down-regulation in mice and psychosis endophenotypes. Neurosci Biobehav Rev 2006; 30: 1065–1077.
Tsankova N, Renthal W, Kumar A, Nestler EJ . Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 2007; 8: 355–367.
Lehner B, Crombie C, Tischler J, Fortunato A, Fraser AG . Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways. Nat Genet 2006; 38: 896–903.
Gray PA, Fu H, Luo P, Zhao Q, Yu J, Ferrari A et al. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 2004; 306: 2255–2257.
Zoltewicz JS, Stewart NJ, Leung R, Peterson AS . Atrophin 2 recruits histone deacetylase and is required for the function of multiple signaling centers during mouse embryogenesis. Development 2004; 131: 3–14.
Herceg Z, Hulla W, Gell D, Cuenin C, Lleonart M, Jackson S et al. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet 2001; 29: 206–211.
Calogero S, Grassi F, Aguzzi A, Voigtlander T, Ferrier P, Ferrari S et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet 1999; 22: 276–280.
Salathia N, Queitsch C . Molecular mechanisms of canalization: Hsp90 and beyond. J Biosci 2007; 32: 457–463.
Nollen EA, Morimoto RI . Chaperoning signaling pathways: molecular chaperones as stress-sensing ‘heat shock’ proteins. J Cell Sci 2002; 115: 2809–2816.
Ruden DM, Xiao L, Garfinkel MD, Lu X . Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer. Hum Mol Genet 2005; 14(Spec No 1): R149–R155.
Pratt WB, Morishima Y, Murphy M, Harrell M . Chaperoning of glucocorticoid receptors. Handb Exp Pharmacol 2006; 172: 111–138.
Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 2007; 16: 1682–1698.
Voss AK, Thomas T, Gruss P . Mice lacking HSP90beta fail to develop a placental labyrinth. Development 2000; 127: 1–11.
Christians ES, Benjamin IJ . The stress or heat shock (HS) response: insights from transgenic mouse models. Methods 2005; 35: 170–175.
Barton M, Volkmar F . How commonly are known medical conditions associated with autism? J Autism Dev Disord 1998; 28: 273–278.
Entezam A, Biacsi R, Orrison B, Saha T, Hoffman GE, Grabczyk E et al. Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model. Gene 2007; 395: 125–134.
Hanson JE, Madison DV . Presynaptic FMR1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome. J Neurosci 2007; 27: 4014–4018.
Reichenberg A, Smith C, Schmeidler J, Silverman JM . Birth order effects on autism symptom domains. Psychiatry Res 2007; 150: 199–204.
Markham JA, Beckel-Mitchener AC, Estrada CM, Greenough WT . Corticosterone response to acute stress in a mouse model of Fragile X syndrome. Psychoneuroendocrinology 2006; 31: 781–785.
Miyashiro KY, Beckel-Mitchener A, Purk TP, Becker KG, Barret T, Liu L et al. RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 2003; 37: 417–431.
Kalueff AV, Gallagher PS, Murphy DL . Are serotonin transporter knockout mice ‘depressed’? Hypoactivity but no anhedonia. NeuroReport 2006; 17: 1347–1351.
Carlson S, Willott JF . The behavioral salience of tones as indicated by prepulse inhibition of the startle response: relationship to hearing loss and central neural plasticity in C57BL/6J mice. Hear Res 1996; 99: 168–175.
D’Amato FR, Scalera E, Sarli C, Moles A . Pups call, mothers rush: does maternal responsiveness affect the amount of ultrasonic vocalizations in mouse pups? Behav Genet 2005; 35: 103–112.
Francis DD, Szegda K, Campbell G, Martin WD, Insel TR . Epigenetic sources of behavioral differences in mice. Nat Neurosci 2003; 6: 445–446.
Weaver IC, Diorio J, Seckl JR, Szyf M, Meaney MJ . Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci 2004; 1024: 182–212.
Weaver IC, Meaney MJ, Szyf M . Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci USA 2006; 103: 3480–3485.
Liu D, Diorio J, Day JC, Francis DD, Meaney MJ . Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci 2000; 3: 799–806.
Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci 2005; 25: 11045–11054.
Makedonski K, Abuhatzira L, Kaufman Y, Razin A, Shemer R . MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. Hum Mol Genet 2005; 14: 1049–1058.
Jordan C, Francke U . Ube3a expression is not altered in Mecp2 mutant mice. Hum Mol Genet 2006; 15: 2210–2215.
Chang Q, Khare G, Dani V, Nelson S, Jaenisch R . The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 2006; 49: 341–348.
Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet 2004; 13: 2679–2689.
Guy J, Gan J, Selfridge J, Cobb S, Bird A . Reversal of neurological defects in a mouse model of Rett syndrome. Science 2007; 315: 1143–1147.
Nadler JJ, Zou F, Huang H, Moy SS, Lauder J, Crawley JN et al. Large-scale gene expression differences across brain regions and inbred strains correlate with a behavioral phenotype. Genetics 2006; 174: 1229–1236.
Chesler EJ, Lu L, Shou S, Qu Y, Gu J, Wang J et al. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 2005; 37: 233–242.
Liu D, Singh RP, Khan AH, Bhavsar K, Lusis AJ, Davis RC et al. Identifying loci for behavioral traits using genome-tagged mice. J Neurosci Res 2003; 74: 562–569.
Bolivar VJ, Cook MN, Flaherty L . Mapping of quantitative trait loci with knockout/congenic strains. Genome Res 2001; 11: 1549–1552.
Nowicki ST, Tassone F, Ono MY, Ferranti J, Croquette MF, Goodlin-Jones B et al. The Prader–Willi phenotype of fragile X syndrome. J Dev Behav Pediatr 2007; 28: 133–138.
Acknowledgements
This work was supported by NIH STAART Grant U54 MH66418 and NICHD Grant P30 HD03110.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moy, S., Nadler, J. Advances in behavioral genetics: mouse models of autism. Mol Psychiatry 13, 4–26 (2008). https://doi.org/10.1038/sj.mp.4002082
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4002082
Keywords
This article is cited by
-
Mitochondrial function influences expression of methamphetamine-induced behavioral sensitization
Scientific Reports (2021)
-
Hippocampal Lnx1–NMDAR multiprotein complex mediates initial social memory
Molecular Psychiatry (2021)
-
A heritable profile of six miRNAs in autistic patients and mouse models
Scientific Reports (2020)
-
Sociability in Fruit Flies: Genetic Variation, Heritability and Plasticity
Behavior Genetics (2018)
-
A novel system for tracking social preference dynamics in mice reveals sex- and strain-specific characteristics
Molecular Autism (2017)
