Overview of Mouse Models of Autism Spectrum Disorders

Alexandra L. Bey1, Yong‐hui Jiang2

1 Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina, 2 Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, North Carolina
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.66
DOI:  10.1002/0471141755.ph0566s66
Online Posting Date:  September, 2014
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Abstract

This overview describes many well characterized mouse models of autism spectrum disorders (ASDs). Mouse models considered here were selected because they are examples of genetically engineered models where human genetic evidence supports a causative relationship between the targeted mutation and the behavioral phenotype. As the ASD diagnosis is based primarily on behavioral evaluations in humans in the domains of social interaction, communication, and restricted interests, the murine phenotypes analogous to human autistic behaviors are highlighted for the different models and behaviors. Although genetically engineered mouse models with good construct and face validity are valuable for identifying and defining underlying pathophysiological mechanisms and for developing potential therapeutic interventions for the human condition, the translational value of various rodent behavioral assays remains a subject of debate. Significant challenges associated with modeling ASDs in rodents because of the clinical and molecular heterogeneity that characterize this disorder are also considered. Curr. Protoc. Pharmacol. 66:5.66.1‐5.66.26. © 2014 by John Wiley & Sons, Inc.

Keywords: autism spectrum disorders; ASDs; mouse models; genetically engineered; behavior; therapeutic interventions

     
 
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Table of Contents

  • Introduction
  • Single‐Gene Syndromic Models
  • Single‐Gene Nonsyndromic Models
  • Models of Human Copy Number Variations (CNVs)
  • Nongenetic Models
  • Conclusions
  • Acknowledgements
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

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Literature Cited

Literature Cited
  Alarcon, M., Abrahams, B.S., Stone, J.L., Duvall, J.A., Perederiy, J.V., Bomar, J.M., Sebat, J., Wigler, M., Martin, C.L., Ledbetter, D.H., Nelson, S.F., Cantor, R.M., and Geschwind, D.H. 2008. Linkage, association, and gene‐expression analyses identify CNTNAP2 as an autism‐susceptibility gene. Am. J. Hum. Genet. 82:150‐159.
  American Psychiatric Association. 2013. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American Psychiatric Publishing, Arlington, Virginia.
  Arking, D.E., Cutler, D.J., Brune, C.W., Teslovich, T.M., West, K., Ikeda, M., Rea, A., Guy, M., Lin, S., Cook, E.H., and Chakravarti, A. 2008. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82:160‐164.
  Autism Developmental Disabilities Monitoring Network. 2014. Prevalence of autism spectrum disorder among children aged 8 years – autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morbid. Mortal. Weekly Rep. Surveill. Summ. 63:1‐21.
  Bader, P.L., Faizi, M., Kim, L.H., Owen, S.F., Tadross, M.R., Alfa, R.W., Bett, G.C., Tsien, R.W., Rasmusson, R.L., and Shamloo, M. 2011. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc. Natl. Acad. Sci. U.S.A. 108:15432‐15437.
  Bena, F., Bruno, D.L., Eriksson, M., van Ravenswaaij‐Arts, C., Stark, Z., Dijkhuizen, T., Gerkes, E., Gimelli, S., Ganesamoorthy, D., Thuresson, A.C., Labalme, A., Till, M., Bilan, F., Pasquier, L., Kitzis, A., Dubourgm, C., Rossi, M., Bottani, A., Gagnebin, M., Sanlaville, D., Gilbert‐Dussardier, B., Guipponi, M., van Haeringen, A., Kriek, M., Ruivenkamp, C., Antonarakis, S.E., Anderlid, B.M., Slater, H.R., and Schoumans, J. 2013. Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am. J. Med. Genet. B 162:388‐403.
  Bett, G.C., Lis, A., Wersinger, S.R., Baizer, J.S., Duffey, M.E., and Rasmusson, R.L. 2012. A mouse model of Timothy syndrome: A complex autistic disorder resulting from a point mutation in Cav1.2. N. Am. J. Med. Sci. 5:135‐140.
  Bhakar, A.L., Dolen, G., and Bear, M.F. 2012. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35:417‐443.
  Blundell, J., Tabuchi, K., Bolliger, M.F., Blaiss, C.A., Brose, N., Liu, X., Sudhof, T.C., and Powell, C.M. 2009. Increased anxiety‐like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav. 8:114‐126.
  Blundell, J., Blaiss, C.A., Etherton, M.R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M.F., Sudhof, T.C., and Powell, C.M. 2010. Neuroligin‐1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30:2115‐2129.
  Bozdagi, O., Sakurai, T., Papapetrou, D., Wang, X., Dickstein, D.L., Takahashi, N., Kajiwara, Y., Yang, M., Katz, A.M., Scattoni, M.L., Harris, M.J., Saxena, R., Silverman, J.L., Crawley, J.N., Zhou, Q., Hof, P.R., and Buxbaum, J.D. 2010. Haploinsufficiency of the autism‐associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism 1:15.
  Bozdagi, O., Tavassoli, T., and Buxbaum, J.D. 2013. Insulin‐like growth factor‐1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol. Autism 4:9.
  Burket, J.A., Benson, A.D., Tang, A.H., and Deutsch, S.I. 2013. D‐Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. Brain Res. Bull. 96:62‐70.
  Burket, J.A., Benson, A.D., Tang, A.H., and Deutsch, S.I. 2014. Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders. Brain Res. Bull. 100:70‐75.
  Butler, M.G., Dasouki, M.J., Zhou, X.P., Talebizadeh, Z., Brown, M., Takahashi, T.N., Miles, J.H., Wang, C.H., Stratton, R., Pilarski, R., and Eng, C. 2005. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42:318‐321.
  Buxbaum, J.D., Cai, G., Chaste, P., Nygren, G., Goldsmith, J., Reichert, J., Anckarsater, H., Rastam, M., Smith, C.J., Silverman, J.M., Hollander, E., Leboyer, M., Gillberg, C., Verloes, A., and Betancur, C. 2007. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am. J. Med. Genet. B 144:484‐491.
  Caglayan, A.O. 2010. Genetic causes of syndromic and nonsyndromic autism. Dev. Med. Child Neurol. 52:130‐138.
  Calfa, G., Percy, A.K., and Pozzo‐Miller, L. 2011. Experimental models of Rett syndrome based on MECP2 dysfunction. Exp. Biol. Med. 236:3‐19.
  Chadman, K.K., Gong, S., Scattoni, M.L., Boltuck, S.E., Gandhy, S.U., Heintz, N., and Crawley, J.N. 2008. Minimal aberrant behavioral phenotypes of neuroligin‐3 R451C knockin mice. Autism Res. 1:147‐158.
  Chamberlain, S.J. and Lalande, M. 2010. Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11‐q13. Neurobiol. Dis. 39:13‐20.
  Chen, R.Z., Akbarian, S., Tudor, M., and Jaenisch, R. 2001. Deficiency of methyl‐CpG binding protein‐2 in CNS neurons results in a Rett‐like phenotype in mice. Nat. Genet. 27:327‐331.
  Chung, L., Bey, A.L., and Jiang, Y.H. 2012. Synaptic plasticity in mouse models of autism spectrum disorders. Kor. J. Physiol. Pharmacol. 16:369‐378.
  Depienne, C., Moreno‐De‐Luca, D., Heron, D., Bouteiller, D., Gennetier, A., Delorme, R., Chaste, P., Siffroi, J.P., Chantot‐Bastaraud, S., Benyahia, B., Trouillard, O., Nygren, G., Kopp, S., Johansson, M., Rastam, M., Burglen, L., Leguern, E., Verloes, A., Leboyer, M., Brice, A., Gillberg, C., and Betancur, C. 2009. Screening for genomic rearrangements and methylation abnormalities of the 15q11‐q13 region in autism spectrum disorders. Biol. Psychiatry 66:349‐359.
  Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D.J., Ramesh, V., and Silva, A.J. 2008. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 14:843‐848.
  El‐Kordi, A., Winkler, D., Hammerschmidt, K., Kastner, A., Krueger, D., Ronnenberg, A., Ritter, C., Jatho, J., Radyushkin, K., Bourgeron, T., Fischer, J., Brose, N., and Ehrenreich, H. 2013. Development of an autism severity score for mice using Nlgn4 null mutants as a construct‐valid model of heritable monogenic autism. Behav. Brain Res. 251:41‐49.
  Eng, C. 2014. PTEN hamartoma tumor syndrome (PHTS). In GeneReviews (R.A. Pagon, M.P. Adam, H.H. Ardinger, T.D. Bird, C.R. Dolan, C.T. Fong, R.J.H. Smith, and K. Stephens, eds.). http://www.ncbi.nlm.nih.gov/books/NBK1488. National Center for Biotechnology Information, Bethesda, Md.
  Etherton, M.R., Blaiss, C.A., Powell, C.M., and Sudhof, T.C. 2009. Mouse neurexin‐1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl. Acad. Sci. U.S.A. 106:17998‐18003.
  Ey, E., Yang, M., Katz, A.M., Woldeyohannes, L., Silverman, J.L., Leblond, C.S., Faure, P., Torquet, N., Le Sourd, A.M., Bourgeron, T., and Crawley, J.N. 2012. Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4. Genes Brain Behav. doi: 10.1111/j.1601‐183X.2012.00849.x. [Epub ahead of print].
  Ganz, M.L. 2007. The lifetime distribution of the incremental societal costs of autism. Arch. Pediatrics Adol. Med. 161:343‐349.
  Glessner, J.T., Wang, K., Cai, G., Korvatska, O., Kim, C.E., Wood, S., Zhang, H., Estes, A., Brune, C.W., Bradfield, J.P., Imielinski, M., Frackelton, E.C., Reichert, J., Crawford, E.L., Munson, J., Sleiman, P.M., Chiavacci, R., Annaiah, K., Thomas, K., Hou, C., Glaberson, W., Flory, J., Otieno, F., Garris, M., Soorya, L., Klei, L., Piven, J., Meyer, K.J., Anagnostou, E., Sakurai, T., Game, R.M., Rudd, D.S., Zurawiecki, D., McDougle, C.J., Davis, L.K., Miller, J., Posey, D.J., Michaels, S., Kolevzon, A., Silverman, J.M., Bernier, R., Levy, S.E., Schultz, R.T., Dawson, G., Owley, T., McMahon, W.M., Wassink, T.H., Sweeney, J.A., Nurnberger, J.I., Coon, H., Sutcliffe, J.S., Minshew, N.J., Grant, S.F., Bucan, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Schellenberg, G.D., and Hakonarson, H. 2009. Autism genome‐wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569‐573.
  Goffin, A., Hoefsloot, L.H., Bosgoed, E., Swillen, A., and Fryns, J.P. 2001. PTEN mutation in a family with Cowden syndrome and autism. Am. J. Med. Genet. 105:521‐524.
  Goffin, D., Allen, M., Zhang, L., Amorim, M., Wang, I.T., Reyes, A.R., Mercado‐Berton, A., Ong, C., Cohen, S., Hu, L., Blendy, J.A., Carlson, G.C., Siegel, S.J., Greenberg, M.E., and Zhou, Z. 2012. Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability, and ERP responses. Nat. Neurosci. 15:274‐283.
  Goorden, S.M., van Woerden, G.M., van der Weerd, L., Cheadle, J.P., and Elgersma, Y. 2007. Cognitive deficits in Tsc1+/‐ mice in the absence of cerebral lesions and seizures. Ann. Neurol. 62:648‐655.
  Grayton, H.M., Missler, M., Collier, D.A., and Fernandes, C. 2013. Altered social behaviours in neurexin‐1‐α knockout mice resemble core symptoms in neurodevelopmental disorders. PloS One 8:e67114.
  Han, S., Tai, C., Westenbroek, R.E., Yu, F.H., Cheah, C.S., Potter, G.B., Rubenstein, J.L., Scheuer, T., de la Iglesia, H.O., and Catterall, W.A. 2012. Autistic‐like behaviour in Scn1a+/‐ mice and rescue by enhanced GABA‐mediated neurotransmission. Nature 489:385‐390.
  Horev, G., Ellegood, J., Lerch, J.P., Son, Y.E., Muthuswamy, L., Vogel, H., Krieger, A.M., Buja, A., Henkelman, R.M., Wigler, M., and Mills, A.A. 2011. Dosage‐dependent phenotypes in models of 16p11.2 lesions found in autism. Proc. Natl. Acad. Sci. U.S.A. 108:17076‐17081.
  Hung, A.Y., Futai, K., Sala, C., Valtschanoff, J.G., Ryu, J., Woodworth, M.A., Kidd, F.L., Sung, C.C., Miyakawa, T., Bear, M.F., Weinberg, R.J., and Sheng, M. 2008. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28:1697‐1708.
  Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I.C., Soderstrom, H., Giros, B., Leboyer, M., Gillberg, C., Bourgeron, T., and Paris Autism Research International Sibpair Study. 2003. Mutations of the X‐linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34:27‐29.
  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., and Brose, N. 2008. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl. Acad. Sci. U.S.A. 105:1710‐1715.
  Jaramillo, T.C., Liu, S., Pettersen, A., Birnbaum, S.G., and Powell, C.M. 2014. Autism‐related neuroligin‐3 mutation alters social behavior and spatial learning. Autism Res. 7:264‐272.
  Jiang, Y.H. and Ehlers, M.D. 2013. Modeling autism by Shank gene mutations in mice. Neuron 78:8‐27.
  Jiang, Y.H., Wang, Y., Xiu, X., Choy, K.W., Pursley, A.N., and Cheung, S.W. 2014. Genetic diagnosis of autism spectrum disorders: The opportunity and challenge in the genomics era. Crit. Rev. Cl. Lab. Sci. doi:10.3109/10408363.2014.910747. [Epub ahead of print].
  Katz, D.M., Berger‐Sweeney, J.E., Eubanks, J.H., Justice, M.J., Neul, J.L., Pozzo‐Miller, L., Blue, M.E., Christian, D., Crawley, J.N., Giustetto, M., Guy, J., Howell, C.J., Kron, M., Nelson, S.B., Samaco, R.C., Schaevitz, L.R., St Hillaire‐Clarke, C., Young, J.L., Zoghbi, H.Y., and Mamounas, L.A. 2012. Preclinical research in Rett syndrome: Setting the foundation for translational success. Dis. Models Mechanisms 5:733‐745.
  Kouser, M., Speed, H.E., Dewey, C.M., Reimers, J.M., Widman, A.J., Gupta, N., Liu, S., Jaramillo, T.C., Bangash, M., Xiao, B., Worley, P.F., and Powell, C.M. 2013. Loss of predominant Shank3 isoforms results in hippocampus‐dependent impairments in behavior and synaptic transmission. J. Neurosci. 33:18448‐18468.
  Kumar, A., Wadhawan, R., Swanwick, C.C., Kollu, R., Basu, S.N., and Banerjee‐Basu, S. 2011. Animal model integration to AutDB, a genetic database for autism. BMC Med. Genom. 4:15.
  Kwon, C.H., Luikart, B.W., Powell, C.M., Zhou, J., Matheny, S.A., Zhang, W., Li, Y., Baker, S.J., and Parada, L.F. 2006. Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377‐388.
  Lacaria, M., Spencer, C., Gu, W., Paylor, R., and Lupski, J.R. 2012. Enriched rearing improves behavioral responses of an animal model for CNV‐based autistic‐like traits. Hum. Mol. Genet. 21:3083‐3096.
  Laumonnier, F., Bonnet‐Brilhault, F., Gomot, M., Blanc, R., David, A., Moizard, M.P., Raynaud, M., Ronce, N., Lemonnier, E., Calvas, P., Laudier, B., Chelly, J., Fryns, J.P., Ropers, H.H., Hamel, B.C., Andres, C., Barthelemy, C., Moraine, C., and 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. 74:552‐557.
  Li, B.M., Liu, X.R., Yi, Y.H., Deng, Y.H., Su, T., Zou, X., and Liao, W.P. 2011. Autism in Dravet syndrome: Prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav. 21:291‐295.
  Meyza, K.Z., Defensor, E.B., Jensen, A.L., Corley, M.J., Pearson, B.L., Pobbe, R.L., Bolivar, V.J., Blanchard, D.C., and Blanchard, R.J. 2013. The BTBR T+ tf/J mouse model for autism spectrum disorders‐in search of biomarkers. Behav. Brain Res. 251:25‐34.
  Miles, J.H. 2011. Autism spectrum disorders–a genetics review. Genet. Med. 13:278‐294.
  Miller, D.T., Nasir, R., Sobeih, M.M., Shen, Y., Wu, B.L., and Hanson, E. 2011. 16p11.2 microdeletion. In GeneReviews (R.A. Pagon, M.P. Adam, T.D. Bird, C.R. Dolan, C.T. Fong, and K. Stephens, eds.). http://www.ncbi.nlm.nih.gov/books/NBK11167. National Center for Biotechnology Information. Bethesda, Md.
  Molina, J., Carmona‐Mora, P., Chrast, J., Krall, P.M., Canales, C.P., Lupski, J.R., Reymond, A., and Walz, K. 2008. Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki‐Lupski syndrome. Hum. Mol. Genet. 17:2486‐2495.
  Moreno‐De‐Luca, D., Sanders, S.J., Willsey, A.J., Mulle, J.G., Lowe, J.K., Geschwind, D.H., State, M.W., Martin, C.L., and Ledbetter, D.H. 2013. Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Mol. Psychiatry 18:1090‐1095.
  Moretti, P. and Zoghbi, H.Y. 2006. MeCP2 dysfunction in Rett syndrome and related disorders. Curr. Opin. Genet. Dev. 16:276‐281.
  Moy, S.S. and Nadler, J.J. 2008. Advances in behavioral genetics: Mouse models of autism. Mol. Psychiatry 13:4‐26.
  Nakatani, J., Tamada, K., Hatanaka, F., Ise, S., Ohta, H., Inoue, K., Tomonaga, S., Watanabe, Y., Chung, Y.J., Banerjee, R., Iwamoto, K., Kato, T., Okazawa, M., Yamauchi, K., Tanda, K., Takao, K., Miyakawa, T., Bradley, A., and Takumi, T. 2009. Abnormal behavior in a chromosome‐engineered mouse model for human 15q11‐13 duplication seen in autism. Cell 137:1235‐1246.
  Napoli, E., Ross‐Inta, C., Wong, S., Hung, C., Fujisawa, Y., Sakaguchi, D., Angelastro, J., Omanska‐Klusek, A., Schoenfeld, R., and Giulivi, C. 2012. Mitochondrial dysfunction in Pten haplo‐insufficient mice with social deficits and repetitive behavior: Interplay between Pten and p53. PloS One 7:e42504.
  Neul, J.L. 2012. The relationship of Rett syndrome and MECP2 disorders to autism. Dialog. Clin. Neurosci. 14:253‐262.
  O'Roak, B.J., Vives, L., Fu, W., Egertson, J.D., Stanaway, I.B., Phelps, I.G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J.B., Turner, E.H., Levy, R., O'Day, D.R., Krumm, N., Coe, B.P., Martin, B.K., Borenstein, E., Nickerson, D.A., Mefford, H.C., Doherty, D., Akey, J.M., Bernier, R., Eichler, E.E., and Shendure, J. 2012a. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619‐1622.
  O'Roak, B.J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B.P., Levy, R., Ko, A., Lee, C., Smith, J.D., Turner, E.H., Stanaway, I.B., Vernot, B., Malig, M., Baker, C., Reilly, B., Akey, J.M., Borenstein, E., Rieder, M.J., Nickerson, D.A., Bernier, R., Shendure, J., and Eichler, E.E. 2012b. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246‐250.
  Peca, J., Feliciano, C., Ting, J.T., Wang, W., Wells, M.F., Venkatraman, T.N., Lascola, C.D., Fu, Z., and Feng, G. 2011. Shank3 mutant mice display autistic‐like behaviours and striatal dysfunction. Nature 472:437‐442.
  Penagarikano, O., Abrahams, B.S., Herman, E.I., Winden, K.D., Gdalyahu, A., Dong, H., Sonnenblick, L.I., Gruver, R., Almajano, J., Bragin, A., Golshani, P., Trachtenberg, J.T., Peles, E., and Geschwind, D.H. 2011. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism‐related deficits. Cell 147:235‐246.
  Potocki, L., Bi, W., Treadwell‐Deering, D., Carvalho, C.M., Eifert, A., Friedman, E.M., Glaze, D., Krull, K., Lee, J.A., Lewis, R.A., Mendoza‐Londono, R., Robbins‐Furman, P., Shaw, C., Shi, X., Weissenberger, G., Withers, M., Yatsenko, S.A., Zackai, E.H., Stankiewicz, P., and Lupski, J.R. 2007. Characterization of Potocki‐Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage‐sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80:633‐649.
  Radyushkin, K., Hammerschmidt, K., Boretius, S., Varoqueaux, F., El‐Kordi, A., Ronnenberg, A., Winter, D., Frahm, J., Fischer, J., Brose, N., and Ehrenreich, H. 2009. Neuroligin‐3‐deficient mice: Model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav. 8:416‐425.
  Reith, R.M., McKenna, J., Wu, H., Hashmi, S.S., Cho, S.H., Dash, P.K., and Gambello, M.J. 2013. Loss of Tsc2 in Purkinje cells is associated with autistic‐like behavior in a mouse model of tuberous sclerosis complex. Neurobiol. Dis. 51:93‐103.
  Restivo, L., Ferrari, F., Passino, E., Sgobio, C., Bock, J., Oostra, B.A., Bagni, C., and Ammassari‐Teule, M. 2005. Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc. Natl. Acad. Sci. U.S.A. 102:11557‐11562.
  Ricard, G., Molina, J., Chrast, J., Gu, W., Gheldof, N., Pradervand, S., Schutz, F., Young, J.I., Lupski, J.R., Reymond, A., and Walz, K. 2010. Phenotypic consequences of copy number variation: Insights from Smith‐Magenis and Potocki‐Lupski syndrome mouse models. PLoS Biol. 8:e1000543.
  Sato, A., Kasai, S., Kobayashi, T., Takamatsu, Y., Hino, O., Ikeda, K., and Mizuguchi, M. 2012. Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat. Comm. 3:1292.
  Schmeisser, M.J., Ey, E., Wegener, S., Bockmann, J., Stempel, A.V., Kuebler, A., Janssen, A.L., Udvardi, P.T., Shiban, E., Spilker, C., Balschun, D., Skryabin, B.V., Dieck, S., Smalla, K.H., Montag, D., Leblond, C.S., Faure, P., Torquet, N., Le Sourd, A.M., Toro, R., Grabrucker, A.M., Shoichet, S.A., Schmitz, D., Kreutz, M.R., Bourgeron, T., Gundelfinger, E.D., and Boeckers, T.M. 2012. Autistic‐like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486:256‐260.
  Schmunk, G. and Gargus, J.J. 2013. Channelopathy pathogenesis in autism spectrum disorders. Frontiers Genet. 4:222.
  Shahbazian, M., Young, J., Yuva‐Paylor, L., Spencer, C., Antalffy, B., Noebels, J., Armstrong, D., Paylor, R., and Zoghbi, H. 2002. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:243‐254.
  Silverman, J.L., Tolu, S.S., Barkan, C.L., and Crawley, J.N. 2010a. Repetitive self‐grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35:976‐989.
  Silverman, J.L., Yang, M., Lord, C., and Crawley, J.N. 2010b. Behavioural phenotyping assays for mouse models of autism. Nat. Rev. Neurosci. 11:490‐502.
  Silverman, J.L., Turner, S.M., Barkan, C.L., Tolu, S.S., Saxena, R., Hung, A.Y., Sheng, M., and Crawley, J.N. 2011. Sociability and motor functions in Shank1 mutant mice. Brain Res. 1380:120‐137.
  Smith, S.E., Zhou, Y.D., Zhang, G., Jin, Z., Stoppel, D.C., and Anderson, M.P. 2011. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci. Transl. Med. 3:103ra197.
  Spencer, C.M., Alekseyenko, O., Hamilton, S.M., Thomas, A.M., Serysheva, E., Yuva‐Paylor, L.A., and Paylor, R. 2011. Modifying behavioral phenotypes in Fmr1KO mice: Genetic background differences reveal autistic‐like responses. Autism Res. 4:40‐56.
  Splawski, I., Timothy, K.W., Priori, S.G., Napolitano, C., and Bloise, R. 2011. Timothy Syndrome. In GeneReviews (R.A. Pagon, M.P. Adam, T.D. Bird, C.R. Dolan, C.T. Fong, and K. Stephens, eds.). http://www.ncbi.nlm.nih.gov/books/NBK1403. National Center for Biotechnology Information. Bethesda, Md.
  Stiles, B., Groszer, M., Wang, S., Jiao, J., and Wu, H. 2004. PTENless means more. Dev. Biol. 273:175‐184.
  Sudhof, T.C. 2008. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455:903‐911.
  Tabuchi, K., Blundell, J., Etherton, M.R., Hammer, R.E., Liu, X., Powell, C.M., and Sudhof, T.C. 2007. A neuroligin‐3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71‐76.
  The Dutch‐Belgian Fragile X Consortium. 1994. Fmr1 knockout mice: A model to study fragile X mental retardation. Cell 78:23‐33.
  Tsai, P.T., Hull, C., Chu, Y., Greene‐Colozzi, E., Sadowski, A.R., Leech, J.M., Steinberg, J., Crawley, J.N., Regehr, W.G., and Sahin, M. 2012. Autistic‐like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647‐651.
  Walz, K., Caratini‐Rivera, S., Bi, W., Fonseca, P., Mansouri, D.L., Lynch, J., Vogel, H., Noebels, J.L., Bradley, A., and Lupski, J.R. 2003. Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: Phenotypic consequences of gene dosage imbalance. Mol. Cell. Biol. 23:3646‐3655.
  Walz, K., Paylor, R., Yan, J., Bi, W., and Lupski, J.R. 2006. Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). J. Clin. Invest. 116:3035‐3041.
  Wang, X., McCoy, P.A., Rodriguiz, R.M., Pan, Y., Je, H.S., Roberts, A.C., Kim, C.J., Berrios, J., Colvin, J.S., Bousquet‐Moore, D., Lorenzo, I., Wu, G., Weinberg, R.J., Ehlers, M.D., Philpot, B.D., Beaudet, A.L., Wetsel, W.C., and Jiang, Y.H. 2011. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20:3093‐3108.
  Wijetunge, L.S., Chattarji, S., Wyllie, D.J., and Kind, P.C. 2013. Fragile X syndrome: From targets to treatments. Neuropharmacology 68:83‐96.
  Wohr, M., Roullet, F.I., Hung, A.Y., Sheng, M., and Crawley, J.N. 2011. Communication impairments in mice lacking Shank1: Reduced levels of ultrasonic vocalizations and scent marking behavior. PloS One 6:e20631.
  Wohr, M., Silverman, J.L., Scattoni, M.L., Turner, S.M., Harris, M.J., Saxena, R., and Crawley, J.N. 2013. Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. Behav. Brain Res. 251:50‐64.
  Won, H., Lee, H.R., Gee, H.Y., Mah, W., Kim, J.I., Lee, J., Ha, S., Chung, C., Jung, E.S., Cho, Y.S., Park, S.G., Lee, J.S., Lee, K., Kim, D., Bae, Y.C., Kaang, B.K., Lee, M.G., and Kim, E. 2012. Autistic‐like social behaviour in Shank2‐mutant mice improved by restoring NMDA receptor function. Nature 486:261‐265.
  Yang, M., Bozdagi, O., Scattoni, M.L., Wohr, M., Roullet, F.I., Katz, A.M., Abrams, D.N., Kalikhman, D., Simon, H., Woldeyohannes, L., Zhang, J.Y., Harris, M.J., Saxena, R., Silverman, J.L., Buxbaum, J.D., and Crawley, J.N. 2012. Reduced excitatory neurotransmission and mild autism‐relevant phenotypes in adolescent Shank3 null mutant mice. J. Neurosci. 32:6525‐6541.
  Ylisaukko‐oja, T., Rehnstrom, K., Auranen, M., Vanhala, R., Alen, R., Kempas, E., Ellonen, P., Turunen, J.A., Makkonen, I., Riikonen, R., Nieminen‐von Wendt, T., von Wendt, L., Peltonen, L., and Jarvela, I. 2005. Analysis of four neuroligin genes as candidates for autism. Eur. J. Hum. Genet. 13:1285‐1292.
  Young, D.M., Schenk, A.K., Yang, S.B., Jan, Y.N., and Jan, L.Y. 2010. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc. Natl. Acad. Sci. U.S.A. 107:11074‐11079.
  Yu, J., He, X., Yao, D., Li, Z., Li, H., and Zhao, Z. 2011. A sex‐specific association of common variants of neuroligin genes (NLGN3 and NLGN4X) with autism spectrum disorders in a Chinese Han cohort. Behav. Brain Funct. 7:13.
  Zhou, J., Blundell, J., Ogawa, S., Kwon, C.H., Zhang, W., Sinton, C., Powell, C.M., and Parada, L.F. 2009. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural‐specific Pten knock‐out mice. J. Neurosci. 29:1773‐1783.
  Zoghbi, H.Y. and Bear, M.F. 2012. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4:pii:a009886.
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