Synaptic proteins and receptors defects in autism spectrum disorders

Frontiers in Cellular Neuroscience

Volumn 8, Issue , 2014, Pages

  Chen, Jianling ^a   Yu, Shunying ^a   Fu, Yingmei ^a   Li, Xiaohong ^b  

^a SHANGHAI JIAO TONG UNIVERSITY SCHOOL OF MEDICINE   (China)

^b NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

Author keywords

Autism spectrum disorders; GABA; PSD 95; SHANK3; Synaptic protein; TAOK2

Indexed keywords

4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID RECEPTOR; CADHERIN; CONTACTIN; CONTACTIN ASSOCIATED PROTEIN 2; EPIDERMAL GROWTH FACTOR; GEPHYRIN; GLUTAMATE RECEPTOR; MEMBRANE PROTEIN; NEUREXIN; NEUROLIGIN 1; POSTSYNAPTIC DENSITY PROTEIN 95; SHANK PROTEIN; SYNAPSE RECEPTOR; SYNAPSIN I; SYNAPSIN II; THOUSAND AND ONE AMINO ACID 2 KINASE; UNCLASSIFIED DRUG;

AUTISM; COPY NUMBER VARIATION; DOWN REGULATION; EVOKED RESPONSE; GENE EXPRESSION; GENE MUTATION; HUMAN; NONHUMAN; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION; SYNAPTIC TRANSMISSION; SYNAPTOGENESIS;

EID: 84907220674     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2014.00276     Document Type: Review

References (142)

1. Alarcón, M., Abrahams, B. S., Stone, J. L., Duvall, J. A., Perederiy, J. V., Bomar, J. M.,et al. (2008). Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet.82, 150-159. doi: 10.1016/j.ajhg.2007.09.005
2. American Psychiatry Association [APA]. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edn. Arlington, VA: American Psychiatric Publishing.
3. Anitha, A., Thanseem, I., Nakamura, K., Yamada, K., Iwayama, Y., Toyota, T.,et al. (2013). Protocadherin alpha (PCDHA) as a novel susceptibility gene for autism. J. Psychiatry Neurosci. 38, 192-198. doi: 10.1503/jpn.120058
4. Arking, D. E., Cutler, D. J., Brune, C. W., Teslovich, T. M., West, K., Ikeda, M.,et al. (2008). A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82, 160-164. doi: 10.1016/j.ajhg.2007.09.015
5. Asperger, H. (1944). Die ‘autistischen psychopathen' im kindesalter. Arch. Psychiatr. Nervenkr. 117, 76-136. doi: 10.1007/BF01837709
6. Autism Genome Project Consortium, Szatmari, P., Paterson, A. D., Zwaigenbaum, L., Roberts, W., Brian, J.,et al. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39, 319-328. doi: 10.1038/ng1985
7. Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M.,et al. (2008). Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 82, 165-173. doi: 10.1016/j.ajhg.2007.09.017
8. Barnby, G., Abbott, A., Sykes, N., Morris, A., Weeks, D. E., Mott, R.,et al. (2005). Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. Am. J. Hum. Genet. 76, 950-966. doi: 10.1086/430454
9. Berkel, S., Marshall, R. C., Weiss, B., Howe, J., Roeth, R., Moog, U.,et al. (2010). Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat. Genet. 42, 489-491. doi: 10.1038/ng.589
10. Berry-Kravis, E. M., Hessl, D., Rathmell, B., Zarevics, P., Cherubini, M., Walton-Bowen, K.,et al. (2012). Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci. Transl. Med. 4:152ra127. doi: 10.1126/scitranslmed.3004214
11. Betancur, C., Sakurai, T., and Buxbaum, J. D. (2009). The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci. 32, 402-412. doi: 10.1016/j.tins.2009.04.003
12. Billstedt, E., Gillberg, I. C., and Gillberg, C. (2005). Autism after adolescence: population-based 13- to 22-year follow-up study of 120 individuals with autism diagnosed in childhood. J. Autism Dev. Disord. 35, 351-360. doi: 10.1007/s10803-005-3302-5
13. Blasi, F., Bacchelli, E., Pesaresi, G., Carone, S., Bailey, A. J., Maestrini, E.,et al. (2006). Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 220-221. doi: 10.1002/ajmg.b.30287
14. Blatt, G. J., Fitzgerald, C. M., Guptill, J. T., Booker, A. B., Kemper, T. L., and Bauman, M. L. (2001). Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J. Autism Dev. Disord. 31, 537-543. doi: 10.1023/A:1013238809666
15. Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A.,et al. (2013). Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur. J. Hum. Genet. 21, 310-316. doi: 10.1038/ejhg.2012.175
16. Bolton, P. F., Dennis, N. R., Browne, C. E., Thomas, N. S., Veltman, M. W., Thompson, R. J.,et al. (2001). The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am. J. Med. Genet. 105, 675-685. doi: 10.1002/ajmg.1551
17. Bozdagi, O., Sakurai, T., Papapetrou, D., Wang, X., Dickstein, D. L., Takahashi, N.,et al. (2010). Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism 1:15. doi: 10.1186/2040-2392-1-15
18. Bremer, A., Giacobini, M., Eriksson, M., Gustavsson, P., Nordin, V., Fernell, E.,et al. (2011). Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156, 115-124. doi: 10.1002/ajmg.b.31142
19. Carlsson, M. L. (1998). Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate-serotonin interactions for pharmacotherapy. J. Neural. Transm. 105, 525-535. doi: 10.1007/s007020050076
20. Chen, Y. W., Lin, H. C., Ng, M. C., Hsiao, Y. H., Wang, C. C., Gean, P. W.,et al. (2014). Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism. Front. Behav. Neurosci. 8:219. doi: 10.3389/fnbeh.2014.00219
21. Chez, M. G., Burton, Q., Dowling, T., Chang, M., Khanna, P., and Kramer, C. (2007). Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J. Child Neurol. 22, 574-579. doi: 10.1177/0883073807302611
22. Chubykin, A. A., Atasoy, D., Etherton, M. R., Brose, N., Kavalali, E. T., Gibson, J. R.,et al. (2007). Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919-931. doi: 10.1016/j.neuron.2007.05.029
23. Corradi, A., Fadda, M., Piton, A., Patry, L., Marte, A., Rossi, P.,et al. (2014). SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum. Mol. Genet. 23, 90-103. doi: 10.1093/hmg/ddt401
24. de Anda, F. C., Rosario, A. L., Durak, O., Tran, T., Gräff, J., Meletis, K.,et al. (2012). Autism spectrum disorder susceptibility gene TAOK2 affects basal dendrite formation in the neocortex. Nat. Neurosci. 15, 1022-1031. doi: 10.1038/nn.3141
25. Dean, C., and Dresbach, T. (2006). Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function. Trends Neurosci. 29, 21-29. doi: 10.1016/j.tins.2005.11.003
26. Depienne, C., Moreno-De-Luca, D., Heron, D., Bouteiller, D., Gennetier, A., Delorme, R.,et al. (2009). Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders.Biol. Psychiatry 66, 349-359. doi: 10.1016/j.biopsych.2009.01.025
27. Dhar, S. U., del Gaudio, D., German, J. R., Peters, S. U., Ou, Z., Bader, P. I.,et al. (2010). 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am. J. Med. Genet. A 152A, 573-581. doi: 10.1002/ajmg.a.33253
28. Dolen, G., Osterweil, E., Rao, B. S., Smith, G. B., Auerbach, B. D., Chattarji, S.,et al. (2007). Correction of fragile X syndrome in mice. Neuron 56, 955-962. doi: 10.1016/j.neuron.2007.12.001
29. Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F.,et al. (2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25-27. doi: 10.1038/ng1933
30. Elsabbagh, M., Divan, G., Koh, Y. J., Kim, Y. S., Kauchali, S., Marcín, C.,et al. (2012). Global prevalence of autism and other pervasive developmental disorders. Autism Res. 5, 160-179. doi: 10.1002/aur.239
31. Erickson, C. A., Veenstra-Vanderweele, J. M., Melmed, R. D., McCracken, J. T., Ginsberg, L. D., Sikich, L.,et al. (2014). STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J. Autism Dev. Disord. 44, 958-964. doi: 10.1007/s10803-013-1963-z
32. Etherton, M. R., Blaiss, C. A., Powell, C. M., and Südhof, 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. doi: 10.1073/pnas.0910297106
33. Etherton, M., Földy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M.,et al. (2011a). Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc. Natl. Acad. Sci. U.S.A. 108, 13764-13769. doi: 10.1073/pnas.1111093108
34. Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J., and Südhof, T. C. (2011b). An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30, 2908-2919. doi: 10.1038/emboj.2011.182
35. Fassio, A., Patry, L., Congia, S., Onofri, F., Piton, A., Gauthier, J.,et al. (2011). SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum. Mol. Genet. 20, 2297-2307. doi: 10.1093/hmg/ddr122
36. Fatemi, S. H., Folsom, T. D., Reutiman, T. J., and Thuras, P. D. (2009). Expression of GABA(B) receptors is altered in brains of subjects with autism. Cerebellum 8, 64-69. doi: 10.1007/s12311-008-0075-3
37. Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., and Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol. Psychiatry 52, 805-810. doi: 10.1016/S0006-3223(02)01430-0
38. Feyder, M., Karlsson, R. M., Mathur, P., Lyman, M., Bock, R., Momenan, R.,et al. (2010). Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. Am. J. Psychiatry 167, 1508-1517. doi: 10.1176/appi.ajp.2010.10040484
39. Földy, C., Malenka, R. C., and Südhof, T. C. (2013). Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron 78, 498-509. doi: 10.1016/j.neuron.2013.02.036
40. Fornasiero, E. F., Raimondi, A., Guarnieri, F. C., Orlando, M., Fesce, R., Benfenati, F.,et al. (2012). Synapsins contribute to the dynamic spatial organization of synaptic vesicles in an activity-dependent manner. J. Neurosci.32, 12214-12227. doi: 10.1523/JNEUROSCI.1554-12.2012
41. Friedman, A., and Luiselli, J. K. (2008). Excessive daytime sleep: behavioral assessment and intervention in a child with autism. Behav. Modif. 32, 548-555. doi: 10.1177/0145445507312187
42. Gauthier, J., Bonnel, A., St-Onge, J., Karemera, L., Laurent, S., Mottron, L.,et al. (2005). NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am. J. Med. Genet. B Neuropsychiatr. Genet.132B, 74-75. doi: 10.1002/ajmg.b.30066
43. Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N.,et al. (2011). Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum. Genet. 130, 563-573. doi: 10.1007/s00439-011-0975-z
44. Gauthier, J., Spiegelman, D., Piton, A., Lafrenière, R. G., Laurent, S., St-Onge, J.,et al. (2009). Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 421-424. doi: 10.1002/ajmg.b.30822
45. Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S.,et al. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569-573. doi: 10.1038/nature07953
46. Greco, B., Managò, F., Tucci, V., Kao, H. T., Valtorta, F., and Benfenati, F. (2013). Autism-related behavioral abnormalities in synapsin knockout mice. Behav. Brain Res. 251, 65-74. doi: 10.1016/j.bbr.2012.12.015
47. Gregor, A., Albrecht, B., Bader, I., Bijlsma, E. K., Ekici, A. B., Engels, H.,et al. (2011). Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med. Genet. 12:106. doi: 10.1186/1471-2350-12-106
48. Grosskreutz, Y., Betz, H., and Kneussel, M. (2003). Rescue of molybdenum cofactor biosynthesis in gephyrin-deficient mice by a Cnx1 transgene. Biochem. Biophys. Res. Commun. 301, 450-455. doi: 10.1016/S0006-291X(02)03062-0
49. Guilmatre, A., Dubourg, C., Mosca, A. L., Legallic, S., Goldenberg, A., Drouin-Garraud, V.,et al. (2009). Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch. Gen. Psychiatry 66, 947-956. doi: 10.1001/archgenpsychiatry.2009.80
50. Guilmatre, A., Huguet, G., Delorme, R., and Bourgeron, T. (2013). The emerging role of SHANK genes in neuropsychiatric disorders. Dev. Neurobiol. 74, 113-122. doi: 10.1002/dneu.22128
51. Guo, H., Xun, G., Peng, Y., Xiang, X., Xiong, Z., Zhang, L.,et al. (2012). Disruption of Contactin 4 in two subjects with autism in Chinese population. Gene 505, 201-205. doi: 10.1016/j.gene.2012.06.051
52. Harada, M., Taki, M. M., Nose, A., Kubo, H., Mori, K., Nishitani, H.,et al. (2011). Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 tesla instrument. J. Autism Dev. Disord. 41, 447-454. doi: 10.1007/s10803-010-1065-0
53. Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R.,et al. (2012). Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl. Med. 4:152ra128. doi: 10.1126/scitranslmed.3004218
54. Howlin, P., Goode, S., Hutton, J., and Rutter, M. (2004). Adult outcome for children with autism. J. Child Psychol. Psychiatry 45, 212-229. doi: 10.1111/j.1469-7610.2004.00215.x
55. Hung, A. Y., Futai, K., Sala, C., Valtschanoff, J. G., Ryu, J., Woodworth, M. A.,et al. (2008). Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28, 1697-1708. doi: 10.1523/JNEUROSCI.3032-07.2008
56. International Schizophrenia Consortium. (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237-241. doi: 10.1038/nature07239
57. Jamain, S., Betancur, C., Quach, H., Philippe, A., Fellous, M., Giros, B.,et al. (2002). Linkage and association of the glutamate receptor 6 gene with autism. Mol. Psychiatry 7, 302-310. doi: 10.1038/sj.mp.4000979
58. Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I. C.,et al. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27-29. doi: 10.1038/ng1136
59. Jamain, S., Radyushkin, K., Hammerschmidt, K., Granon, S., Boretius, S., Varoqueaux, F.,et al. (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. doi: 10.1073/pnas.0711555105
60. Kanner, L. (1943). Autistic disturbance of affective contact. Nerv. Child 2, 217-250.
61. Kelleher, R. J. III, Geigenmüller, U., Hovhannisyan, H., Trautman, E., Pinard, R., Rathmell, B.,et al. (2012). High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS ONE7:e35003. doi: 10.1371/journal.pone.0035003
62. Kim, H. G., Kishikawa, S., Higgins, A. W., Seong, I. S., Donovan, D. J., Shen, Y.,et al. (2008). Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82, 199-207. doi: 10.1016/j.ajhg.2007.09.011
63. King, B. H., Wright, D. M., Handen, B. L., Sikich, L., Zimmerman, A. W., McMahon, W.,et al. (2001). Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J. Am. Acad. Child Adolesc. Psychiatry 40, 658-665. doi: 10.1097/00004583-200106000-00010
64. King, M., and Bearman, P. (2009). Diagnostic change and the increased prevalence of autism. Int. J. Epidemiol. 38, 1224-1234. doi: 10.1093/ije/dyp261
65. Kneussel, M., Brandstätter, J. H., Laube, B., Stahl, S., Müller, U., and Betz, H. (1999). Loss of postsynaptic GABA(A) receptor clustering in gephyrin-deficient mice. J. Neurosci. 19, 9289-9297.
66. Kwasnicka-Crawford, D. A., Roberts, W., and Scherer, S. W. (2007). Characterization of an autism-associated segmental maternal heterodisomy of the chromosome 15q11-13 region. J. Autism Dev. Disord. 37, 694-702. doi: 10.1007/s10803-006-0225-8
67. Lai, M. C., Lombardo, M. V., and Baron-Cohen, S. (2014). Autism. Lancet 383, 896-910. doi: 10.1016/S0140-6736(13)61539-1
68. Laumonnier, F., Bonnet-Brilhault, F., Gomot, M., Blanc, R., David, A., Moizard, M. P.,et al. (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. doi: 10.1086/382137
69. Leblond, C. S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G.,et al. (2012). Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet.8:e1002521. doi: 10.1371/journal.pgen.1002521
70. Levy, D., Ronemus, M., Yamrom, B., Lee, Y. H., Leotta, A., Kendall, J.,et al. (2011). Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886-897. doi: 10.1016/j.neuron.2011.05.015
71. Li, X., Zou, H., and Brown, W. T. (2012). Genes associated with autism spectrum disorder. Brain Res. Bull. 88, 543-552. doi: 10.1016/j.brainresbull.2012.05.017
72. Lim, S., Naisbitt, S., Yoon, J., Hwang, J. I., Suh, P. G., Sheng, M.,et al. (1999). Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J. Biol. Chem. 274, 29510-29518. doi: 10.1074/jbc.274.41.29510
73. Lintas, C., and Persico, A. M. (2009). Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J. Med. Genet. 46, 1-8. doi: 10.1136/jmg.2008.060871
74. Lionel, A. C., Crosbie, J., Barbosa, N., Goodale, T., Thiruvahindrapuram, B., Rickaby, J.,et al. (2011). Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci. Transl. Med.3:95ra75. doi: 10.1126/scitranslmed.3002464
75. Lionel, A. C., Vaags, A. K., Sato, D., Gazzellone, M. J., Mitchell, E. B., Chen, H. Y.,et al. (2013). Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Hum. Mol. Genet.22, 2055-2066. doi: 10.1093/hmg/ddt056
76. Liu, Y., Du, Y., Liu, W., Yang, C., Liu, Y., Wang, H.,et al. (2013). Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. PLoS ONE 8:e56639. doi: 10.1371/journal.pone.0056639
77. Lotter, V. (1966). Epidemiology of autistic conditions in young children. Soc. Psychiatry Psychiatr. Epidemiol. 1, 124-135.
78. Lugo, J. N., Smith, G. D., Arbuckle, E. P., White, J., Holley, A. J., Floruta, C. M.,et al. (2014). Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. Front. Mol. Neurosci. 7:27. doi: 10.3389/fnmol.2014.00027
79. Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J.,et al. (2008). Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477-488. doi: 10.1016/j.ajhg.2007.12.009
80. Martin, E. R., Menold, M. M., Wolpert, C. M., Bass, M. P., Donnelly, S. L., Ravan, S. A.,et al. (2000). Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am. J. Med. Genet.96, 43-48. doi: 10.1002/(SICI)1096-8628(20000207)96:1<43::AID-AJMG9>3.0.CO;2-3
81. Meguro-Horike, M., Yasui, D. H., Powell, W., Schroeder, D. I., Oshimura, M., Lasalle, J. M.,et al. (2011). Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. Hum. Mol. Genet. 20, 3798-3810. doi: 10.1093/hmg/ddr298
82. Mendez, M. A., Horder, J., Myers, J., Coghlan, S., Stokes, P., Erritzoe, D.,et al. (2013). The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study. Neuropharmacology 68, 195-201. doi: 10.1016/j.neuropharm.2012.04.008
83. 2+ channels to synaptic vesicle exocytosis. Nature 423, 939-948. doi: 10.1038/nature01755
84. Moessner, R., Marshall, C. R., Sutcliffe, J. S., Skaug, J., Pinto, D., Vincent, J.,et al. (2007). Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289-1297. doi: 10.1086/522590
85. Mori, T., Mori, K., Fujii, E., Toda, Y., Miyazaki, M., Harada, M.,et al. (2012). Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study. Brain Dev. 34, 648-654. doi: 10.1016/j.braindev.2011.10.007
86. Morrow, E. M., Yoo, S. Y., Flavell, S. W., Kim, T. K., Lin, Y., Hill, R. S.,et al. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218-223. doi: 10.1126/science.1157657
87. Murdoch, J. D., and State, M. W. (2013). Recent developments in the genetics of autism spectrum disorders. Curr. Opin. Genet. Dev. 23, 310-315. doi: 10.1016/j.gde.2013.02.003
88. Nakatani, J., Tamada, K., Hatanaka, F., Ise, S., Ohta, H., Inoue, K.,et al. (2009). Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137, 1235-1246. doi: 10.1016/j.cell.2009.04.024
89. Novarino, G., El-Fishawy, P., Kayserili, H., Meguid, N. A., Scott, E. M., Schroth, J.,et al. (2012). Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338, 394-397. doi: 10.1126/science.1224631
90. O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P.,et al. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246-250. doi: 10.1038/nature10989
91. Oblak, A., Gibbs, T. T., and Blatt, G. J. (2009). Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Autism Res. 2, 205-219. doi: 10.1002/aur.88
92. Oblak, A., Gibbs, T. T., and Blatt, G. J. (2013). Reduced serotonin receptor subtypes in a limbic and a neocortical region in autism. Autism Res. 6, 571-583. doi: 10.1002/aur.1317
93. Oblak, A. L., Gibbs, T. T., and Blatt, G. J. (2011). Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 1380, 218-228. doi: 10.1016/j.brainres.2010.09.021
94. Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N.,et al. (2011). Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437-442. doi: 10.1038/nature09965
95. Peñagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H.,et al. (2011). Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235-246. doi: 10.1016/j.cell.2011.08.040
96. Phelan, M. C. (2008). Deletion 22q13.3 syndrome. Orphanet J. Rare Dis. 3:14. doi: 10.1186/1750-1172-3-14
97. Pinto, D. A., Pagnamenta, T., Klei, L., Anney, R., Merico, D., Regan, R.,et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368-372. doi: 10.1038/nature09146
98. Posey, D. J., Kem, D. L., Swiezy, N. B., Sweeten, T. L., Wiegand, R. E., and McDougle, C. J. (2004). A pilot study of D-cycloserine in subjects with autistic disorder. Am. J. Psychiatry 161, 2115-2117. doi: 10.1176/appi.ajp.161.11.2115
99. Poulopoulos, A., Aramuni, G., Meyer, G., Soykan, T., Hoon, M., Papadopoulos, T.,et al. (2009). Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 63, 628-642. doi: 10.1016/j.neuron.2009.08.023
100. Purcell, A. E., Jeon, O. H., Zimmerman, A. W., Blue, M. E., and Pevsner, J. (2001). Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57, 1618-1628. doi: 10.1212/WNL.57.9.1618
101. Ramanathan, S., Woodroffem, A., Flodman, P. L., Mays, L. Z., Hanouni, M., Modahl, C. B.,et al. (2004). A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R. BMC Med. Genet. 5:10. doi: 10.1186/1471-2350-5-10
102. Redies, C., Hertel, N., and Hübner, C. A. (2012). Cadherins and neuropsychiatric disorders. Brain Res. 1470, 130-144. doi: 10.1016/j.brainres.2012.06.020
103. Rice, C. (2012). Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1-19.
104. Roohi, J., Montagna, C., Tegay, D. H., Palmer, L. E., DeVincent, C., Pomeroy, J. C.,et al. (2009). Disruption of contactin 4 in three subjects with autism spectrum disorder. J. Med. Genet. 46, 176-182. doi: 10.1136/jmg.2008.057505
105. Rosahl, T. W., Spillane, D., Missler, M., Herz, J., Selig, D. K., Wolff, J. R.,et al. (1995). Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 375, 488-493. doi: 10.1038/375488a0
106. Sadakata, T., Washida, M., Iwayama, Y., Shoji, S., Sato, Y., Ohkura, T.,et al. (2007). Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J. Clin. Invest. 117, 931-943. doi: 10.1172/JCI29031
107. Sampath, S., Bhat, S., Gupta, S., O'Connor, A., West, A. B., Arking, D. E.,et al. (2013). Defining the contribution of CNTNAP2 to autism susceptibility. PLoS ONE 8:e77906. doi: 10.1371/journal.pone.0077906
108. Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D.,et al. (2011). Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863-885. doi: 10.1016/j.neuron.2011.05.002
109. Sanz-Clemente, A., Nicoll, R. A., and Roche, K. W. (2013). Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist 19, 62-75. doi: 10.1177/1073858411435129
110. Sato, D., Lionel, A. C., Leblond, C. S., Prasad, A., Pinto, D., Walker, S.,et al. (2012). SHANK1 deletions in males with autism spectrum disorder. Am. J. Hum. Genet. 90, 879-887. doi: 10.1016/j.ajhg.2012.03.017
111. Saunders, J. A., Tatard-Leitman, V. M., Suh, J., Billingslea, E. N., Roberts, T. P., and Siegel, S. J. (2013). Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes. Autism Res. 6, 69-77. doi: 10.1002/aur.1264
112. Schmeisser, M. J., Ey, E., Wegener, S., Bockmann, J., Stempel, A. V., Kuebler, A.,et al. (2012). Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256-260. doi: 10.1038/nature11015
113. Schnell, E., Bensen, A. L., Washburn, E. K., and Westbrook, G. L. (2012). Neuroligin-1 overexpression in newborn granule cells in vivo. PLoS ONE 7:e48045. doi: 10.1371/journal.pone.0048045
114. Sheng, M., and Kim, E. (2000). The Shank family of scaffold proteins. J. Cell Sci. 113(Pt 11), 1851-1856.
115. Silverman, J. L., Turner, S. M., Barkan, C. L., Tolu, S. S., Saxena, R., Hung, A. Y.,et al. (2011). Sociability and motor functions in Shank1 mutant mice. Brain Res. 1380, 120-137. doi: 10.1016/j.brainres.2010.09.026
116. Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., and Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J. Am. Acad. Child Adolesc. Psychiatry 47, 921-929. doi: 10.1097/CHI.0b013e318179964f
117. Stein, M. B., Yang, B. Z., Chavira, D. A., Hitchcock, C. A., Sung, S. C., Shipon-Blum, E.,et al. (2011). A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-related traits. Biol. Psychiatry 69, 825-831. doi: 10.1016/j.biopsych.2010.11.008
118. Strauss, K. A., Puffenberger, E. G., Huentelman, M. J., Gottlieb, S., Dobrin, S. E., Parod, J. M.,et al. (2006). Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N. Engl. J. Med. 354, 1370-1377. doi: 10.1056/NEJMoa052773
119. Sundaram, S. K., Huq, A. M., Wilson, B. J., and Chugani, H. T. (2010). Tourette syndrome is associated with recurrent exonic copy number variants. Neurology 74, 1583-1590. doi: 10.1212/WNL.0b013e3181e0f147
120. Tabuchi, K., Blundell, J., Etherton, M. R., Hammer, R. E., Liu, X., Powell, C. M.,et al. (2007). A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71-76. doi: 10.1126/science.1146221
121. Tabuchi, K., and Sudhof, T. C. (2002). Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. Genomics 79, 849-859. doi: 10.1006/geno.2002.6780
122. Talebizadeh, Z., Bittel, D. C., Veatch, O. J., Butler, M. G., Takahashi, T. N., and Miles, J. H. (2004). Do known mutations in neuroligin genes (NLGN3 and NLGN4) cause autism? J. Autism Dev. Disord. 34, 735-736. doi: 10.1007/s10803-004-5295-x
123. Tarabeux, J., Kebir, O., Gauthier, J., Hamdan, F. F., Xiong, L., Piton, A.,et al. (2011). Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl. Psychiatry 1:e55. doi: 10.1038/tp.2011.52
124. Vaags, A. K., Lionel, A. C., Sato, D., Goodenberger, M., Stein, Q. P., Curran, S.,et al. (2012). Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am. J. Hum. Genet. 90, 133-141. doi: 10.1016/j.ajhg.2011.11.025
125. Vincent, J. B., Kolozsvari, D., Roberts, W. S., Bolton, P. F., Gurling, H. M., and Scherer, S. W. (2004). Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B, 82-84. doi: 10.1002/ajmg.b.30069
126. Waga, C., Okamoto, N., Ondo, Y., Fukumura-Kato, R., Goto, Y., Kohsaka, S.,et al. (2011). Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development. Psychiatr. Genet. 21, 208-211. doi: 10.1097/YPG.0b013e328341e069
127. Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M.,et al. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539-543. doi: 10.1126/science.1155174
128. Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S.,et al. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528-533. doi: 10.1038/nature07999
129. Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C.,et al. (2011). Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093-3108. doi: 10.1093/hmg/ddr212
130. Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R.,et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667-675. doi: 10.1056/NEJMoa075974
131. Wermter, A. K., Kamp-Becker, I., Strauch, K., Schulte-Körne, G., and Remschmidt, H. (2008). No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 535-537. doi: 10.1002/ajmg.b.30618
132. Wilson, H. L., Crolla, J. A., Walker, D., Artifoni, L., Dallapiccola, B., Takano, T.,et al. (2008). Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development. Eur. J. Hum. Genet. 16, 1301-1310. doi: 10.1038/ejhg.2008.107
133. Wilson, H. L., Wong, A. C., Shaw, S. R., Tse, W. Y., Stapleton, G. A., Phelan, M. C.,et al. (2003). Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J. Med. Genet. 40, 575-584. doi: 10.1136/jmg.40.8.575
134. Wöhr, 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. doi: 10.1371/journal.pone.0020631
135. Won, H., Lee, H. R., Gee, H. Y., Mah, W., Kim, J. I., Lee, J.,et al. (2012). Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261-265. doi: 10.1038/nature11208
136. Yan, J., Oliveira, G., Coutinho, A., Yang, C., Feng, J., Katz, C.,et al. (2005). Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol. Psychiatry 10, 329-332. doi: 10.1038/sj.mp.4001629
137. Yang, M., Bozdagi, O., Scattoni, M. L., Wöhr, M., Roullet, F. I., Katz, A. M.,et al. (2012). Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J. Neurosci. 32, 6525-6541. doi: 10.1523/JNEUROSCI.6107-11.2012
138. Yip, J., Soghomonian, J. J., and Blatt, G. J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 113, 559-568. doi: 10.1007/s00401-006-0176-3
139. Yoo, H. J., Cho, I. H., Park, M., Yang, S. Y., and Kim, S. A. (2012). Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders. Neurosci. Lett. 512, 89-93. doi: 10.1016/j.neulet.2012.01.061
140. Yoo, J., Bakes, J., Bradley, C., Collingridge, G. L., and Kaang, B. K. (2014). Shank mutant mice as an animal model of autism. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369:20130143. doi: 10.1098/rstb.2013.0143
141. Zhang, D., Cheng, L., Qian, Y., Alliey-Rodriguez, N., Kelsoe, J. R., Greenwood, T.,et al. (2009). Singleton deletions throughout the genome increase risk of bipolar disorder. Mol. Psychiatry 14, 376-380. doi: 10.1038/mp.2008.144
142. Zuko, A., Kleijer, K. T., Oguro-Ando, A., Kas, M. J., van Daalen, E., van der Zwaag, B.,et al. (2013). Contactins in the neurobiology of autism. Eur. J. Pharmacol. 719, 63-74. doi: 10.1016/j.ejphar.2013.07.016