Autism spectrum disorder (ASD) is defined by impaired social interaction and communication accompanied by stereotyped behaviors and restricted interests. Although ASD is common, its genetic and clinical features are highly heterogeneous. A number of recent breakthroughs have dramatically advanced our understanding of ASD from the standpoint of human genetics and neuropathology. These studies highlight the period of fetal development and the processes of chromatin structure, synaptic function, and neuron-glial signaling. The initial efforts to systematically integrate findings of multiple levels of genomic data and studies of mouse models have yielded new clues regarding ASD pathophysiology. This early work points to an emerging convergence of disease mechanisms in this complex and etiologically heterogeneous disorder.


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Literature Cited

  1. 1. Am. Psychiatr. Assoc. 2013. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: Am. Psychiatr. Publ, 5th. ed. [Google Scholar]
  2. 2. Autism Dev. Disabil. Monit. Netw. Surveill. Year 2010 Princ. Investig 2014. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morb. Mortal. Wkly. Rep. 63:1–21 [Google Scholar]
  3. Kanner L. 3.  1943. Autistic disturbances of affective contact. Nervous Child 2:217–50 [Google Scholar]
  4. Lord C, Petkova E, Hus V, Gan W, Lu F. 4.  et al. 2012. A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch. Gen. Psychiatry 69:306–13 [Google Scholar]
  5. McCracken JT, McGough J, Shah B, Cronin P, Hong D. 5.  et al. 2002. Risperidone in children with autism and serious behavioral problems. N. Engl. J. Med. 347:314–21 [Google Scholar]
  6. Wing L. 6.  2000. Past and future of research on Asperger syndrome. Asperger Syndrome A Klin, FR Volkmar, SS Sparrow 418–32 New York: Guilford [Google Scholar]
  7. Kolevzon A, Smith CJ, Schmeidler J, Buxbaum JD, Silverman JM. 7.  2004. Familial symptom domains in monozygotic siblings with autism. Am. J. Med. Genet. B 129B:76–81 [Google Scholar]
  8. Daniels A, Rosenberg R, Law JK, Lord C, Kaufmann W, Law P. 8.  2011. Stability of initial autism spectrum disorder diagnoses in community settings. J. Autism Dev. Disord. 41:110–21 [Google Scholar]
  9. Berg J, Geschwind D. 9.  2012. Autism genetics: searching for specificity and convergence. Genome Biol. 13:1–16 [Google Scholar]
  10. Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK. 10.  et al. 2007. The epidemiology of autism spectrum disorders. Annu. Rev. Public Health 28:235–58 [Google Scholar]
  11. Christensen J, Grønborg T, Sørensen M, Schendel D, Parner ET. 11.  et al. 2013. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309:1696–703 [Google Scholar]
  12. Lowe TL, Tanaka K, Seashore MR, Young J, Cohen DJ. 12.  1980. Detection of phenylketonuria in autistic and psychotic children. JAMA 243:126–28 [Google Scholar]
  13. Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM. 13.  et al. 2012. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338:394–97 [Google Scholar]
  14. Abrahams BS, Geschwind DH. 14.  2008. Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9:341–55 [Google Scholar]
  15. Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE. 15.  et al. 2006. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N. Engl. J. Med. 354:1370–77 [Google Scholar]
  16. Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L. 16.  et al. 2014. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 46:380–84 [Google Scholar]
  17. Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N. 17.  et al. 2011. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 128:e488–95 [Google Scholar]
  18. Rosenberg RE, Law J, Yenokyan G, McGready J, Kaufmann WE, Law PA. 18.  2009. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch. Pediatr. Adolesc. Med. 163:907–14 [Google Scholar]
  19. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B. 19.  et al. 2011. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68:1095–102 [Google Scholar]
  20. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E. 20.  et al. 1995. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25:63–77 [Google Scholar]
  21. Wang K, Zhang H, Ma D, Bucan M, Glessner JT. 21.  et al. 2009. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–33 [Google Scholar]
  22. Ma D, Salyakina D, Jaworski JM, Konidari I, Whitehead PL. 22.  et al. 2009. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73:263–73 [Google Scholar]
  23. Weiss LA, Arking DE. 23.  Gene Discov. Proj. Johns Hopkins, Autism Consort 2009. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802–8 [Google Scholar]
  24. Anney R, Klei L, Pinto D, Almeida J, Bacchelli E. 24.  et al. 2012. Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum. Mol. Genet. 21:4781–92 [Google Scholar]
  25. Anney R, Klei L, Pinto D, Regan R, Conroy J. 25.  et al. 2010. A genome-wide scan for common alleles affecting risk for autism. Hum. Mol. Genet. 19:4072–82 [Google Scholar]
  26. Klei L, Sanders S, Murtha M, Hus V, Lowe J. 26.  et al. 2012. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3:9 [Google Scholar]
  27. Stein JL, Parikshak NN, Geschwind DH. 27.  2013. Rare inherited variation in autism: beginning to see the forest and a few trees. Neuron 77:209–11 [Google Scholar]
  28. 28. Cross-Disord. Group Psychiatr. Genomics Consort 2013. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45:984–94 [Google Scholar]
  29. Curran S, Bolton P, Rozsnyai K, Chiocchetti A, Klauck SM. 29.  et al. 2011. No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder. Am. J. Med. Genet. B 156:633–39 [Google Scholar]
  30. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C. 30.  et al. 2010. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42:579–89 [Google Scholar]
  31. Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kahler AK. 31.  et al. 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45:1150–59 [Google Scholar]
  32. Stone JL, Merriman B, Cantor RM, Geschwind DH, Nelson SF. 32.  2007. High density SNP association study of a major autism linkage region on chromosome 17. Hum. Mol. Genet. 16:704–15 [Google Scholar]
  33. Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV. 33.  et al. 2008. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82:150–59 [Google Scholar]
  34. Strom SP, Stone JL, Ten Bosch JR, Merriman B, Cantor RM. 34.  et al. 2010. High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Mol. Psychiatry 15:996–1005 [Google Scholar]
  35. Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH. 35.  et al. 2007. A unified genetic theory for sporadic and inherited autism. PNAS 104:12831–36 [Google Scholar]
  36. Kenny EM, Cormican P, Furlong S, Heron E, Kenny G. 36.  et al. 2014. Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol. Psychiatry 19:872–79 [Google Scholar]
  37. Cukier H, Dueker N, Slifer S, Lee J, Whitehead P. 37.  et al. 2014. Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. Mol. Autism 5:1 [Google Scholar]
  38. Toma C, Torrico B, Hervas A, Valdes-Mas R, Tristan-Noguero A. 38.  et al. 2014. Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Mol. Psychiatry 19:784–90 [Google Scholar]
  39. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y. 39.  et al. 2008. Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218–23 [Google Scholar]
  40. Nava C, Lamari F, Heron D, Mignot C, Rastetter A. 40.  et al. 2012. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl. Psychiatry 2:e179 [Google Scholar]
  41. Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K. 41.  et al. 2013. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77:259–73 [Google Scholar]
  42. Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A. 42.  et al. 2013. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 77:235–42 [Google Scholar]
  43. Vissers LELM, de Ligt J, Gilissen C, Janssen I, Steehouwer M. 43.  et al. 2010. A de novo paradigm for mental retardation. Nat. Genet. 42:1109–12 [Google Scholar]
  44. Fischbach GD, Lord C. 44.  2010. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68:192–95 [Google Scholar]
  45. Bundey S, Hardy C, Vickers S, Kilpatrick M, Corbett J. 45.  1994. Duplication of the 15q1113 region in a patient with autism, epilepsy and ataxia. Dev. Med. Child Neurol. 36:736–42 [Google Scholar]
  46. Kozma C. 46.  1998. On cognitive variability in velocardiofacial syndrome: profound mental retardation and autism. Am. J. Med. Genet. 81:269–70 [Google Scholar]
  47. Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR. 47.  1999. Xp deletions associated with autism in three females. Hum. Genet. 104:43–48 [Google Scholar]
  48. Lauritsen M, Mors O, Mortensen P, Ewald H. 48.  1999. Infantile autism and associated autosomal chromosome abnormalities: a register based study and a literature survey. J. Child Psychol. Psychiatry 40:335–45 [Google Scholar]
  49. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C. 49.  et al. 2003. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34:27–29 [Google Scholar]
  50. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P. 50.  et al. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39:25–27 [Google Scholar]
  51. Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A. 51.  et al. 2011. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70:886–97 [Google Scholar]
  52. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J. 52.  et al. 2007. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39:319–28 [Google Scholar]
  53. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT. 53.  et al. 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863–85 [Google Scholar]
  54. Itsara A, Wu H, Smith JD, Nickerson DA, Romieu I. 54.  et al. 2010. De novo rates and selection of large copy number variation. Genome Res. 20:1469–81 [Google Scholar]
  55. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C. 55.  et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:445–49 [Google Scholar]
  56. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D. 56.  et al. 2010. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–72 [Google Scholar]
  57. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L. 57.  et al. 2008. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82:477–88 [Google Scholar]
  58. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ. 58.  et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–41 [Google Scholar]
  59. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT. 59.  et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358:667–75 [Google Scholar]
  60. Sun JX, Helgason A, Masson G, Ebenesersdottir SS, Li H. 60.  et al. 2012. A direct characterization of human mutation based on microsatellites. Nat. Genet. 44:1161–65 [Google Scholar]
  61. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P. 61.  et al. 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471–75 [Google Scholar]
  62. Campbell CD, Chong JX, Malig M, Ko A, Dumont BL. 62.  et al. 2012. Estimating the human mutation rate using autozygosity in a founder population. Nat. Genet. 44:1277–81 [Google Scholar]
  63. Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D. 63.  et al. 2012. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151:1431–42 [Google Scholar]
  64. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I. 64.  et al. 2012. De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–99 [Google Scholar]
  65. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N. 65.  et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–50 [Google Scholar]
  66. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE. 66.  et al. 2012. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–45 [Google Scholar]
  67. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB. 67.  et al. 2012. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619–22 [Google Scholar]
  68. Werling D, Lowe J, Luo R, Cantor R, Geschwind D. 68.  2014. Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder. Mol. Autism 5:13 [Google Scholar]
  69. Martin-Ruiz CM, Lee M, Perry RH, Baumann M, Court JA, Perry EK. 69.  2004. Molecular analysis of nicotinic receptor expression in autism. Mol. Brain Res. 123:81–90 [Google Scholar]
  70. Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Reutiman TJ. 70.  et al. 2005. Reelin signaling is impaired in autism. Biol. Psychiatry 57:777–87 [Google Scholar]
  71. Purcell A, Jeon O, Zimmerman A, Blue M, Pevsner J. 71.  2001. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57:1618–28 [Google Scholar]
  72. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y. 72.  et al. 2011. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380–84 [Google Scholar]
  73. Zikopoulos B, Barbas H. 73.  2010. Changes in prefrontal axons may disrupt the network in autism. J. Neurosci. 30:14595–609 [Google Scholar]
  74. Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B. 74.  et al. 2008. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol. Dis. 30:303–11 [Google Scholar]
  75. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. 75.  2002. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol. Psychiatry 52:805–10 [Google Scholar]
  76. Yip J, Soghomonian JJ, Blatt G. 76.  2007. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 113:559–68 [Google Scholar]
  77. Laurence JA, Fatemi SH. 77.  2005. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 4:206–10 [Google Scholar]
  78. Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR. 78.  et al. 2012. Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLOS Genet. 8:e1002592 [Google Scholar]
  79. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C. 79.  et al. 2011. Neuron number and size in prefrontal cortex of children with autism. JAMA 306:2001–10 [Google Scholar]
  80. Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C. 80.  et al. 2012. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum. Mol. Genet. 21:4171–86 [Google Scholar]
  81. Eran A, Li JB, Vatalaro K, McCarthy J, Rahimov F. 81.  et al. 2013. Comparative RNA editing in autistic and neurotypical cerebella. Mol. Psychiatry 18:1041–48 [Google Scholar]
  82. Schain RJ, Yannet H. 82.  1960. Infantile autism: an analysis of 50 cases and a consideration of certain relevant neurophysiologic concepts. J. Pediatr. 57:560–67 [Google Scholar]
  83. Bauman M, Kemper TL. 83.  1985. Histoanatomic observations of the brain in early infantile autism. Neurology 35:866–66 [Google Scholar]
  84. Kemper TL, Bauman ML. 84.  1993. The contribution of neuropathologic studies to the understanding of autism. Neurol. Clin. 11:175–87 [Google Scholar]
  85. Simms M, Kemper T, Timbie C, Bauman M, Blatt G. 85.  2009. The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups. Acta Neuropathol. 118:673–84 [Google Scholar]
  86. Bailey A, Luthert P, Dean A, Harding B, Janota I. 86.  et al. 1998. A clinicopathological study of autism. Brain 121:889–905 [Google Scholar]
  87. Schumann CM, Amaral DG. 87.  2006. Stereological analysis of amygdala neuron number in autism. J. Neurosci. 26:7674–79 [Google Scholar]
  88. Raymond GV, Bauman ML, Kemper TL. 88.  1995. Hippocampus in autism: a Golgi analysis. Acta Neuropathol. 91:117–19 [Google Scholar]
  89. Lawrence YA, Kemper TL, Bauman ML, Blatt GJ. 89.  2010. Parvalbumin-, calbindin-, and calretinin-immunoreactive hippocampal interneuron density in autism. Acta Neurol. Scand. 121:99–108 [Google Scholar]
  90. Wegiel J, Kuchna I, Nowicki K, Imaki H, Wegiel J. 90.  et al. 2010. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 119:755–70 [Google Scholar]
  91. Rutishauser U, Tudusciuc O, Wang S, Mamelak AN, Ross IB, Adolphs R. 91.  2013. Single-neuron correlates of atypical face processing in autism. Neuron 80:887–99 [Google Scholar]
  92. Haznedar MM, Buchsbaum MS, Wei TC, Hof PR, Cartwright C. 92.  et al. 2000. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am. J. Psychiatry 157:1994–2001 [Google Scholar]
  93. Fatemi SH, Aldinger K, Ashwood P, Bauman M, Blaha C. 93.  et al. 2012. Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11:777–807 [Google Scholar]
  94. Whitney E, Kemper T, Bauman M, Rosene D, Blatt G. 94.  2008. Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum 7:406–16 [Google Scholar]
  95. Kemper TL, Bauman M. 95.  1998. Neuropathology of infantile autism. J. Neuropathol. Exp. Neurol. 57:645–52 [Google Scholar]
  96. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. 96.  2005. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57:67–81 [Google Scholar]
  97. Sajdel-Sulkowska E, Xu M, Koibuchi N. 97.  2009. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum 8:366–72 [Google Scholar]
  98. Sheikh AM, Li X, Wen G, Tauqeer Z, Brown WT, Malik M. 98.  2010. Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects. Neuroscience 165:363–70 [Google Scholar]
  99. Whitney ER, Kemper TL, Rosene DL, Bauman ML, Blatt GJ. 99.  2009. Density of cerebellar basket and stellate cells in autism: evidence for a late developmental loss of Purkinje cells. J. Neurosci. Res. 87:2245–54 [Google Scholar]
  100. Fournier K, Hass C, Naik S, Lodha N, Cauraugh J. 100.  2010. Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. J. Autism Dev. Disord. 40:1227–40 [Google Scholar]
  101. Strick PL, Dum RP, Fiez JA. 101.  2009. Cerebellum and nonmotor function. Annu. Rev. Neurosci. 32:413–34 [Google Scholar]
  102. Courchesne E, Townsend J, Akshoomoff NA, Saitoh O, Yeung-Courchesne R. 102.  et al. 1994. Impairment in shifting attention in autistic and cerebellar patients. Behav. Neurosci. 108:848–65 [Google Scholar]
  103. Coleman P, Romano J, Lapham L, Simon W. 103.  1985. Cell counts in cerebral cortex of an autistic patient. J. Autism Dev. Disord. 15:245–55 [Google Scholar]
  104. Guerin P, Lyon G, Barthelemy C, Sostak E, Chevrollier V. 104.  et al. 1996. Neuropathological study of a case of autistic syndrome with severe mental retardation. Dev. Med. Child Neurol. 38:203–11 [Google Scholar]
  105. Hutsler JJ, Love T, Zhang H. 105.  2007. Histological and magnetic resonance imaging assessment of cortical layering and thickness in autism spectrum disorders. Biol. Psychiatry 61:449–57 [Google Scholar]
  106. Oblak AL, Rosene DL, Kemper TL, Bauman ML, Blatt GJ. 106.  2011. Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism. Autism Res. 4:200–11 [Google Scholar]
  107. van Kooten IAJ, Palmen SJMC, von Cappeln P, Steinbusch HWM, Korr H. 107.  et al. 2008. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 131:987–99 [Google Scholar]
  108. Uppal N, Gianatiempo I, Wicinski B, Schmeidler J, Heinsen H. 108.  et al. 2014. Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism. Mol. Autism 5:17 [Google Scholar]
  109. Mukaetova-Ladinska EB, Arnold H, Jaros E, Perry R, Perry E. 109.  2004. Depletion of MAP2 expression and laminar cytoarchitectonic changes in dorsolateral prefrontal cortex in adult autistic individuals. Neuropathol. Appl. Neurobiol. 30:615–23 [Google Scholar]
  110. Casanova MF, Buxhoeveden DP, Switala AE, Roy E. 110.  2002. Minicolumnar pathology in autism. Neurology 58:428–32 [Google Scholar]
  111. Buxhoeveden DP, Semendeferi K, Buckwalter J, Schenker N, Switzer R, Courchesne E. 111.  2006. Reduced minicolumns in the frontal cortex of patients with autism. Neuropathol. Appl. Neurobiol. 32:483–91 [Google Scholar]
  112. Casanova MF, El-Baz A, Vanbogaert E, Narahari P, Switala A. 112.  2010. A topographic study of minicolumnar core width by lamina comparison between autistic subjects and controls: possible minicolumnar disruption due to an anatomical element in-common to multiple laminae. Brain Pathol. 20:451–58 [Google Scholar]
  113. Hutsler JJ, Zhang H. 113.  2010. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 1309:83–94 [Google Scholar]
  114. Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR. 114.  et al. 2014. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370:1209–19 [Google Scholar]
  115. Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K. 115.  et al. 2010. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry 68:368–76 [Google Scholar]
  116. Tetreault N, Hakeem A, Jiang S, Williams B, Allman E. 116.  et al. 2012. Microglia in the cerebral cortex in autism. J. Autism Dev. Disord. 42:2569–84 [Google Scholar]
  117. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M. 117.  et al. 2013. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70:49–58 [Google Scholar]
  118. Rodriguez JI, Kern JK. 118.  2011. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol. 7:205–13 [Google Scholar]
  119. Bailey A, Luthert P, Bolton P, Le Couteur A, Rutter M, Harding B. 119.  1993. Autism and megalencephaly. Lancet 341:1225–26 [Google Scholar]
  120. Lainhart JE, Piven J, Wzorek M, Landa R, Santangelo SL. 120.  et al. 1997. Macrocephaly in children and adults with autism. J. Am. Acad. Child Adolesc. Psychiatry 36:282–90 [Google Scholar]
  121. Aylward EH, Minshew N, Field K, Sparks B, Singh N. 121.  2002. Effects of age on brain volume and head circumference in autism. Neurology 59:175–83 [Google Scholar]
  122. Courchesne E, Carper R, Akshoomoff N. 122.  2003. Evidence of brain overgrowth in the first year of life in autism. JAMA 290:337–44 [Google Scholar]
  123. Vanderver A, Tonduti D, Kahn I, Schmidt J, Medne L. 123.  et al. 2014. Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations. Am. J. Med. Genet. A 164:627–33 [Google Scholar]
  124. Courchesne E, Müller RA, Saitoh O. 124.  1999. Brain weight in autism: normal in the majority of cases, megalencephalic in rare cases. Neurology 52:1057–59 [Google Scholar]
  125. Piven J, Arndt S, Bailey J, Havercamp S, Andreasen NC, Palmer P. 125.  1995. An MRI study of brain size in autism. Am. J. Psychiatry 152:1145–49 [Google Scholar]
  126. Hardan AY, Minshew NJ, Mallikarjuhn M, Keshavan MS. 126.  2001. Brain volume in autism. J. Child Neurol. 16:421–24 [Google Scholar]
  127. Hazlett HC, Poe MD, Gerig G, Smith RG, Piven J. 127.  2006. Cortical gray and white brain tissue volume in adolescents and adults with autism. Biol. Psychiatry 59:1–6 [Google Scholar]
  128. Freitag CM, Luders E, Hulst HE, Narr KL, Thompson PM. 128.  et al. 2009. Total brain volume and corpus callosum size in medication-naïve adolescents and young adults with autism spectrum disorder. Biol. Psychiatry 66:316–19 [Google Scholar]
  129. Courchesne E, Karns C, Davis H, Ziccardi R, Carper R. 129.  et al. 2001. Unusual brain growth patterns in early life in patients with autistic disorder an MRI study. Neurology 57:245–54 [Google Scholar]
  130. Redcay E, Courchesne E. 130.  2005. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol. Psychiatry 58:1–9 [Google Scholar]
  131. Hazlett H, Poe M, Gerig G, Smith RG, Provenzale J. 131.  et al. 2005. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch. Gen. Psychiatry 62:1366–76 [Google Scholar]
  132. Carper RA, Courchesne E. 132.  2005. Localized enlargement of the frontal cortex in early autism. Biol. Psychiatry 57:126–33 [Google Scholar]
  133. Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM. 133.  2008. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur. Psychiatry 23:289–99 [Google Scholar]
  134. Rojas D, Peterson E, Winterrowd E, Reite M, Rogers S, Tregellas J. 134.  2006. Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiatry 6:1–13 [Google Scholar]
  135. Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H. 135.  et al. 2004. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J. Neurosci. 24:6392–401 [Google Scholar]
  136. Courchesne E, Yeung-Courchesne R, Hesselink JR, Jernigan TL. 136.  1988. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N. Engl. J. Med. 318:1349–54 [Google Scholar]
  137. Just MA, Cherkassky VL, Keller TA, Kana RK, Minshew NJ. 137.  2007. Functional and anatomical cortical underconnectivity in autism: evidence from an fMRI study of an executive function task and corpus callosum morphometry. Cereb. Cortex 17:951–61 [Google Scholar]
  138. Nickl-Jockschat T, Habel U, Michel TM, Manning J, Laird AR. 138.  et al. 2012. Brain structure anomalies in autism spectrum disorder—a meta-analysis of VBM studies using anatomic likelihood estimation. Hum. Brain Mapp. 33:1470–89 [Google Scholar]
  139. McAlonan GM, Cheung V, Cheung C, Suckling J, Lam GY. 139.  et al. 2005. Mapping the brain in autism. A voxel-based MRI study of volumetric differences and intercorrelations in autism. Brain 128:268–76 [Google Scholar]
  140. Yachnis AT, Rorke LB. 140.  1999. Neuropathology of Joubert syndrome. J. Child Neurol. 14:655–59 [Google Scholar]
  141. Armstrong DD. 141.  2002. Neuropathology of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 8:72–76 [Google Scholar]
  142. Mizuguchi M, Takashima S. 142.  2001. Neuropathology of tuberous sclerosis. Brain Dev. 23:508–15 [Google Scholar]
  143. Chadman KK, Yang M, Crawley JN. 143.  2009. Criteria for validating mouse models of psychiatric diseases. Am. J. Med. Genet. B 150B:1–11 [Google Scholar]
  144. Nestler EJ, Hyman SE. 144.  2010. Animal models of neuropsychiatric disorders. Nat. Neurosci. 13:1161–69 [Google Scholar]
  145. Crawley JN. 145.  2007. Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol. 17:448–59 [Google Scholar]
  146. Peñagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A. 146.  et al. 2011. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147:235–46 [Google Scholar]
  147. Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV. 147.  et al. 2012. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486:256–60 [Google Scholar]
  148. Peca J, Feliciano C, Ting JT, Wang W, Wells MF. 148.  et al. 2011. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–42 [Google Scholar]
  149. Smith SE, Zhou YD, Zhang G, Jin Z, Stoppel DC, Anderson MP. 149.  2011. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci. Transl. Med. 3:103ra97 [Google Scholar]
  150. Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP. 150.  et al. 2007. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav. Brain Res. 176:4–20 [Google Scholar]
  151. Wagner G, Reuhl K, Cheh M, McRae P, Halladay A. 151.  2006. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J. Autism Dev. Disord. 36:779–93 [Google Scholar]
  152. Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, Croen LA. 152.  2013. Maternal infection during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. In press. doi: 10.1007/s10803-013-2016-3 [Google Scholar]
  153. Harris KM. 153.  1999. Structure, development, and plasticity of dendritic spines. Curr. Opin. Neurobiol. 9:343–48 [Google Scholar]
  154. Zoghbi HY. 154.  2003. Postnatal neurodevelopmental disorders: meeting at the synapse?. Science 302:826–30 [Google Scholar]
  155. Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S. 155.  et al. 2008. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. PNAS 105:1710–15 [Google Scholar]
  156. Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X. 156.  et al. 2007. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76 [Google Scholar]
  157. Etherton M, Foldy C, Sharma M, Tabuchi K, Liu X. 157.  et al. 2011. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. PNAS 108:13764–69 [Google Scholar]
  158. Phelan K, McDermid HE. 158.  2012. The 22q13.3 deletion syndrome (Phelan–McDermid syndrome). Mol. Syndromol. 2:186–201 [Google Scholar]
  159. Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, Sonnenblick LI, Rudie JD. 159.  et al. 2010. Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Sci. Transl. Med. 2:56ra80 [Google Scholar]
  160. Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL. 160.  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 [Google Scholar]
  161. Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS. 161.  et al. 2011. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20:3093–108 [Google Scholar]
  162. Won H, Lee HR, Gee HY, Mah W, Kim JI. 162.  et al. 2012. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486:261–65 [Google Scholar]
  163. Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B. 163.  et al. 2003. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J. Cell Biol. 162:1149–60 [Google Scholar]
  164. Huber KM, Gallagher SM, Warren ST, Bear MF. 164.  2002. Altered synaptic plasticity in a mouse model of fragile X mental retardation. PNAS 99:7746–50 [Google Scholar]
  165. Bear MF, Huber KM, Warren ST. 165.  2004. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27:370–77 [Google Scholar]
  166. Nosyreva ED, Huber KM. 166.  2006. Metabotropic receptor–dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J. Neurophysiol. 95:3291–95 [Google Scholar]
  167. Irwin SA, Galvez R, Greenough WT. 167.  2000. Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb. Cortex 10:1038–44 [Google Scholar]
  168. Dolen G, Osterweil E, Rao BS, Smith GB, Auerbach BD. 168.  et al. 2007. Correction of fragile X syndrome in mice. Neuron 56:955–62 [Google Scholar]
  169. El Idrissi A, Ding XH, Scalia J, Trenkner E, Brown WT, Dobkin C. 169.  2005. Decreased GABAA receptor expression in the seizure-prone fragile X mouse. Neurosci. Lett. 377:141–46 [Google Scholar]
  170. D'Hulst C, De Geest N, Reeve SP, Van Dam D, De Deyn PP. 170.  et al. 2006. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 1121:238–45 [Google Scholar]
  171. Selby L, Zhang C, Sun QQ. 171.  2007. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci. Lett. 412:227–32 [Google Scholar]
  172. Sadakata T, Furuichi T. 172.  2009. Developmentally regulated Ca2+-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion and is associated with autism susceptibility. Cerebellum 8:312–22 [Google Scholar]
  173. Gharani N, Benayed R, Mancuso V, Brzustowicz LM, Millonig JH. 173.  2004. Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Mol. Psychiatry 9:474–84 [Google Scholar]
  174. Kuemerle B, Zanjani H, Joyner A, Herrup K. 174.  1997. Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. J. Neurosci. 17:7881–89 [Google Scholar]
  175. Sgado P, Genovesi S, Kalinovsky A, Zunino G, Macchi F. 175.  et al. 2013. Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: implications for autism spectrum disorders. Exp. Neurol. 247:496–505 [Google Scholar]
  176. Stiles BL. 176.  2009. Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. Int. J. Biochem. Cell Biol. 41:757–61 [Google Scholar]
  177. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA. 177.  et al. 2006. Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377–88 [Google Scholar]
  178. Zhou J, Blundell J, Ogawa S, Kwon CH, Zhang W. 178.  et al. 2009. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29:1773–83 [Google Scholar]
  179. Luikart BW, Schnell E, Washburn EK, Bensen AL, Tovar KR, Westbrook GL. 179.  2011. Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J. Neurosci. 31:4345–54 [Google Scholar]
  180. Haws ME, Jaramillo TC, Espinosa F, Widman AJ, Stuber GD. 180.  et al. 2014. PTEN knockdown alters dendritic spine/protrusion morphology, not density. J. Comp. Neurol. 522:1171–90 [Google Scholar]
  181. Eluvathingal TJ, Behen ME, Chugani HT, Janisse J, Bernardi B. 181.  et al. 2006. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J. Child Neurol. 21:846–51 [Google Scholar]
  182. Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR. 182.  et al. 2012. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647–51 [Google Scholar]
  183. Reith RM, McKenna J, Wu H, Hashmi SS, Cho SH. 183.  et al. 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 [Google Scholar]
  184. Auerbach BD, Osterweil EK, Bear MF. 184.  2011. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480:63–68 [Google Scholar]
  185. Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C. 185.  et al. 2012. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149:525–37 [Google Scholar]
  186. Wang IT, Allen M, Goffin D, Zhu X, Fairless AH. 186.  et al. 2012. Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. PNAS 109:21516–21 [Google Scholar]
  187. Anderson GM, Horne WC, Chatterjee D, Cohen DJ. 187.  1990. The hyperserotonemia of autism. Ann. N.Y. Acad. Sci. 600:331–40 discussion 41–42 [Google Scholar]
  188. Cook EH, Leventhal BL. 188.  1996. The serotonin system in autism. Curr. Opin. Pediatr. 8:348–54 [Google Scholar]
  189. Azmitia EC. 189.  2007. Serotonin and brain: evolution, neuroplasticity, and homeostasis. Int. Rev. Neurobiol. 77:31–56 [Google Scholar]
  190. Kim SJ, Cox N, Courchesne R, Lord C, Corsello C. 190.  et al. 2002. Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Mol. Psychiatry 7:278–88 [Google Scholar]
  191. Conroy J, Meally E, Kearney G, Fitzgerald M, Gill M, Gallagher L. 191.  2004. Serotonin transporter gene and autism: a haplotype analysis in an Irish autistic population. Mol. Psychiatry 9:587–93 [Google Scholar]
  192. Cohen IL, Liu X, Schutz C, White BN, Jenkins EC. 192.  et al. 2003. Association of autism severity with a monoamine oxidase A functional polymorphism. Clin. Genet. 64:190–97 [Google Scholar]
  193. Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA. 193.  et al. 2003. Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter–deficient mice. Biol. Psychiatry 54:960–71 [Google Scholar]
  194. Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA. 194.  et al. 2012. Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. PNAS 109:5469–74 [Google Scholar]
  195. Bortolato M, Godar SC, Alzghoul L, Zhang J, Darling RD. 195.  et al. 2013. Monoamine oxidase A and A/B knockout mice display autistic-like features. Int. J. Neuropsychopharmacol. 16:869–88 [Google Scholar]
  196. Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ. 196.  et al. 2004. Examination of AVPR1a as an autism susceptibility gene. Mol. Psychiatry 9:968–72 [Google Scholar]
  197. Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP. 197.  2008. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol. Psychiatry 13:980–88 [Google Scholar]
  198. Munesue T, Yokoyama S, Nakamura K, Anitha A, Yamada K. 198.  et al. 2010. Two genetic variants of CD38 in subjects with autism spectrum disorder and controls. Neurosci. Res. 67:181–91 [Google Scholar]
  199. Ross HE, Young LJ. 199.  2009. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front. Neuroendocrinol. 30:534–47 [Google Scholar]
  200. Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M. 200.  et al. 2005. Pervasive social deficits, but normal parturition, in oxytocin receptor–deficient mice. PNAS 102:16096–101 [Google Scholar]
  201. Higashida H, Yokoyama S, Munesue T, Kikuchi M, Minabe Y, Lopatina O. 201.  2011. Cd38 gene knockout juvenile mice: a model of oxytocin signal defects in autism. Biol. Pharm. Bull. 34:1369–72 [Google Scholar]
  202. Ferguson JN, Aldag JM, Insel TR, Young LJ. 202.  2001. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J. Neurosci. 21:8278–85 [Google Scholar]
  203. Jin D, Liu HX, Hirai H, Torashima T, Nagai T. 203.  et al. 2007. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446:41–45 [Google Scholar]
  204. Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E. 204.  et al. 2011. Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol. Psychiatry 69:875–82 [Google Scholar]
  205. Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S. 205.  et al. 2007. Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav. Brain Res. 178:123–27 [Google Scholar]
  206. Ring RH. 206.  2011. A complicated picture of oxytocin action in the central nervous system revealed. Biol. Psychiatry 69:818–19 [Google Scholar]
  207. Verkhratsky A. 207.  2010. Physiology of neuronal-glial networking. Neurochem. Int. 57:332–43 [Google Scholar]
  208. Pekny M, Wilhelmsson U, Pekna M. 208.  2014. The dual role of astrocyte activation and reactive gliosis. Neurosci. Lett. 565:30–38 [Google Scholar]
  209. Frick LR, Williams K, Pittenger C. 209.  2013. Microglial dysregulation in psychiatric disease. Clin. Dev. Immunol. 2013:608654 [Google Scholar]
  210. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G. 210.  et al. 2014. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17:400–6 [Google Scholar]
  211. Geschwind DH. 211.  2008. Autism: many genes, common pathways?. Cell 135:391–95 [Google Scholar]
  212. Geschwind DH, Konopka G. 212.  2009. Neuroscience in the era of functional genomics and systems biology. Nature 461:908–15 [Google Scholar]
  213. Ben-David E, Shifman S. 213.  2012. Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLOS Genet. 8:e1002556 [Google Scholar]
  214. Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D. 214.  2011. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70:898–907 [Google Scholar]
  215. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT. 215.  et al. 2013. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155:997–1007 [Google Scholar]
  216. Parikshak NN, Luo R, Zhang A, Won H, Lowe JK. 216.  et al. 2013. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155:1008–21 [Google Scholar]
  217. Steinberg J, Webber C. 217.  2013. The roles of FMRP-regulated genes in autism spectrum disorder: single- and multiple-hit genetic etiologies. Am. J. Hum. Genet. 93:825–39 [Google Scholar]
  218. Dolmetsch R, Geschwind DH. 218.  2011. The human brain in a dish: the promise of iPSC-derived neurons. Cell 145:831–34 [Google Scholar]
  219. Geschwind DH, Levitt P. 219.  2007. Autism spectrum disorders: developmental disconnection syndromes. Curr. Opin. Neurobiol. 17:103–11 [Google Scholar]
  220. Courchesne E, Pierce K. 220.  2005. Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr. Opin. Neurobiol. 15:225–30 [Google Scholar]
  221. Casanova M, Kooten IJ, Switala A, Engeland H, Heinsen H. 221.  et al. 2006. Minicolumnar abnormalities in autism. Acta Neuropathol. 112:287–303 [Google Scholar]
  222. Assaf M, Jagannathan K, Calhoun VD, Miller L, Stevens MC. 222.  et al. 2010. Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder patients. NeuroImage 53:247–56 [Google Scholar]
  223. Koshino H, Carpenter PA, Minshew NJ, Cherkassky VL, Keller TA, Just MA. 223.  2005. Functional connectivity in an fMRI working memory task in high-functioning autism. NeuroImage 24:810–21 [Google Scholar]
  224. Just MA, Keller TA, Malave VL, Kana RK, Varma S. 224.  2012. Autism as a neural systems disorder: a theory of frontal-posterior underconnectivity. Neurosci. Biobehav. Rev. 36:1292–313 [Google Scholar]
  225. Kleinhans NM, Richards T, Sterling L, Stegbauer KC, Mahurin R. 225.  et al. 2008. Abnormal functional connectivity in autism spectrum disorders during face processing. Brain 131:1000–12 [Google Scholar]
  226. Di Martino A, Kelly C, Grzadzinski R, Zuo XN, Mennes M. 226.  et al. 2011. Aberrant striatal functional connectivity in children with autism. Biol. Psychiatry 69:847–56 [Google Scholar]
  227. Turner KC, Frost L, Linsenbardt D, McIlroy JR, Müller R. 227.  2006. Atypically diffuse functional connectivity between caudate nuclei and cerebral cortex in autism. Behav. Brain Funct. 2:34 [Google Scholar]
  228. Anderson JS, Druzgal TJ, Froehlich A, DuBray MB, Lange N. 228.  et al. 2011. Decreased interhemispheric functional connectivity in autism. Cereb. Cortex 21:1134–46 [Google Scholar]
  229. Courchesne E, Pierce K. 229.  2005. Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int. J. Dev. Neurosci. 23:153–70 [Google Scholar]
  230. Ebert DH, Greenberg ME. 230.  2013. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493:327–37 [Google Scholar]
  231. Ben-David E, Shifman S. 231.  2013. Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol. Psychiatry 18:1054–56 [Google Scholar]
  232. Fatemi SH, Folsom T, Kneeland R, Yousefi M, Liesch S, Thuras P. 232.  2013. Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex. Mol. Autism 4:21 [Google Scholar]
  233. Silverman JL, Tolu SS, Barkan CL, Crawley JN. 233.  2009. Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35:976–89 [Google Scholar]
  234. Mehta MV, Gandal MJ, Siegel SJ. 234.  2011. mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism. PLOS ONE 6:e26077 [Google Scholar]
  235. Dolan BM, Duron SG, Campbell DA, Vollrath B, Rao BSS. 235.  et al. 2013. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. PNAS 110:5671–76 [Google Scholar]
  236. Han S, Tai C, Jones CJ, Scheuer T, Catterall WA. 236.  2014. Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81:1282–89 [Google Scholar]
  237. Buchovecky CM, Turley SD, Brown HM, Kyle SM, McDonald JG. 237.  et al. 2013. A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45:1013–20 [Google Scholar]
  238. Levitt JG, Blanton RE, Smalley S, Thompson PM, Guthrie D. 238.  et al. 2003. Cortical sulcal maps in autism. Cereb. Cortex 13:728–35 [Google Scholar]
  239. Weinstein M, Ben-Sira L, Levy Y, Zachor DA, Itzhak EB. 239.  et al. 2011. Abnormal white matter integrity in young children with autism. Hum. Brain Mapp. 32:534–43 [Google Scholar]
  240. Shukla DK, Keehn B, Müller RA. 240.  2011. Tract-specific analyses of diffusion tensor imaging show widespread white matter compromise in autism spectrum disorder. J. Child Psychol. Psychiatry 52:286–95 [Google Scholar]
  241. Rudie JD, Hernandez LM, Brown JA, Beck-Pancer D, Colich NL. 241.  et al. 2012. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron 75:904–15 [Google Scholar]
  242. Ecker C, Ronan L, Feng Y, Daly E, Murphy C. 242.  et al. 2013. Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder. PNAS 110:13222–27 [Google Scholar]
  243. Murias M, Webb SJ, Greenson J, Dawson G. 243.  2007. Resting state cortical connectivity reflected in EEG coherence in individuals with autism. Biol. Psychiatry 62:270–73 [Google Scholar]
  244. Koshino H, Kana RK, Keller TA, Cherkassky VL, Minshew NJ, Just MA. 244.  2008. fMRI investigation of working memory for faces in autism: visual coding and underconnectivity with frontal areas. Cereb. Cortex 18:289–300 [Google Scholar]
  245. Di Martino A, Yan CG, Li Q, Denio E, Castellanos FX. 245.  et al. 2014. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Mol. Psychiatry 19:659–67 [Google Scholar]
  246. Khan S, Gramfort A, Shetty NR, Kitzbichler MG, Ganesan S. 246.  et al. 2013. Local and long-range functional connectivity is reduced in concert in autism spectrum disorders. PNAS 110:3107–12 [Google Scholar]
  247. Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR. 247.  et al. 2011. Mouse model of Timothy syndrome recapitulates triad of autistic traits. PNAS 108:15432–37 [Google Scholar]
  248. Irie F, Badie-Mahdavi H, Yamaguchi Y. 248.  2012. Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. PNAS 109:5052–56 [Google Scholar]
  249. Jiang M, Ash RT, Baker SA, Suter B, Ferguson A. 249.  et al. 2013. Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome. J. Neurosci. 33:19518–33 [Google Scholar]
  250. Etherton MR, Blaiss CA, Powell CM, Südhof TC. 250.  2009. Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. PNAS 106:17998–8003 [Google Scholar]
  251. Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS. 251.  et al. 2012. Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489:385–90 [Google Scholar]
  252. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W. 252.  et al. 2008. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 14:843–48 [Google Scholar]
  253. Winslow JT, Insel TR. 253.  2002. The social deficits of the oxytocin knockout mouse. Neuropeptides 36:221–29 [Google Scholar]
  254. Carter MD, Shah CR, Muller CL, Crawley JN, Carneiro AMD, Veenstra-VanderWeele J. 254.  2011. Absence of preference for social novelty and increased grooming in integrin β3 knockout mice: initial studies and future directions. Autism Res. 4:57–67 [Google Scholar]
  255. Gunn RK, Huentelman MJ, Brown RE. 255.  2011. Are Sema5a mutant mice a good model of autism? A behavioral analysis of sensory systems, emotionality and cognition. Behav. Brain Res. 225:142–50 [Google Scholar]
  256. Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D. 256.  2014. Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Mol. Psychiatry. doi: 10.1038/mp.2014.124 [Google Scholar]

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