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Lessons learned from studying syndromic autism spectrum disorders


Syndromic autism spectrum disorders represent a group of childhood neurological conditions, typically associated with chromosomal abnormalities or mutations in a single gene. The discovery of their genetic causes has increased our understanding of the molecular pathways critical for normal cognitive and social development. Human studies have revealed that the brain is particularly sensitive to changes in dosage of various proteins from transcriptional and translational regulators to synaptic proteins. Investigations of these disorders in animals have shed light on previously unknown pathogenic mechanisms leading to the identification of potential targets for therapeutic intervention. The demonstration of reversibility of several phenotypes in adult mice is encouraging, and brings hope that with novel therapies, skills and functionality might improve in affected children and young adults. As new research reveals points of convergence between syndromic and nonsyndromic autism spectrum disorders, we believe there will be opportunities for shared therapeutics for this class of conditions.

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Figure 1: Timeline of key discoveries in the history of ASD research, with a focus on genetic advances.
Figure 2: Animal and cellular models for ASDs.

Debbie Maizels/Nature Publishing Group; KTSDESIGN/ Alfred Pasieka/Science Photo Library; Roxana Wegner

Figure 3: Mutations in syndromic and nonsyndromic ASD.

Debbie Maizels/Nature Publishing Group


  1. 1

    Kanner, L. Autistic disturbances of affective contact. Nervous Child 2, 217–250 (1943).

    Google Scholar 

  2. 2

    Chakrabarti, S. & Fombonne, E. Pervasive developmental disorders in preschool children. J. Am. Med. Assoc. 285, 3093–3099 (2001).

    CAS  Google Scholar 

  3. 3

    Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators & Centers for Disease Control & Prevention (CDC). Prevalence of autism spectrum disorder among children aged 8 years – autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill. Summ. 63, 1–21 (2014).

  4. 4

    Buescher, A.V., Cidav, Z., Knapp, M. & Mandell, D.S. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 168, 721–728 (2014).

    PubMed  Google Scholar 

  5. 5

    Verkerk, A.J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    CAS  PubMed  Google Scholar 

  6. 6

    Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).

    CAS  Google Scholar 

  7. 7

    Van Esch, H. et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Fryer, A.E. et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1, 659–661 (1987).

    CAS  PubMed  Google Scholar 

  9. 9

    Kandt, R.S. et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat. Genet. 2, 37–41 (1992).

    CAS  PubMed  Google Scholar 

  10. 10

    Butler, M.G. et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumor suppressor gene mutations. J. Med. Genet. 42, 318–321 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Sandin, S. et al. The familial risk of autism. J. Am. Med. Assoc. 311, 1770–1777 (2014).

    CAS  Google Scholar 

  12. 12

    Weiss, L.A., Arking, D.E., Daly, M.J. & Chakravarti, A. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461, 802–808 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    International Molecular Genetic Study of Autism Consortium (IMGSAC). A genome-wide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am. J. Hum. Genet. 69, 570–581 (2001).

  14. 14

    Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).

  15. 15

    Anney, R. et al. Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum. Mol. Genet. 21, 4781–4792 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Sanders, S.J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Sanders, S.J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    O'Roak, B.J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).

    CAS  Article  Google Scholar 

  20. 20

    Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).

    CAS  Article  Google Scholar 

  21. 21

    Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    O'Callaghan, F.J., Shiell, A.W., Osborne, J.P. & Martyn, C.N. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 351, 1490 (1998).

    CAS  PubMed  Google Scholar 

  23. 23

    Curatolo, P., Bombardieri, R. & Jozwiak, S. Tuberous sclerosis. Lancet 372, 657–668 (2008).

    CAS  PubMed  Google Scholar 

  24. 24

    van Slegtenhorst, M. et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805–808 (1997).

    CAS  PubMed  Google Scholar 

  25. 25

    European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315 (1993).

  26. 26

    Richards, C., Jones, C., Groves, L., Moss, J. & Oliver, C. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry 2, 909–916 (2015).

    PubMed  Google Scholar 

  27. 27

    Jeste, S.S., Sahin, M., Bolton, P., Ploubidis, G.B. & Humphrey, A. Characterization of autism in young children with tuberous sclerosis complex. J. Child Neurol. 23, 520–525 (2008).

    PubMed  Google Scholar 

  28. 28

    Jeste, S.S. et al. Symptom profiles of autism spectrum disorder in tuberous sclerosis complex. Neurology 87, 766–772 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Ehninger, D. et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat. Med. 14, 843–848 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Sato, A. et al. Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat. Commun. 3, 1292 (2012).

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Santini, E. & Klann, E. Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci. Signal. 7, re10 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Martin, J.P. & Bell, J. A pedigree of mental defect showing sex-linkage. J. Neurol. Psychiatry 6, 154–157 (1943).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Lubs, H.A., Stevenson, R.E. & Schwartz, C.E. Fragile X and X-linked intellectual disability: four decades of discovery. Am. J. Hum. Genet. 90, 579–590 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Hagerman, R., Au, J. & Hagerman, P. FMR1 premutation and full mutation molecular mechanisms related to autism. J. Neurodev. Disord. 3, 211–224 (2011).

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Schaefer, G.B. & Mendelsohn, N.J. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet. Med. 10, 4–12 (2008).

    PubMed  Google Scholar 

  36. 36

    Hatton, D.D. et al. Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am. J. Med. Genet. A. 140A, 1804–1813 (2006).

    PubMed  Google Scholar 

  37. 37

    Rogers, S.J., Wehner, D.E. & Hagerman, R. The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J. Dev. Behav. Pediatr. 22, 409–417 (2001).

    CAS  PubMed  Google Scholar 

  38. 38

    Dissanayake, C., Bui, Q., Bulhak-Paterson, D., Huggins, R. & Loesch, D.Z. Behavioural and cognitive phenotypes in idiopathic autism versus autism associated with fragile X syndrome. J. Child Psychol. Psychiatry 50, 290–299 (2009).

    PubMed  Google Scholar 

  39. 39

    Smith, L.E., Barker, E.T., Seltzer, M.M., Abbeduto, L. & Greenberg, J.S. Behavioral phenotype of fragile X syndrome in adolescence and adulthood. Am. J. Intellect. Dev. Disabil. 117, 1–17 (2012).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Wolff, J.J. et al. Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism. J. Am. Acad. Child Adolesc. Psychiatry 51, 1324–1332 (2012).

    PubMed  PubMed Central  Google Scholar 

  41. 41

    Hall, S.S., Lightbody, A.A., Hirt, M., Rezvani, A. & Reiss, A.L. Autism in fragile X syndrome: a category mistake? J. Am. Acad. Child Adolesc. Psychiatry 49, 921–933 (2010).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Sutcliffe, J.S. et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum. Mol. Genet. 1, 397–400 (1992).

    CAS  PubMed  Google Scholar 

  43. 43

    Zalfa, F. et al. A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nat. Neurosci. 10, 578–587 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Darnell, J.C., Mostovetsky, O. & Darnell, R.B. FMRP RNA targets: identification and validation. Genes Brain Behav. 4, 341–349 (2005).

    CAS  PubMed  Google Scholar 

  45. 45

    Dahlhaus, R. & El-Husseini, A. Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndrome. Behav. Brain Res. 208, 96–105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Bear, M.F., Huber, K.M. & Warren, S.T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).

    CAS  PubMed  Google Scholar 

  47. 47

    D'Hulst, C. et al. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 1121, 238–245 (2006).

    CAS  PubMed  Google Scholar 

  48. 48

    Chahrour, M. & Zoghbi, H.Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).

    CAS  Google Scholar 

  49. 49

    Rett, A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien. Med. Wochenschr. 116, 723–726 (1966).

    CAS  PubMed  Google Scholar 

  50. 50

    Hagberg, B., Aicardi, J., Dias, K. & Ramos, O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann. Neurol. 14, 471–479 (1983).

    CAS  PubMed  Google Scholar 

  51. 51

    Neul, J.L. The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues Clin. Neurosci. 14, 253–262 (2012).

    PubMed  PubMed Central  Google Scholar 

  52. 52

    Percy, A.K. Rett syndrome: exploring the autism link. Arch. Neurol. 68, 985–989 (2011).

    PubMed  PubMed Central  Google Scholar 

  53. 53

    Zoghbi, H.Y. & Bear, M.F. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4, a009886 (2012).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    Spooren, W., Lindemann, L., Ghosh, A. & Santarelli, L. Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. Trends Pharmacol. Sci. 33, 669–684 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007).

    CAS  PubMed  Google Scholar 

  56. 56

    McGraw, C.M., Samaco, R.C. & Zoghbi, H.Y. Adult neural function requires MeCP2. Science 333, 186 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Lubs, H. et al. XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28. Am. J. Med. Genet. 85, 243–248 (1999).

    CAS  PubMed  Google Scholar 

  58. 58

    Collins, A.L. et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13, 2679–2689 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Meins, M. et al. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J. Med. Genet. 42, e12 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    del Gaudio, D. et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 8, 784–792 (2006).

    CAS  PubMed  Google Scholar 

  61. 61

    Friez, M.J. et al. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 118, e1687–e1695 (2006).

    PubMed  Google Scholar 

  62. 62

    Peters, S.U. et al. The behavioral phenotype in MECP2 duplication syndrome: a comparison with idiopathic autism. Autism Res. 6, 42–50 (2013).

    PubMed  Google Scholar 

  63. 63

    Ramocki, M.B. et al. Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann. Neurol. 66, 771–782 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Lugtenberg, D. et al. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy. Eur. J. Hum. Genet. 17, 444–453 (2009).

    CAS  PubMed  Google Scholar 

  65. 65

    Sztainberg, Y. et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature 528, 123–126 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Potocki, L. et al. 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 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Battaglia, A. The inv dup(15) or idic(15) syndrome: a clinically recognizable neurogenetic disorder. Brain Dev. 27, 365–369 (2005).

    PubMed  Google Scholar 

  68. 68

    Dierssen, M. Down syndrome: the brain in trisomic mode. Nat. Rev. Neurosci. 13, 844–858 (2012).

    CAS  PubMed  Google Scholar 

  69. 69

    Miczek, K.A., Maxson, S.C., Fish, E.W. & Faccidomo, S. Aggressive behavioral phenotypes in mice. Behav. Brain Res. 125, 167–181 (2001).

    CAS  PubMed  Google Scholar 

  70. 70

    Wang, F., Kessels, H.W. & Hu, H. The mouse that roared: neural mechanisms of social hierarchy. Trends Neurosci. 37, 674–682 (2014).

    CAS  PubMed  Google Scholar 

  71. 71

    Hulbert, S.W. & Jiang, Y.H. Monogenic mouse models of autism spectrum disorders: common mechanisms and missing links. Neuroscience 321, 3–23 (2016).

    CAS  PubMed  Google Scholar 

  72. 72

    Siviy, S.M. & Panksepp, J. In search of the neurobiological substrates for social playfulness in mammalian brains. Neurosci. Biobehav. Rev. 35, 1821–1830 (2011).

    PubMed  Google Scholar 

  73. 73

    Mabunga, D.F., Gonzales, E.L., Kim, J.W., Kim, K.C. & Shin, C.Y. Exploring the validity of valproic acid animal model of autism. Exp. Neurobiol. 24, 285–300 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. 74

    Chomiak, T., Turner, N. & Hu, B. What we have learned about autism spectrum disorder from valproic acid. Patholog. Res. Int. 2013, 712758 (2013).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Kim, K.C. et al. The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol. Lett. 201, 137–142 (2011).

    CAS  PubMed  Google Scholar 

  76. 76

    Bambini-Junior, V. et al. Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain Res. 1408, 8–16 (2011).

    CAS  PubMed  Google Scholar 

  77. 77

    Schneider, T. & Przewłocki, R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30, 80–89 (2005).

    CAS  PubMed  Google Scholar 

  78. 78

    Schneider, T. et al. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology 33, 728–740 (2008).

    CAS  PubMed  Google Scholar 

  79. 79

    Engineer, C.T. et al. Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome. Neurobiol. Dis. 83, 26–34 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. 80

    Till, S.M. et al. Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. Hum. Mol. Genet. 24, 5977–5984 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Esclassan, F., Francois, J., Phillips, K.G., Loomis, S. & Gilmour, G. Phenotypic characterization of nonsocial behavioral impairment in neurexin 1a knockout rats. Behav. Neurosci. 129, 74–85 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Patterson, P.H. Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Martin, L.A. et al. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav. Immun. 22, 806–816 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Bauman, M.D. et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl. Psychiatry 3, e278 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Liu, Z. et al. Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2. Nature 530, 98–102 (2016).

    CAS  PubMed  Google Scholar 

  86. 86

    Beltrão-Braga, P.C. & Muotri, A.R. Modeling autism spectrum disorders with human neurons. Brain Res. (2016).

  87. 87

    Marchetto, M.C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Nageshappa, S. et al. Altered neuronal network and rescue in a human MECP2 duplication model. Mol. Psychiatry 21, 178–188 (2016).

    CAS  PubMed  Google Scholar 

  89. 89

    Urbach, A., Bar-Nur, O., Daley, G.Q. & Benvenisty, N. Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407–411 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Chamberlain, S.J. et al. Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proc. Natl. Acad. Sci. USA 107, 17668–17673 (2010).

    CAS  Google Scholar 

  91. 91

    Pa ca, S.P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17, 1657–1662 (2011).

    Google Scholar 

  92. 92

    Shcheglovitov, A. et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503, 267–271 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Griesi-Oliveira, K. et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol. Psychiatry 20, 1350–1365 (2015).

    CAS  PubMed  Google Scholar 

  94. 94

    Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375–390 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Ramocki, M.B. & Zoghbi, H.Y. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455, 912–918 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Nelson, S.B. & Valakh, V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Kelleher, R.J., III & Bear, M.F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Ebert, D.H. & Greenberg, M.E. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

    CAS  Google Scholar 

  101. 101

    Darnell, J.C. & Klann, E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat. Neurosci. 16, 1530–1536 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Baudouin, S.J. et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 338, 128–132 (2012).

    CAS  PubMed  Google Scholar 

  103. 103

    Lombardi, L.M., Baker, S.A. & Zoghbi, H.Y. MECP2 disorders: from the clinic to mice and back. J. Clin. Invest. 125, 2914–2923 (2015).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Chen, R.Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327–331 (2001).

    CAS  PubMed  Google Scholar 

  105. 105

    Guy, J., Hendrich, B., Holmes, M., Martin, J.E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001).

    CAS  Google Scholar 

  106. 106

    Samaco, R.C. et al. Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum. Mol. Genet. 22, 96–109 (2013).

    CAS  PubMed  Google Scholar 

  107. 107

    Samaco, R.C. et al. A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17, 1718–1727 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Baker, S.A. et al. An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152, 984–996 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Heckman, L.D., Chahrour, M.H. & Zoghbi, H.Y. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife 3, 02676 (2014).

    Google Scholar 

  110. 110

    Lyst, M.J. et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902 (2013).

    CAS  Google Scholar 

  111. 111

    Na, E.S. et al. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J. Neurosci. 32, 3109–3117 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Carney, R.M. et al. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr. Neurol. 28, 205–211 (2003).

    PubMed  Google Scholar 

  113. 113

    Loat, C.S. et al. Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes Brain Behav. 7, 754–760 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Samaco, R.C., Nagarajan, R.P., Braunschweig, D. & LaSalle, J.M. Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum. Mol. Genet. 13, 629–639 (2004).

    CAS  PubMed  Google Scholar 

  115. 115

    Nagarajan, R.P., Hogart, A.R., Gwye, Y., Martin, M.R. & LaSalle, J.M. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1, e1–e11 (2006).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Gennarino, V.A. et al. NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. Elife 4, 10782 (2015).

    Google Scholar 

  117. 117

    Kuwano, Y. et al. Autism-associated gene expression in peripheral leucocytes commonly observed between subjects with autism and healthy women having autistic children. PLoS One 6, e24723 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Thanseem, I. et al. Elevated transcription factor specificity protein 1 in autistic brains alters the expression of autism candidate genes. Biol. Psychiatry 71, 410–418 (2012).

    CAS  PubMed  Google Scholar 

  119. 119

    Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006).

    CAS  Google Scholar 

  120. 120

    Chao, H.T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Ito-Ishida, A., Ure, K., Chen, H., Swann, J.W. & Zoghbi, H.Y. Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes. Neuron 88, 651–658 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Han, S. et al. Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Weisenfeld, N.I. et al. A magnetic resonance imaging study of cerebellar volume in tuberous sclerosis complex. Pediatr. Neurol. 48, 105–110 (2013).

    PubMed  PubMed Central  Google Scholar 

  125. 125

    Reith, R.M., Way, S., McKenna, J., III, Haines, K. & Gambello, M.J. Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiol. Dis. 43, 113–122 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Bauman, M.L. & Kemper, T.L. Neuroanatomic observations of the brain in autism: a review and future directions. Int. J. Dev. Neurosci. 23, 183–187 (2005).

    PubMed  Google Scholar 

  127. 127

    Tsai, P.T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Reith, R.M. et al. 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 (2013).

    CAS  PubMed  Google Scholar 

  129. 129

    Costa, R.M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002).

    CAS  PubMed  Google Scholar 

  130. 130

    Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007).

    PubMed  PubMed Central  Google Scholar 

  131. 131

    Meng, L. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518, 409–412 (2015).

    CAS  PubMed  Google Scholar 

  132. 132

    Mei, Y. et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530, 481–484 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Rogers, S.J. & Vismara, L.A. Evidence-based comprehensive treatments for early autism. J. Clin. Child Adolesc. Psychol. 37, 8–38 (2008).

    PubMed  PubMed Central  Google Scholar 

  134. 134

    Paul, R. Interventions to improve communication in autism. Child Adolesc. Psychiatr. Clin. N. Am. 17, 835–856 (2008).

    PubMed  PubMed Central  Google Scholar 

  135. 135

    Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Oguro-Ando, A. et al. Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Mol. Psychiatry 20, 1069–1078 (2015).

    CAS  PubMed  Google Scholar 

  137. 137

    Castro, J. et al. Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome. Proc. Natl. Acad. Sci. USA 111, 9941–9946 (2014).

    CAS  PubMed  Google Scholar 

  138. 138

    Tropea, D. et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl. Acad. Sci. USA 106, 2029–2034 (2009).

    CAS  PubMed  Google Scholar 

  139. 139

    Kline, D.D., Ogier, M., Kunze, D.L. & Katz, D.M. Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice. J. Neurosci. 30, 5303–5310 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Levenga, J., de Vrij, F.M., Oostra, B.A. & Willemsen, R. Potential therapeutic interventions for fragile X syndrome. Trends Mol. Med. 16, 516–527 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Jeste, S.S. & Geschwind, D.H. Clinical trials for neurodevelopmental disorders: At a therapeutic frontier. Sci. Transl. Med. 8, 321fs1 (2016).

    PubMed  PubMed Central  Google Scholar 

  142. 142

    Gadalla, K.K. et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol. Ther. 21, 18–30 (2013).

    CAS  PubMed  Google Scholar 

  143. 143

    Garg, S.K. et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J. Neurosci. 33, 13612–13620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Beaudet, A.L. & Meng, L. Gene-targeting pharmaceuticals for single-gene disorders. Hum. Mol. Genet. 25 R1, R18–R26 (2016).

    Google Scholar 

  145. 145

    Hao, S. et al. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature 526, 430–434 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat. Rev. Neurosci. 16, 551–563 (2015).

    CAS  PubMed  Google Scholar 

  147. 147

    Bavelier, D., Levi, D.M., Li, R.W., Dan, Y. & Hensch, T.K. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J. Neurosci. 30, 14964–14971 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Castrén, E., Elgersma, Y., Maffei, L. & Hagerman, R. Treatment of neurodevelopmental disorders in adulthood. J. Neurosci. 32, 14074–14079 (2012).

    PubMed  PubMed Central  Google Scholar 

  149. 149

    Soorya, L. et al. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol. Autism 4, 18 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Splawski, I. et al. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Huda Y Zoghbi.

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Sztainberg, Y., Zoghbi, H. Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci 19, 1408–1417 (2016).

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