Review Article | Published:

From the genetic architecture to synaptic plasticity in autism spectrum disorder

Nature Reviews Neuroscience volume 16, pages 551563 (2015) | Download Citation

Abstract

Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

Key points

  • Twin and familial studies reveal that autism spectrum disorder (ASD) traits are highly heritable.

  • The genetic landscape of ASD is made of common and rare variants and can be different from one individual to another.

  • Most of the ASD-risk genes are involved in chromatin remodelling, regulation of protein synthesis and degradation, or synaptic plasticity.

  • In cellular and animal models, mutations in the ASD-risk genes lead to a distortion of typical neuronal connectivity by decreasing or increasing synapse strength or number.

  • Compensatory mechanisms, such as genetic buffering and synaptic homeostasis, could modulate the severity of these mutations.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Autistic disturbances of affective contact. Nerv. Child 2, 217–250 (1943).

  2. 2.

    Die “autistischen Psychopathen” im Kindesalter. Arch. Psychiatr. Nervenkr. 177, 76–137 (in German) (1944). References 1 and 2 are the first reports of individuals diagnosed with autism.

  3. 3.

    & The Autisms 4th edn (Oxford University Press, 2012).

  4. 4.

    The quantitative nature of autistic social impairment. Pediatr. Res. 69, 55R–62R (2011).

  5. 5.

    et al. Social communication competence and functional adaptation in a general population of children: preliminary evidence for sex-by-verbal IQ differential risk. J. Am. Acad. Child Adolesc. Psychiatry 48, 128–137 (2009).

  6. 6.

    , , , & Phenotypic and genetic overlap between autistic traits at the extremes of the general population. J. Am. Acad. Child Adolesc. Psychiatry 45, 1206–1214 (2006).

  7. 7.

    Developmental Disabilities Monitoring Network Surveillance Year Principal Ivestigators, Centers for Disease Control and 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).

  8. 8.

    et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 5, 160–179 (2012).

  9. 9.

    The ESSENCE in child psychiatry: Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Res. Dev. Disabil. 31, 1543–1551 (2010).

  10. 10.

    et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. 12, 406–414 (2013). References 9 and 10 highlight the need to take into account the different symptoms and developmental brain dysfunctions observed in individuals with ASD.

  11. 11.

    et al. Essential versus complex autism: definition of fundamental prognostic subtypes. Am. J. Med. Genet. A 135, 171–180 (2005).

  12. 12.

    et al. Severe multisensory speech integration deficits in high-functioning school-aged children with autism spectrum disorder (ASD) and their resolution during early adolescence. Cereb. Cortex 25, 298–312 (2013).

  13. 13.

    , , & Sensory processing in autism: a review of neurophysiologic findings. Pediatr. Res. 69, 48R–54R (2011).

  14. 14.

    & Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr. Opin. Neurobiol. 15, 225–230 (2005).

  15. 15.

    , , , & Functional and anatomical cortical underconnectivity in autism: evidence from an fMRI study of an executive function task and corpus callosum morphometry. Cereb. Cortex 17, 951–961 (2007).

  16. 16.

    et al. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait. Biol. Psychiatry 74, 576–584 (2013). An important paper highlighting the importance of considering the covariates of genetic ancestry, height and age in interpreting the results on head circumference in patients with ASD.

  17. 17.

    et al. Neural signatures of autism. Proc. Natl Acad. Sci. USA 107, 21223–21228 (2010).

  18. 18.

    & Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013).

  19. 19.

    et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

  20. 20.

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

  21. 21.

    , , & A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 37, 95–105 (2014).

  22. 22.

    et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014).

  23. 23.

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

  24. 24.

    et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014). References 22–24 report the results of whole-exome sequencing in large samples of patients with ASD.

  25. 25.

    Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

  26. 26.

    , & Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011).

  27. 27.

    et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet. 26, 363–372 (2010).

  28. 28.

    & Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455, 912–918 (2008).

  29. 29.

    , & The intense world syndrome — an alternative hypothesis for autism. Front. Neurosci. 1, 77–96 (2007).

  30. 30.

    , & The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat. Neurosci. 18, 302–309 (2015).

  31. 31.

    & Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat. Neurosci. 9, 1221–1225 (2006).

  32. 32.

    et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am. J. Hum. Genet. 91, 1022–1032 (2012).

  33. 33.

    et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493, 216–220 (2013).

  34. 34.

    Genome of the Netherlands Consortium. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet. 46, 818–825 (2014).

  35. 35.

    et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).

  36. 36.

    , & The genetic landscapes of autism spectrum disorders. Annu. Rev. Genom. Hum. Genet. 14, 191–213 (2013).

  37. 37.

    Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011).

  38. 38.

    et al. Evidence that autistic traits show the same etiology in the general population and at the quantitative extremes (5%, 2.5%, and 1%). Arch. Gen. Psychiatry 68, 1113–1121 (2011).

  39. 39.

    et al. Autism spectrum disorders and autistic like traits: similar etiology in the extreme end and the normal variation. Arch. Gen. Psychiatry 69, 46–52 (2012). References 38 and 39 are epidemiological papers that report independent results indicating that autistic traits in individuals from the general population and in clinical cases of ASD have similar aetiology.

  40. 40.

    & Autism spectrum disorders and autistic traits: a decade of new twin studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156, 255–274 (2011).

  41. 41.

    et al. The familial risk of autism. JAMA 311, 1770–1777 (2014).

  42. 42.

    et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68, 1095–1102 (2011).

  43. 43.

    , , , & Sibling recurrence and the genetic epidemiology of autism. Am. J. Psychiatry 167, 1349–1356 (2010).

  44. 44.

    et al. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am. J. Psychiatry 171, 1206–1213 (2014).

  45. 45.

    , , , & The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010).

  46. 46.

    , , & A twin study of autism symptoms in Sweden. Mol. Psychiatry 16, 1039–1047 (2010).

  47. 47.

    et al. Autistic-like traits and their association with mental health problems in two nationwide twin cohorts of children and adults. Psychol. Med. 41, 2423–2433 (2011).

  48. 48.

    , , & Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat. Neurosci. 17, 782–790 (2014).

  49. 49.

    et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3, 9 (2012).

  50. 50.

    Cross-Disorder Group of the Psychiatric Genomics Consortium et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).

  51. 51.

    et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881–885 (2014). References 49–51 use quantitative genetics methods to show that an important proportion of the heritability of ASD is captured by common SNPs.

  52. 52.

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

  53. 53.

    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).

  54. 54.

    et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569–573 (2009).

  55. 55.

    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).

  56. 56.

    et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94, 677–694 (2014).

  57. 57.

    et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat. Genet. 42, 203–209 (2010).

  58. 58.

    et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367, 1321–1331 (2012). References 55–58 report the detection of CNVs in large, independent samples of patients with ASD or developmental delay and highlight the presence of multiple hits.

  59. 59.

    et al. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet. 8, e1002521 (2012).

  60. 60.

    et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat. Med. 21, 185–191 (2015).

  61. 61.

    et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431–1442 (2012).

  62. 62.

    et al. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat. Genet. 46, 742–747 (2014).

  63. 63.

    et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27–29 (2003).

  64. 64.

    et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25–27 (2007). References 63 and 64 are the first reports of mutations affecting synaptic proteins in people with ASD.

  65. 65.

    et al. SHANK1 deletions in males with autism spectrum disorder. Am. J. Hum. Genet. 90, 879–887 (2012).

  66. 66.

    Rethinking the nature of genetic vulnerability to autistic spectrum disorders. Trends Genet. 23, 387–395 (2007).

  67. 67.

    & Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat. Rev. Neurol. 10, 74–81 (2014).

  68. 68.

    , , & The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15, 133–141 (2014).

  69. 69.

    et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 77, 235–242 (2013).

  70. 70.

    et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am. J. Hum. Genet. 93, 249–263 (2013).

  71. 71.

    From genotype to phenotype: buffering mechanisms and the storage of genetic information. Bioessays 22, 1095–1105 (2000).

  72. 72.

    4th, & Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001).

  73. 73.

    et al. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72–85 (2011).

  74. 74.

    et al. Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341–345 (2013).

  75. 75.

    3rd et al. HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151, 821–834 (2012).

  76. 76.

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

  77. 77.

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

  78. 78.

    , , & The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol. 27, 631–652 (2011).

  79. 79.

    et al. Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons. Stem Cells 30, 2128–2139 (2012).

  80. 80.

    et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010).

  81. 81.

    et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89–93 (2015).

  82. 82.

    , & MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007).

  83. 83.

    et al. MEF2C haploinsufficiency caused either by microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 47, 22–29 (2009).

  84. 84.

    et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc. Natl Acad. Sci. USA 105, 9391–9396 (2008).

  85. 85.

    et al. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151, 1581–1594 (2012).

  86. 86.

    et al. Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children. J. Med. Genet. 44, 556–561 (2007).

  87. 87.

    et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

  88. 88.

    et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263–276 (2014). This paper reports a comprehensive genetic and clinical exploration of patients with CHD8 mutations, one of the most frequent genetic causes of ASD.

  89. 89.

    & Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).

  90. 90.

    & Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307–318 (2009).

  91. 91.

    3rd & The autistic neuron: troubled translation? Cell 135, 401–406 (2008).

  92. 92.

    et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83, 1131–1143 (2014).

  93. 93.

    , & Genetic disorders associated with macrocephaly. Am. J. Med. Genet. A 146, 2023–2037 (2008).

  94. 94.

    & What can we learn about autism from studying fragile X syndrome? Dev. Neurosci. 33, 379–394 (2011).

  95. 95.

    , & The FMRP regulon: from targets to disease convergence. Front. Neurosci. 7, 191 (2013).

  96. 96.

    et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79, 1169–1182 (2013).

  97. 97.

    et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493, 411–415 (2013).

  98. 98.

    et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493, 371–377 (2013).

  99. 99.

    & Ubiquitination in postsynaptic function and plasticity. Annu. Rev. Cell Dev. Biol. 26, 179–210 (2010).

  100. 100.

    et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010).

  101. 101.

    , & Alternative splicing controls selective trans-synaptic interactions of the neuroligin–neurexin complex. Neuron 51, 171–178 (2006).

  102. 102.

    et al. Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for β-neurexins. Biochemistry 45, 12816–12827 (2006).

  103. 103.

    et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, 1601–1614 (2011).

  104. 104.

    et al. Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins. Neuron 84, 386–398 (2014).

  105. 105.

    , , & Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies. Trends Cell Biol. 21, 594–603 (2011).

  106. 106.

    , & Functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders. Annu. Rev. Neurosci. 35, 49–71 (2012).

  107. 107.

    , , , & Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119, 1013–1026 (2004).

  108. 108.

    , & Control of excitatory and inhibitory synapse formation by neuroligins. Science 307, 1324–1328 (2005).

  109. 109.

    et al. Neuroligins determine synapse maturation and function. Neuron 51, 741–754 (2006).

  110. 110.

    et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919–931 (2007). The first paper describing that NLGNs specify and validate synapses via an activity-dependent mechanism.

  111. 111.

    et al. Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number. Nat. Neurosci. 15, 1667–1674 (2012).

  112. 112.

    et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 338, 128–132 (2012). This paper reports the convergence of synaptic pathophysiology in fragile X syndrome mouse models and NLGN3-knockout mice, and the rescue of the NLGN3 alterations by re-expression of NLGN3 in juvenile mice.

  113. 113.

    & The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3, a005678 (2011).

  114. 114.

    & The dynamic synapse. Neuron 80, 691–703 (2013).

  115. 115.

    et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 10, e1004580 (2014). This paper provides a comprehensive genetic and clinical exploration of patients with SHANK mutations.

  116. 116.

    et al. SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol. Psychiatry 17, 71–84 (2012).

  117. 117.

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

  118. 118.

    et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011).

  119. 119.

    et al. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28, 1697–1708 (2008).

  120. 120.

    et al. Sociability and motor functions in Shank1 mutant mice. Brain Res. 1380, 120–137 (2011).

  121. 121.

    , , , & Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS ONE 6, e20631 (2011).

  122. 122.

    et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012).

  123. 123.

    et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012).

  124. 124.

    et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism 1, 15 (2010).

  125. 125.

    et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093–3108 (2011).

  126. 126.

    et al. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J. Neurosci. 32, 6525–6541 (2012).

  127. 127.

    , & Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 4, 5–16 (2010).

  128. 128.

    et al. Progress toward treatments for synaptic defects in autism. Nat. Med. 19, 685–694 (2013).

  129. 129.

    et al. Structural and molecular interrogation of intact biological systems. Nature 497, 332–337 (2013).

  130. 130.

    et al. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370, 1209–1219 (2014).

  131. 131.

    , , , & Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892–896 (1998). This paper reports the first evidence of synaptic scaling in neocortical neurons.

  132. 132.

    Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annu. Rev. Neurosci. 34, 89–103 (2011).

  133. 133.

    & Dendritic signalling and homeostatic adaptation. Curr. Opin. Neurobiol. 19, 327–335 (2009).

  134. 134.

    , & Homeostatic synaptic plasticity: from single synapses to neural circuits. Curr. Opin. Neurobiol. 22, 516–521 (2012).

  135. 135.

    & Unraveling mechanisms of homeostatic synaptic plasticity. Neuron 66, 337–351 (2010).

  136. 136.

    & Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (1996).

  137. 137.

    & More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory. Trends Neurosci. 33, 17–26 (2010).

  138. 138.

    Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387 (2008).

  139. 139.

    & Activity-dependent regulation of NR2B translation contributes to metaplasticity in mouse visual cortex. Neuropharmacology 52, 200–214 (2007).

  140. 140.

    et al. Hippocampal synaptic metaplasticity requires the activation of NR2B-containing NMDA receptors. Brain Res. Bull. 84, 137–143 (2011).

  141. 141.

    , & Endocannabinoids facilitate the induction of LTP in the hippocampus. Nat. Neurosci. 5, 723–724 (2002).

  142. 142.

    & Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron 43, 871–881 (2004).

  143. 143.

    & Sleep and synaptic homeostasis: a hypothesis. Brain Res. Bull. 62, 143–150 (2003).

  144. 144.

    , & Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science 324, 109–112 (2009).

  145. 145.

    , , & Local sleep and learning. Nature 430, 78–81 (2004).

  146. 146.

    et al. Neuroligin-1 links neuronal activity to sleep–wake regulation. Proc. Natl Acad. Sci. USA 110, 9974–9979 (2013).

  147. 147.

    et al. Drosophila neuroligin 4 regulates sleep through modulating GABA transmission. J. Neurosci. 33, 15545–15554 (2013).

  148. 148.

    The possible interplay of synaptic and clock genes in autism spectrum disorders. Cold Spring Harb. Symp. Quant. Biol. 72, 645–654 (2007).

  149. 149.

    et al. Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis. Neuron 68, 1143–1158 (2010).

  150. 150.

    , & Brain-derived neurotrophic factor in children with autism spectrum disorder. Ann. Neurosci. 21, 129–133 (2014).

  151. 151.

    , & Possible role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder: current status. J. Coll. Physicians Surg. Pak. 24, 274–278 (2014).

  152. 152.

    et al. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol. Psychiatry 20, 440–446 (2014).

  153. 153.

    et al. Circulating levels of neurotrophic factors in autism spectrum disorders. Neuro Endocrinol. Lett. 35, 380–384 (2014).

  154. 154.

    et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol. Psychiatry 13, 90–98 (2008).

  155. 155.

    et al. The serotonin–N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders. Transl Psychiatry 4, e479 (2014).

  156. 156.

    et al. N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc. Natl Acad. Sci. USA 107, 3876–3881 (2010).

  157. 157.

    Critical period regulation. Annu. Rev. Neurosci. 27, 549–579 (2004).

  158. 158.

    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). This article describes the largest GWAS in psychiatric disorders, highlighting the role of the common variants in schizophrenia and revealing that large numbers of patients and controls are required to identify risk alleles.

  159. 159.

    et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013).

  160. 160.

    et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013).

  161. 161.

    et al. Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Nature 511, 236–240 (2014).

  162. 162.

    et al. Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Hum. Mol. Genet. 22, 2055–2066 (2013).

  163. 163.

    & Why autism must be taken apart. J. Autism Dev. Disord. 44, 1788–1792 (2014).

  164. 164.

    & Can we measure autism? Sci. Transl Med. 5, 209ed18 (2013).

  165. 165.

    Changing perceptions: the power of autism. Nature 479, 33–35 (2011). References 163–165 highlight the importance of studying autism from a new perspective, with the integration of clinical, molecular and biochemical characteristics in a patient-information commons and by taking into account not only the deficits but also the abilities and strengths of people with autism.

  166. 166.

    , & Protein homeostasis and the phenotypic manifestation of genetic diversity: principles and mechanisms. Annu. Rev. Genet. 44, 189–216 (2010). A comprehensive review on the concept of genetic buffering.

  167. 167.

    et al. Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Mol. Psychiatry 19, 784–790 (2014).

  168. 168.

    & Tracking rates of transcription and splicing in vivo. Nat. Struct. Mol. Biol. 16, 1123–1124 (2009).

  169. 169.

    et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013).

  170. 170.

    et al. SynGAP isoforms exert opposing effects on synaptic strength. Nat. Commun. 3, 900 (2012).

  171. 171.

    et al. Linkage and association of the glutamate receptor 6 gene with autism. Mol. Psychiatry 7, 302–310 (2002).

  172. 172.

    , & Neuronal regulation of alternative pre-mRNA splicing. Nat. Rev. Neurosci. 8, 819–831 (2007).

  173. 173.

    et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).

  174. 174.

    et al. 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon–intron boundary. Nat. Struct. Mol. Biol. 19, 1037–1043 (2012).

  175. 175.

    et al. Transsynaptic signaling by activity-dependent cleavage of neuroligin-1. Neuron 76, 396–409 (2012).

  176. 176.

    et al. Activity-dependent proteolytic cleavage of neuroligin-1. Neuron 76, 410–422 (2012).

  177. 177.

    et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008).

  178. 178.

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

Download references

Acknowledgements

The author thanks Sophie Calderari, Guillaume Dumas, Elodie Ey, Eva Loth, Thomas Rolland and Roberto Toro for their discussions and reading of the manuscript. This work was funded by the Institut Pasteur, Fondation Bettencourt Schueller, Centre National de la Recherche Scientifique, University Paris Diderot, Agence Nationale de la Recherche (SynDivAutism), the Conny-Maeva Charitable Foundation, Fondation Cognacq-Jay, the Orange Foundation and Fondation FondaMental. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contribution.

Author information

Affiliations

  1. Human Genetics and Cognitive Functions Unit, Institut Pasteur.

    • Thomas Bourgeron
  2. CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France.

    • Thomas Bourgeron
  3. Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 5 rue Thomas Mann, 75013 Paris, France.

    • Thomas Bourgeron
  4. Fondation FondaMental, Hôpital Albert Chenevier, 40 rue de Mesly, 94000 Créteil, France.

    • Thomas Bourgeron

Authors

  1. Search for Thomas Bourgeron in:

Competing interests

The author declares no competing financial interests.

Corresponding author

Correspondence to Thomas Bourgeron.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (table)

    Examples of genes associated with ASD and their main clinical phenotypes.

  2. 2.

    Supplementary information S2 (figure)

    Proteins associated with ASD and their binding partners.

Glossary

Dysmorphic features

Differences in body structure compared with that in the general population. Dysmorphic features can be isolated or multiple and vary from mild anomalies, such as minor malformations of the fingers, to more severe differences, such as microcephaly.

Synaptic homeostasis

Crosstalk between the presynaptic and the postsynaptic sides of the synapse that allows the tight regulation of synaptic strength and thus maintains excitability within a narrow range. It stabilizes neuronal circuits and ensures the fidelity of communication within the neuronal network despite sensory and/or growth-dependent changes.

Single-nucleotide variants

(SNVs). DNA-sequence variations occurring within a population. SNV is the general term for all such variations. Single-nucleotide polymorphism is usually used for SNVs occurring in > 1% of the population.

Copy-number variants

(CNVs). Variations in the number of copies of one segment of DNA. CNVs include deletions and duplications.

Psychological and cognitive tests

Various self- and parent-reports designed to reliably quantify autistic traits in the general population and in clinical cases. Examples of theses scales are the social responsiveness scale and the autism spectrum quotient.

Heritability

The proportion of the phenotypic variance that is due to genetic factors. In the narrow sense, heritability includes only the additive genetic component. However, in the broad sense, heritability includes both the additive and the dominance genetic components.

Dominance components

Part of the genetic contribution to a phenotype, the other part of which is the additive component. Some genes have an additive effect on the quantitative trait, whereas other genes may exhibit a dominant gene action, which will mask the contribution of the recessive alleles at the locus.

Quantitative molecular genetics

A branch of population genetics that assesses the heritability of continuously distributed phenotypes based on their molecular genetic signatures. For example, the Genome-Wide Complex Trait Analysis (GCTA) software estimates genomic relationships between pairs of conventionally unrelated individuals using single-nucleotide polymorphism (SNP) data.

Gene dosage

The number of copies of a gene that are present in a cell. An abnormal gene dosage (by gene deletion or duplication) can result in abnormal levels of gene product formation. Gene dosage compensation to adjust the normal level of gene product can occur at different levels (transcription, translation and degradation).

Genetic buffer

The process by which an individual's genetic background can moderate or counteract the phenotypic effect of deleterious mutations.

Chromatin remodelling

The dynamic modification of chromatin architecture to allow or deny access of condensed genomic DNA to the regulatory transcription machinery proteins, thereby controlling gene expression.

X inactivation

A process by which one of the two copies of the X chromosome present in female mammals is inactivated.

Synaptic scaling

A form of synaptic plasticity that adjusts the strength of a neuron's excitatory synapses up or down to stabilize firing.

Metaplasticity

The plasticity of synaptic plasticity (that is, the prior history of activity of a synapse determines its current plasticity).

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrn3992

Further reading