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SHANK proteins: roles at the synapse and in autism spectrum disorder

Nature Reviews Neuroscience volume 18, pages 147–157 (2017)Cite this article

Subjects

Key Points

  • SH3 and multiple ankyrin repeat domains proteins (SHANKs) are encoded by SHANK1, SHANK2 and SHANK3 genes. The three different SHANK genes can produce multiple protein isoforms that are differentially expressed according to developmental stages, cell types and brain regions.

  • Mutations in SHANK genes are a potential monogenic cause for autism spectrum disorder.

  • Neurobiological studies in animal models indicate a wide array of functions for SHANK proteins, from synaptic scaffolding to regulating spine morphology and neurotransmission.

  • Mutant mice carrying different Shank1, Shank2 or Shank3 mutations have some distinct and shared phenotypes at the molecular and functional level. All mutants seem to have altered molecular composition of excitatory synapses and altered neurotransmission, and often display impaired social interaction and repetitive behaviour.

  • Different mutations within the same SHANKgene may cause distinct synaptic and circuitry defects and thus may be responsible for the different clinical features that are seen in patients.

  • Despite being a neurodevelopmental disorder, some neurobiological alterations in autism spectrum disorder may be reversible in adulthood.

  • Adult restoration of SHANK3 levels or restoration of downstream mediators may be a useful therapeutic approach to alleviate some of the synaptic and behavioural impairments that are associated with SHANK3 mutations.

Abstract

Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2 and SHANK3, which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour.

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Figure 1: Shank genes: structure and intragenic promoters.
Figure 2: Expression patterns of Shank genes and SHANK3 isoforms.
Figure 3: SHANK-interacting proteins in the postsynaptic site.

References

  1. Sheng, M. & Hoogenraad, C. C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Ahmari, S. E. & Smith, S. J. Knowing a nascent synapse when you see it. Neuron 34, 333–336 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Kano, M. & Hashimoto, K. Synapse elimination in the central nervous system. Curr. Opin. Neurobiol. 19, 154–161 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Sheng, M. & Kim, E. The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3, a005678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Leblond, C. S. et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 10, e1004580 (2014). This study demonstrates a correlation between SHANK1, SHANK2 and SHANK3 mutations and the degree of cognitive impairment. The authors show that patients with SHANK3 mutations have more-severe cognitive deficits than those with SHANK1 or SHANK2 mutations and suggest SHANK mutation screening in clinical practice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gauthier, J. et al. Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150, 421–424 (2009).

    Article  CAS  Google Scholar 

  7. Boccuto, L. et al. Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur. J. Hum. Genet. 21, 310–316 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Sala, C., Vicidomini, C., Bigi, I., Mossa, A. & Verpelli, C. Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders. J. Neurochem. 135, 849–858 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Peça, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011). This study describes the first Shank3 -mutant mice with PDZ domain deletion (exon 13 and exon 16 deletion). These mice show synaptic dysfunction and autism-related behavioural phenotypes such as impaired social interaction and stereotyped and/or repetitive behaviour.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Naisbitt, S. et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569–582 (1999). This study provides the first description of the SHANK family of synaptic proteins.

    Article  CAS  PubMed  Google Scholar 

  11. Wang, X., Xu, Q., Bey, A. L., Lee, Y. & Jiang, Y. Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice. Mol. Autism 5, 30 (2014). This study addresses the functional and transcriptional regulation of different SHANK3 isoforms. The results suggest that different SHANK3 isoforms have distinct functions and that the different SHANK3 mutations found in patients with ASD disrupt only specific isoforms and result in distinct phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jiang, Y. -H & Ehlers, M. D. Modeling autism by SHANK gene mutations in mice. Neuron 78, 8–27 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Beri, S. et al. DNA methylation regulates tissue-specific expression of Shank3. J. Neurochem. 101, 1380–1391 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Ching, T.-T. et al. Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3. Nat. Genet. 37, 645–651 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lim, S. et al. Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Mol. Cell. Neurosci. 17, 385–397 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Böckers, T. M. et al. Synaptic scaffolding proteins in rat brain: ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein α-fodrin. J. Biol. Chem. 276, 40104–40112 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Mameza, M. G. et al. SHANK3 gene mutations associated with autism facilitate ligand binding to the shank3 ankyrin repeat region. J. Biol. Chem. 288, 26697–26708 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Uchino, S. et al. Direct interaction of post-synaptic density-95/Dlg/ZO-1 domain-containing synaptic molecule Shank3 with GluR1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor. J. Neurochem. 97, 1203–1214 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Tu, J. C. et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23, 583–592 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Hayashi, M. K. et al. The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137, 159–171 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Baron, M. K. et al. An architectural framework that may lie at the core of the postsynaptic density. Science 311, 531–535 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Boeckers, T. M. et al. C-Terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3. J. Neurochem. 92, 519–524 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Grabrucker, A. M. et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 30, 569–581 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Guilmatre, A., Huguet, G., Delorme, R. & Bourgeron, T. The emerging role of SHANK genes in neuropsychiatric disorders. Dev. Neurobiol. 74, 113–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Boeckers, T. M., Bockmann, J., Kreutz, M. R. & Gundelfinger, E. D. ProSAP/Shank proteins — a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J. Neurochem. 81, 903–910 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Okamoto, P. M., Gamby, C., Wells, D., Fallon, J. & Vallee, R. B. Dynamin isoform-specific interaction with the Shank/ProSAP scaffolding proteins of the postsynaptic density and actin cytoskeleton. J. Biol. Chem. 276, 48458–48465 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McWilliams, R. R., Gidey, E., Fouassier, L., Weed, S. A. & Doctor, R. B. Characterization of an ankyrin repeat-containing Shank2 isoform (Shank2E) in liver epithelial cells. Biochem. J. 380, 181–191 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012). This study describes one of the first Shank2 -mutant mice (exon 17 deletion; PDZ domain deletion). These mice show autism-related behavioural phenotypes and hyperactivity.

    Article  CAS  PubMed  Google Scholar 

  31. Lim, S. et al. Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J. Biol. Chem. 274, 29510–29518 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Peça, J., Ting, J. & Feng, G. SnapShot: autism and the synapse. Cell 147, 706–706.e1 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Böckers, T. M. et al. Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3′ untranslated region of Shank1 mRNA. Mol. Cell. Neurosci. 26, 182–190 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Zitzer, H., Hönck, H. H., Bächner, D., Richter, D. & Kreienkamp, H. J. Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain. J. Biol. Chem. 274, 32997–33001 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Lee, J. et al. Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit. Front. Cell. Neurosci. 9, 94 (2015).

    PubMed  PubMed Central  Google Scholar 

  36. Wang, X. et al. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat. Commun. 7, 11459 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mei, Y. et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530, 481–484 (2016). This is the first report to show that adult restoration of the Shank3 gene selectively rescues certain synaptic defects and some autism-related behavioural phenotypes such as social interaction and stereotyped and/or repetitive behaviour in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lai, M. C. et al. Cognition in males and females with autism: similarities and differences. PLoS ONE 7, e47198 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders — Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1–19 (2012).

  40. American Psychiatric Association (eds). Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Association Publishing, 2013).

  41. Rosenberg, R. E. et al. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch. Pediatr. Adolesc. Med. 163, 907–914 (2009).

    Article  PubMed  Google Scholar 

  42. Geschwind, D. H. Advances in autism. Annu. Rev. Med. 60, 367–380 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huguet, G., Ey, E. & Bourgeron, T. The genetic landscapes of autism spectrum disorders. Annu. Rev. Genomics Hum. Genet. 14, 191–213 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Phelan, K. & McDermid, H. E. The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol. Syndromol. 2, 186–201 (2012).

    CAS  PubMed  Google Scholar 

  47. Phelan, M. C. et al. 22Q13 deletion syndrome. Am. J. Med. Genet. 101, 91–99 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Bonaglia, M. C. et al. Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am. J. Hum. Genet. 69, 261–268 (2001). This study is the first to describe a possible association between PMS and disruption of the SHANK3 gene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bonaglia, M. C. et al. Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with phelan/mcdermid syndrome. PLoS Genet. 7, e1002173 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wilson, H. L. et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J. Med. Genet. 40, 575–584 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wilson, H. L. et al. Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development. Eur. J. Hum. Genet. 16, 1301–1310 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Moessner, R. et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289–1297 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Durand, C. M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25–27 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Berkel, S. et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat. Genet. 42, 489–491 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Okabe, S. Molecular anatomy of the postsynaptic density. Mol. Cell. Neurosci. 34, 503–518 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Emes, R. D. & Grant, S. G. N. Evolution of synapse complexity and diversity. Annu. Rev. Neurosci. 35, 111–131 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Boeckers, T. M. The postsynaptic density. Cell Tissue Res. 326, 409–422 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Montgomery, J. M., Zamorano, P. L. & Garner, C. C. MAGUKs in synapse assembly and function: an emerging view. Cell. Mol. Life Sci. 61, 911–929 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Sheng, M. & Kim, E. The Shank family of scaffold proteins. J. Cell Sci. 113, 1851–1856 (2000).

    CAS  PubMed  Google Scholar 

  60. Tao-Cheng, J. H., Dosemeci, A., Gallant, P. E., Smith, C. & Reese, T. Activity induced changes in the distribution of Shanks at hippocampal synapses. Neuroscience 168, 11–17 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tao-Cheng, J. H., Yang, Y., Reese, T. S. & Dosemeci, A. Differential distribution of shank and GKAP at the postsynaptic density. PLoS ONE 10, e0118750 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bozdagi, O. 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). This study describes the first Shank3 -mutant mice (exon 4 and exon 9 deletion). These mice show some ASD-relevant phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kouser, M. et al. Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J. Neurosci. 33, 18448–18468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhou, Y. et al. Mice with Shank3 mutations associated with ASD and schizophrenia display both shared and distinct defects. Neuron 89, 147–162 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Hung, A. Y. et al. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28, 1697–1708 (2008). This study describes the first Shank1 -mutant mice (exon 14 and exon 15 deletion; PDZ domain deletion).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Won, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012). This study describes one of the first Shank2 -mutant mice (exon 6 and exon 7 deletion). These mice show autism-related behavioural phenotypes and NMDAR dysfunction.

    Article  CAS  PubMed  Google Scholar 

  69. Roussignol, G. et al. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J. Neurosci. 25, 3560–3570 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Peixoto, R., Wang, W., Croney, D., Kozorovitskiy, Y. & Sabatini, B. Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B−/− mice. Nat. Neurosci. 19, 716–724 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yi, F. et al. Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352, aaf2669 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gogolla, N., Takesian, A. E., Feng, G., Fagiolini, M. & Hensch, T. K. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Filice, F., Vörckel, K. J., Sungur, A. Ö., Wöhr, M. & Schwaller, B. Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Mol. Brain 9, 10 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lu, C. et al. Micro-electrode array recordings reveal reductions in both excitation and inhibition in cultured cortical neuron networks lacking Shank3. Mol. Psychiatry 21, 159–168 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Rubenstein, J. L. R. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bourgeron, T. A synaptic trek to autism. Curr. Opin. Neurobiol. 19, 231–234 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Bernhardt, B. C. & Singer, T. The neural basis of empathy. Annu. Rev. Neurosci. 35, 1–23 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Frith, C. D. The social brain? Phil. Trans. R. Soc. B 362, 671–678 (2007).

    Article  PubMed  Google Scholar 

  81. Lamm, C. & Singer, T. The role of anterior insular cortex in social emotions. Brain Struct. Funct. 214, 579–591 (2010).

    Article  PubMed  Google Scholar 

  82. Barak, B. & Feng, G. Neurobiology of social behavior abnormalities in autism and Williams syndrome. Nat. Neurosci. 19, 647–655 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gauthier, J. et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc. Natl Acad. Sci. USA 107, 7863–7868 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Han, K. et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 503, 72–77 (2013). This study shows that mice with SHANK3 overexpression exhibit synaptic dysfunction and manic-like phenotypes, thus reinforcing the idea that proper Shank3 gene dosage is crucial.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  86. Mao, W. et al. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur. J. Neurosci. 41, 1025–1035 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Wöhr, M., Roullet, F. I., Hung, A. Y., Sheng, M. & Crawley, J. N. Communication impairments in mice lacking shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS ONE 6, e20631 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lim, C.-S. et al. Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice. Neuropharmacology 112, 104–112 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Peter, S. et al. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nat. Commun. 7, 12627 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lord, C., Cook, E. H., Leventhal, B. L. & Amaral, D. G. Autism spectrum disorders. Neuron 28, 355–363 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Amaral, D., Geschwind, D. & Dawson, G. Autism Spectrum Disorders (Oxford Univ. Press, 2011).

    Book  Google Scholar 

  92. Swiech, L. et al. In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat. Biotechnol. 33, 102–106 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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). This study shows for the first time a robust phenotypic reversal, both in immature and in mature adult animal models of Rett syndrome, by induced expression of MeCP2.

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Clement, J. P. et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151, 709–723 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bidinosti, M. et al. CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency. Science 351, 1199–1203 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Vicidomini, C. et al. Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2016.30 (2016).

  99. Duffney, L. J. et al. Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 11, 1400–1413 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lee, E.-J. et al. Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation. Nat. Commun. 6, 7168 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jaramillo, T. C. et al. Altered striatal synaptic function and abnormal behaviour in Shank3 Exon4-9 deletion mouse model of autism. Autism Res. 9, 350–375 (2016).

    Article  PubMed  Google Scholar 

  102. Speed, H. E. et al. Autism-associated insertion mutation (InsG) of Shank3 Exon 21 causes impaired synaptic transmission and behavioral deficits. J. Neurosci. 35, 9648–9665 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank N. Chen for critical comments and editing the manuscript, N. Sousa (Minho University, Portugal) and all members of the Feng laboratory for support and helpful discussion. Research related to this work in the laboratory of G.F. is supported by the Poitras Center for Affective Disorders Research at the Massachusetts Institute of Technology (MIT), Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, National Institute of Mental Health (MH097104), Nancy Lurie Marks Family Foundation, Simons Foundation Autism Research Initiative (SFARI grant 178130) and Simons Center for the Social Brain at MIT. P.M. is supported by Society in Science, The Branco Weiss Fellowship, administered by Eidgenössische Technische Hochschule (ETH) Zürich, and European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 89–2016).

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Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, 02139, Massachusetts, USA

    Patricia Monteiro & Guoping Feng

  2. Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, 02142, Massachusetts, USA

    Patricia Monteiro & Guoping Feng

  3. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4704–553, Portugal

    Patricia Monteiro

  4. Life and Health Sciences Research Institute (ICVS)/3B's PT Government Associate Laboratory, University of Minho, Braga/Guimarães, 4710–057, Braga, Portugal

    Patricia Monteiro

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  1. Patricia Monteiro
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Correspondence to Guoping Feng.

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Glossary

Intragenic promoters

Promoters located within the body of the residing gene, regulating its activity. Intragenic promoters are mainly active in tissue-specific gene expression.

Alternative splicing

A process whereby different mRNAs can be produced from a single gene through the differential incorporation of exons into the mature transcript during splicing. Frequently, various mature proteins are generated from a single gene.

Epigenetic mechanisms

A mechanism of a stable change in gene expression that does not involve changes in DNA sequence.

Concordance

The occurrence of a trait in both of two related individuals, such as twins or siblings.

Ring chromosomes

Structural aberrations of chromosomes, the long and short arms of which fuse together to form a ring. Ring chromosomes can have variable size and genetic content and are often associated with large terminal deletions.

Interstitial deletions

The loss of one or more segments of DNA within a single chromosome (intra-chromosomal deletion), thereby joining genes that were previously far apart.

Unbalanced translocations

Translocations are chromosomal abnormalities that are characterized by place exchange of parts of two or more different chromosomes. Balanced translocations have no net loss or gain of any chromosomal material, whereas unbalanced translocations have unequal exchange of chromosomal material, hence resulting in loss or gain of extra genes.

Microdeletions

Small interstitial deletions of DNA (up to 5 Mb).

Breakpoints

The specific sites of chromosomal breakage that are associated with a particular chromosomal rearrangement.

Perineuronal nets

Aggregates of extracellular matrix molecules that embed cell bodies, axon initial segments and proximal dendrites of a subset of neurons in a mesh-like structure.

Excitation/inhibition (E/I) ratio

The relationship between synaptic excitation and inhibition, two opposing forces in terms of neurotransmission.

Multisensory integration

The neural processes that are involved in synthesizing information from cross-modal stimuli.

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Monteiro, P., Feng, G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci 18, 147–157 (2017). https://doi.org/10.1038/nrn.2016.183

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