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Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries

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Abstract

The Shank family proteins are enriched at the postsynaptic density (PSD) of excitatory glutamatergic synapses. They serve as synaptic scaffolding proteins and appear to play a critical role in the formation, maintenance and functioning of synapse. Increasing evidence from genetic association and animal model studies indicates a connection of SHANK genes defects with the development of neuropsychiatric disorders. In this review, we first update the current understanding of the SHANK family genes and their encoded protein products. We then denote the literature relating their alterations to the risk of neuropsychiatric diseases. We further review evidence from animal models that provided molecular insights into the biological as well as pathogenic roles of Shank proteins in synapses, and the potential relationship to the development of abnormal neurobehavioral phenotypes.

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Data Availability

All data and material files are available upon request.

Abbreviations

PSD:

Postsynaptic density

ASD:

Autism spectrum disorders

PMS:

Phelan–McDermid Syndrome

AD:

Alzheimer’s disease

SCZ:

Schizophrenia

BPD:

Bipolar disorders

ID:

Intellectual disability

DD:

Developmental delay

GWAS:

Genome-Wide Association Studies

SNP:

Single nucleotide polymorphism

NMDA:

N-Methyl-d-aspartate

ANK:

Ankyrin repeat domain

PDZ:

Postsynaptic density protein 95-discs large homologue 1-zonula occludens 1 domain

PRO:

Proline-rich region

SAM:

Sterile alpha motif

SH3:

SRC homology 3 domain superfamily

BDNF:

Brain-derived neurotrophic factor

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

DLGAP1, 2, 3:

Discs large associated protein 1, 2, 3

SLC6A3:

Solute carrier family 6 (neurotransmitter transporter, dopamine), member 3

References

  • Alexandrov PN, ZhaoY VJ, Lin C, Lukiw WJ (2017) Deficits in the proline-rich synapse-associated Shank3 protein in multiple neuropsychiatric disorders. Front Neurol 8:670

    Article  PubMed  PubMed Central  Google Scholar 

  • Ana DSC, Degenhardt F, Strohmaier J et al (2017) Investigation of SHANK3 in schizophrenia. Am J Med Genet B 174:390–398

    Article  CAS  Google Scholar 

  • Bai Y, Qiu S, Li Y et al (2018) Genetic association between SHANK2 polymorphisms and susceptibility to autism spectrum disorder. IUBMB Life 70:763–776

    Article  CAS  PubMed  Google Scholar 

  • Balaan C, Corley MJ, Eulalio T et al (2019) Juvenile Shank3b deficient mice present with behavioral phenotype relevant to autism spectrum disorder. Behav Brain Res 356:137–147

  • Berg EL, Copping NA, Rivera JK et al (2018) Developmental social communication deficits in the Shank3 rat model of Phelan–McDermid syndrome and autism spectrum disorder. Autism Res Off J Int Soc Autism Res 11:587–601

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bey AL, Wang X, YanH KN, Passman RL, Yang Y et al (2018) Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors. Transl Psychiatry 8:94

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boccuto L, Lauri M, Sarasua SM, Skinner CD, Buccella D, Dwivedi A et al (2013) Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur J Hum Genet 21:310–316

    Article  CAS  PubMed  Google Scholar 

  • Böckers TM, Mameza MG, Kreutz MR et al (2001) Synaptic scaffolding proteins in rat brain: ankyrin b repeats of the multidomain Shank protein family interact with the cytoskeletal protein α-fodrin. J Biol Chem 276:40104–40112

    Article  PubMed  CAS  Google Scholar 

  • Boeckers TM, Kreutz MR, Winter C et al (1999) Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density. J Neurosci 19:6506–6518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bonaglia MC, Giorda R, Beri S et al (2011) Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genet 7:e1002173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonaglia MC, Giorda R, Borgatti R et al (2001) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonaglia MC, Giorda R, Mani E et al (2006) Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet 43:822–828

    Article  CAS  PubMed  Google Scholar 

  • Bozdagi O, Sakurai T, Papapetrou D, Scattoni ML et al (2010) Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism 1:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Britt-Marie A, Jacqueline SG, Ran A et al (2002) FISH-mapping of a 100-kb terminal 22q13 deletion. Hum Genet 110:439–443

    Article  Google Scholar 

  • Chantell B, Corley MJ, Tiffany E et al (2018) Juvenile Shank3b deficient mice present with behavioral phenotype relevant to autism spectrum disorder. Behav Brain Res 356:137–147

    Google Scholar 

  • Chen CH, Chen HI, Liao HM et al (2016) Clinical and molecular characterization of three genomic rearrangements at chromosome 22q13.3 associated with autism spectrum disorder. Psychiatr Genet 27:23–33

    Article  CAS  Google Scholar 

  • Chilian B, Abdollahpour H, Bierhals T et al (2013) Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci. Clin Genet 84:560–565

    Article  CAS  PubMed  Google Scholar 

  • Cochoy DM, Kolevzon A, Kajiwara Y, Schoen M, Pascual LM, Lurie S et al (2015) Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. Mol Autism 6:23

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Collins SM, Galvez R (2018) Neocortical SHANK1 regulation of forebrain dependent associative learning. Neurobiol Learn Mem 155:173–179

    Article  CAS  PubMed  Google Scholar 

  • Copping NA, Berg EL, Foley GM et al (2017) Touchscreen learning deficits and normal social approach behavior in the Shank3B model of Phelan–McDermid Syndrome and autism. Neuroscience 345:155–165

    Article  CAS  PubMed  Google Scholar 

  • Crews L, Masliah E (2010) Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 19:R12-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crisafulli C, Chiesa A, Han C et al (2013) Case–control association study of 36 single-nucleotide polymorphisms within 10 candidate genes for major depression and bipolar disorder. Psychiatry Res 209:121–123

    Article  CAS  PubMed  Google Scholar 

  • De Rubeis S, Siper PM, Durkin A et al (2018) Delineation of the genetic and clinical spectrum of Phelan–McDermid syndrome caused by SHANK3 point mutations. Mol Autism 9:31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Denayer A, Van Esch H, Ravel TD et al (2012) Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol 3:14–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhamne SC, Silverman JL, Supe CE (2017) Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism. Mol Autism 8:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Drapeau E, Riad M, Kajiwara Y, Buxbaum JD (2018) Behavioral phenotyping of an improved mouse model of Phelan–McDermid Syndrome with a complete deletion of the Shank3 gene. eNeuro 5:ENEURO.0046-18

    Article  Google Scholar 

  • Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F et al (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39:25–27

    Article  CAS  PubMed  Google Scholar 

  • Engineer CT, Rahebi KC, Borland MS, Buell EP, Kilgard MP (2018) Shank3-Deficient rats exhibit degraded cortical responses to sound: Shank3 rats exhibit degraded cortical responses. Autism Res 11:59–68

    Article  PubMed  Google Scholar 

  • Failla P, Romano C, Alberti A (2007) Schizophrenia in a patient with subtelomeric duplication of chromosome 22q. Clin Genet 71:599–601

    Article  CAS  PubMed  Google Scholar 

  • Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE (1995) The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet 9:132–140

    Article  CAS  PubMed  Google Scholar 

  • Fischetto R, Palumbo O, Ortolani F et al (2017) Clinical and molecular characterization of a second family with the 12q14 microdeletion syndrome and review of the literature. Am J Med Genet A 173:1922–1930

    Article  CAS  PubMed  Google Scholar 

  • Fromer MPA, Kavanagh DH, Williams HJ et al (2014) De novo mutations in schizophrenia implicate synaptic networks. Nature 506:179–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu YJ, Liu D, Guo JL et al (2020) Dynamic change of shanks gene mRNA expression and DNA methylation in epileptic rat model and human patients. Mol Neurobiol 57:3712–3726

    Article  CAS  PubMed  Google Scholar 

  • Gauthier J, Champagne N, Lafreniere RG et al (2010) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gauthier J, Spiegelman D, Piton A et al (2009) Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B 150B:421–424

    Article  CAS  Google Scholar 

  • Gong Y, Lippa CF, Zhu J, Lin Q, Rosso AL (2009) Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer’s disease. Brain Res 1292:191–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gouder L, Vitrac A, Goubran-Botros H et al (2019) Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations. Sci Rep 9:94

  • Grabrucker AM, Schmeisser MJ, Schoen M, Boeckers TM (2011) Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies. Trends Cell Biol 21:594–603

    Article  CAS  PubMed  Google Scholar 

  • Guo B, Chen J, Chen Q et al (2019) Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nat Neurosci 22:1223–1234

    Article  CAS  PubMed  Google Scholar 

  • Guilmatre A, Huguet G, Delorme R et al (2014) The emerging role of SHANK genes in neuropsychiatric disorders. Dev Neurobiol 74:113–122

    Article  CAS  PubMed  Google Scholar 

  • Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  • Han K, Holder JL, Schaaf CP et al (2013) SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 503:72–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harony-Nicolas H, Kay M, du Hoffmann J et al (2017) Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. eLife 6:e18904

  • Hayashi MK, Tang C, Verpelli C et al (2009) The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137:159–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Homann OR, Misura K, Lamas E et al (2016) Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness. Mol Psychiatry 21:1690–1695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hung AY, Futai K, Sala C et al (2008) Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J Neurosci 28:1697–1708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaramillo TC, Speed HE, Xuan Z, Reimers JM, Liu S, Powell CM (2015) Altered striatal synaptic function and abnormal behaviour in Shank3 Exon 4–9 deletion mouse model of autism. Autism Res Off J Int Soc Autism Res 9:350

    Article  Google Scholar 

  • Jaramillo TC, Speed HE, Xuan Z et al (2016) Altered striatal synaptic function and abnormal behaviour in Shank3 Exon4-9 deletion mouse model of autism. Autism Res 9:350–375

  • Jaramillo TC, Speed HE, Xuan Z et al (2017) Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res 10:42–65

    Article  PubMed  Google Scholar 

  • Jaramillo TC, Xuan Z, Reimers JM, Escamilla CO, Liu S, Powell CM (2020) Early restoration of Shank3 expression in Shank3 knockout mice prevents core ASD-like behavioural phenotypes. eNeuro 7:ENEURO03320319

    Article  Google Scholar 

  • Jeffries AR, Curran S, Elmslie F et al (2005) Molecular and phenotypic characterization of ring chromosome 22. Am J Med Genet A 137:139–147

    Article  PubMed  Google Scholar 

  • Kabitzke PA, Brunner D, He D et al (2018) Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder. Genes Brain Behav 17:4

    Article  CAS  PubMed  Google Scholar 

  • Kanani F, Study D, Balasubramanian M (2018) SHANK3 variant as a cause of nonsyndromal autism in an 11-year-old boy and a review of published literature. Clin Dysmorphol 27:1

    Article  Google Scholar 

  • Kim R, Kim J, Chung C, Ha S, Kim E (2018) Cell-type-specific Shank2 deletion in mice leads to differential synaptic and behavioral phenotypes. J Neurosci 38:2684–2617

    Article  Google Scholar 

  • Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A (2020) Psychiatric illness and regression in individuals with Phelan–McDermid syndrome. J Neurodev Disord 12:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Ko HG, Oh SB, Zhuo M, Kaang BK (2016) Reduced acute nociception and chronic pain in Shank2−/− mice. Mol Pain 12:1–5

    Article  Google Scholar 

  • Kolevzon A, Cai G, Soorya L et al (2011) Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities. Brain Res 1380:98–105

    Article  CAS  PubMed  Google Scholar 

  • Kolevzon A, Delaby E, Berry-Kravis E, Buxbaum JD, Betancur C (2019) Neuropsychiatric decompensation in adolescents and adults with Phelan–McDermid syndrome: a systematic review of the literature. Mol Autism 10:50

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leblond CS, Heinrich J, Delorme R et al (2012) Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 8:e1002521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leblond CS, Nava C, Polge A et al (2014) Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet 10:e1004580

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee S, Lee E, Kim R et al (2018) Shank2 deletion in parvalbumin neurons leads to moderate hyperactivity, enhanced self-grooming and suppressed seizure susceptibility in mice. Front Mol Neurosci 11:209

  • Lee YS, Yu NK, Chun JW et al (2020) Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder. Mol Brain 13:54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lennertz L, Wagner M, Wolwer W et al (2012) A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis. Eur Arch Psychiatry Clin Neurosci 262:117–124

    Article  PubMed  Google Scholar 

  • Lim CS, Kim H, YuNK KSJ, Kaang BK (2017) Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice. Neuropharmacology 112:104–112

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lim S, Sala C, Yoon J et al (2001) A novel postsynaptic density protein that directly interacts with the shank family of proteins. Mol Cell Neurosci 17:385–397

    Article  CAS  PubMed  Google Scholar 

  • Luciani JJ, Mas PD, Depetris D et al (2003) Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations. J Med Genet 40:690–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacGillavry HD, Kerr JM, Kassner J, Frost NA, Blanpied TA (2016) Shank-cortactin interactions control actin dynamics to maintain flexibility of neuronal spines and synapses. Eur J Neurosci 43:179–193

    Article  PubMed  Google Scholar 

  • Mameza MG, Dvoretskova E, Bamann M et al (2013) SHANK3 gene mutations associated with autism facilitate ligand binding to the shank3 ankyrin repeat region. J Biol Chem 288:26697–26708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marshall CR, Noor A, Vincent JB et al (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcou CA, Studinski Jones AL, Murphree ML, Kirmani S, Hoppman NL (2017) De novo 11q deletion including SHANK2 in a patient with global developmental delay. Am J Med Genet A 173:801–805

    Article  CAS  PubMed  Google Scholar 

  • Maunakea AK, Nagarajan RP, Bilenky M et al (2020) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monteiro P, Feng GP (2017) SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci 18:147–157

    Article  CAS  PubMed  Google Scholar 

  • Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J et al (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mossa A, Giona F, Pagano J, Sala C, Verpelli C (2017) SHANK genes in autism: defining therapeutic targets. Prog Neuropsychopharmacol Biol Psychiatry 84:416–423

    Article  PubMed  CAS  Google Scholar 

  • Naisbitt S, Kim E, Tu JC et al (1999) Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23:569–582

    Article  CAS  PubMed  Google Scholar 

  • Nesslinger NJ, Gorski JL, Kurczynski TW et al (1994) Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am J Hum Genet 54:464–472

    CAS  PubMed  PubMed Central  Google Scholar 

  • Noor A, Lionel AC, Cohen-Woods S et al (2014) Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes. Am J Med Genet B 165B:303–313

    Article  CAS  Google Scholar 

  • Okamoto N, Kubota T, Nakamura Y et al (2007) 22q13 Microduplication in two patients with common clinical manifestations: a recognizable syndrome? Am J Med Genet A 143A:2804–2809

    Article  CAS  PubMed  Google Scholar 

  • Ortiz A, Bradler K, Garnham J, Slaney C, Alda M (2015) Nonlinear dynamics of mood regulation in bipolar disorder. Bipolar Disord 17:139–149

    Article  PubMed  Google Scholar 

  • Pappas AL, Bey AL, Wang X, Rossi M, Jiang YH (2017) Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight 2:e92052

    Article  PubMed Central  Google Scholar 

  • Peca J, Feliciano C, Ting JT et al (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peter SA, Ten Brinke MM, Stedehouder J et al (2016) Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nat Commun 1:12627

    Article  CAS  Google Scholar 

  • Peykov S, Berkel S, Schoen M et al (2015) Identification and functional characterization of rare SHANK2 variants in schizophrenia. Mol Psychiatry 20:1489–1498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pham E, Crews L, Ubhi K et al (2010) Progressive accumulation of amyloid-beta oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J 277(14):3051–3067

    Article  PubMed  PubMed Central  Google Scholar 

  • Phelan K, McDermid HE (2012) The 22q13.3 deletion syndrome (Phelan–McDermid syndrome). Mol Syndromol 2:186–201

    Article  CAS  PubMed  Google Scholar 

  • Pinto D, Pagnamenta AT, Klei L et al (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin L, Ma K, Wang ZJ, Hu Z, Yan Z (2018) Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci 21:564–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu S, Li Y, Bai Y et al (2019) SHANK1 polymorphisms and SNP–SNP interactions among SHANK family: a possible cue for recognition to autism spectrum disorder in infant age. Autism Res 12:375–383

    Article  PubMed  Google Scholar 

  • Qiu S, Li Y, Li Y et al (2018) Association between SHANK3 polymorphisms and susceptibility to autism spectrum disorder. Gene 651:100–105

    Article  CAS  PubMed  Google Scholar 

  • Rendall AR, Perrino PA, Buscarello AN, Fitch RH (2019) Shank3B mutant mice display pitch discrimination enhancements and learning deficits. Int J Dev Neurosci 72:13–21

  • Roselli F, Hutzler P, Wegerich Y, Livrea P, Almeida OF (2009) Disassembly of shank and homer synaptic clusters is driven by soluble beta-amyloid(1–40) through divergent NMDAR-dependent signalling pathways. PLoS ONE 4:e6011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sarasua SM, Boccuto L, Sharp JL et al (2014) Clinical and genomic evaluation of 201 patients with Phelan–McDermid syndrome. Hum Genet 133:847–859

    Article  CAS  PubMed  Google Scholar 

  • Sato D, LionelAC LCS et al (2012) SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet 90:879–887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmeisser MJ, Ey E, Wegener S et al (2012) Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486:256–260

    Article  CAS  PubMed  Google Scholar 

  • Seungjoon L, Eunee L, Ryunhee K et al (2018) Shank2 deletion in parvalbumin neurons leads to moderate hyperactivity, enhanced self-grooming and suppressed seizure susceptibility in mice. Front Mol Neurosci 11:209

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sheng M, Sabatini BL, Sudhof TC (2012) Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol 4(5):a005777

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Silverman JL, Turner SM, Barkan CL et al (2011) Sociability and motor functions in Shank1 mutant mice. Brain Res 1380:120–137

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455:903–911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sungur AO, Jochner MCE, Hani H, Ayse K, Holger G, Rainer KWS, Markus W (2017) Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder. Hippocampus 27:906–919

    Article  CAS  PubMed  Google Scholar 

  • Sungur AÖ, Redecker TM, Andres E et al (2018) Reduced efficacy of d-amphetamine and 3,4-methylenedioxymethamphetamine in inducing hyperactivity in mice lacking the postsynaptic scaffolding protein SHANK1. Front Mol Neurosci 11:419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sungur AO, Schwarting RK, Wohr M (2016) Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context. Autism Res 9:696–709

    Article  PubMed  Google Scholar 

  • Sungur AO, Vorckel KJ, Schwarting RK, Wohr M (2014) Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context. J Neurosci Methods 234:92–100

    Article  CAS  PubMed  Google Scholar 

  • Tatavarty V, Pacheco AT, Kuhnle CG, Lin H, Turrigiano GG (2017) Autism-associated Shank3 is essential for homeostatic compensation in rodent V1. Neuron 106:769–777

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Verhoeven WM, Egger JI, Willemsen MH, Leijer GJD, Kleefstra T et al (2012) Phelan–McDermid syndrome in two adult brothers: atypical bipolar disorder as its psychopathological phenotype? Neuropsychiatr Dis Treat 8:175–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vicidomini C, Ponzoni L, Lim D et al (2016) Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. Mol Psychiatry 22:689–702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vucurovic K, Landais E, Delahaigue C et al (2012) Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Eur J Med Genet 55:625–629

    Article  PubMed  Google Scholar 

  • Wang T, Guo H, Xiong B et al (2016a) De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun 7:13316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Adamski CJ, Bondar VV et al (2019a) A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability. Mol Psychiatry 25:2504–2516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang L, Pang K, Han K et al (2019b) An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function. Mol Psychiatry 25:2534–2555

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang W, Li C, Chen Q et al (2017) Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism. J Clin Investig 127:1978–1990

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Bey AL, Katz BM et al (2016b) Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun 7:11459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang ZJ, Zhong P, Ma K et al (2019c) Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry 25:2517–2533

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Watt JL, Olson IA, Johnston AW, Ross HS, Couzin DA, Stephen GSA (1985) Familial pericentric inversion of chromosome 22 with a recombinant subject illustrating a ‘pure’ partial monosomy syndrome. J Med Genet 22:283–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wegener S, Buschler A, Stempel AV et al (2018) Defective synapse maturation and enhanced synaptic plasticity in Shank2 Deltaex7(−/−) mice. eNeuro 5:ENEURO0398-17

    Article  Google Scholar 

  • Wischmeijer A, Magini P, Giorda R et al (2011) Olfactory receptor-related duplicons mediate a microdeletion at 11q13.2q13.4 associated with a syndromic phenotype. Mol Syndromol 1:176–184

    Article  CAS  PubMed  Google Scholar 

  • Wohr M, Roullet FI, Hung AY, Sheng M, Crawley JN (2011) Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS ONE 6:e20631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong AC, Ning Y, Flint J et al (1997) Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation. Am J Hum Genet 60:113–120

    CAS  PubMed  PubMed Central  Google Scholar 

  • Won H, Lee HR, Gee HY et al (2012) Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486:261–265

    Article  CAS  PubMed  Google Scholar 

  • Yang YWX, Jiang YH (2018) SHANK2 harbors potentially pathogenic mutations associated with bipolar disorder. Bipolar Disord 20:63–141

    Google Scholar 

  • Yang Z, Kaiser T, Monteiro P et al (2016) Mice with Shank3 mutations associated with ASD and schizophrenia display both shared and distinct defects. Neuron 89:147–162

    Article  CAS  Google Scholar 

  • Yoo T, Cho H, Lee J, Park H, Kim E (2018) GABA neuronal deletion of Shank3 exons 14–16 in mice suppresses striatal excitatory synaptic input and induces social and locomotor abnormalities. Front Cell Neurosci 12:341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo T, Cho H, Park H, Lee J, Kim E (2019a) Shank3 exons 14–16 deletion in glutamatergic neurons leads to social and repetitive behavioral deficits associated with increased cortical layer 2/3 neuronal excitability. Front Cell Neurosci 13:458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo YE, Yoo T, Lee S et al (2019b) Shank3 mice carrying the human Q321R mutation display enhanced self-grooming, abnormal electroencephalogram patterns, and suppressed neuronal excitability and seizure susceptibility. Front Mol Neurosci 12:155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaslavsky K, Zhang WB, McCready FP et al (2019) SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons. Nat Neurosci 22:556–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Sun XY, Zhang LY (2017) MicroRNA-7/Shank3 axis involved in schizophrenia pathogenesis. J Clin Neurosci 22:1254–1257

    Article  CAS  Google Scholar 

  • Zhang Y, Gao BB, Xiong Y et al (2016) Expression of SHANK3 in the temporal neocortex of patients with intractable temporal epilepsy and epilepsy rat models. Cell Mol Neurobiol 37:1–11

    Google Scholar 

  • Zhao Y, Jaber VR, LeBeauf A, Sharfman NM, Lukiw WJ (2019) MicroRNA-34a (miRNA-34a) mediated down-regulation of the post-synaptic cytoskeletal element SHANK3 in sporadic Alzheimer’s disease (AD). Front Neurol 10:28

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Kaiser T, Monteiro P et al (2016) Mice with Shank3 mutations associated with ASD and schizophrenia display both shared and distinct defects. Neuron 89:147–162

  • Zhou Y, Sharma J, Ke Q et al (2019) Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature 570:326–331

    Article  CAS  PubMed  Google Scholar 

  • Zwanenburg RJ, Ruiter SA, Van Den Heuvel ER, Flapper BC, Van Ravenswaaij-Arts CM (2016) Developmental phenotype in Phelan–McDermid (22q13.3 deletion) syndrome: a systematic and prospective study in 34 children. J Neurodev Disord 8:16

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work has been supported through funding from the National Natural Science Foundation, China (Grant Number 81671299), The Hunan Natural Science Foundation (Grant Number 2018JJ2648).

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Author notes

  1. Lily Wan and Du Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Lily Wan, Du Liu, Wen-Biao Xiao, Bo-Xin Zhang, Zhao-Hui Luo & Bo Xiao

  2. Taikang Tongji Hospital, Wuhan, 430050, Hubei, China

    Du Liu

  3. Department of Anatomy and Neurobiology, Central South University, Changsha, 410013, Hunan, China

    Xiao-Xin Yan

Authors
  1. Lily Wan
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  2. Du Liu
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  3. Wen-Biao Xiao
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  4. Bo-Xin Zhang
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  5. Xiao-Xin Yan
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  6. Zhao-Hui Luo
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Contributions

L-W and D-L drafted the manuscript; W-BX and B-XZ draw the figures; Z-HL designed the outline and revised the manuscript; X-XY proof-edited and finalized the manuscript; BX provided financial support. All of the authors have approved of the publication of the manuscript.

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Correspondence to Zhao-Hui Luo or Bo Xiao.

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All procedures were followed in accordance with the Ethical Standards of the Responsible Committee on Animal and Human Experimentation (The Ethics Review Committee of Xiangya Hospital, Numbers 201603296 and 201603297) and with the Helsinki Declaration of 1964 and later versions.

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Wan, L., Liu, D., Xiao, WB. et al. Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries. Cell Mol Neurobiol 42, 1623–1643 (2022). https://doi.org/10.1007/s10571-021-01054-x

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