Publikationsserver der Universitätsbibliothek Marburg

Titel:Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: From Brain to Behavior
Autor:Sungur, Ayse Özge
Weitere Beteiligte: Wöhr, Markus (Dr.)
URN: urn:nbn:de:hebis:04-z2017-06725
DDC: Psychologie
Titel (trans.):Aufklärung der Funktion von SHANK1 in einem Mausmodell für Autismus-Spektrum-Störung: vom Gehirn zum Verhalten


Maus, Verhaltensforschung, postsynaptische Gerüstproteine, Autismus, excitatory synapse, scaffolding proteins, SHANK, mouse model, communication ,, postsynaptic density, Exzitatorische Synapse, Ultraschallvokalisation, Autismus-Spektrum-Störung, ultrasonic vocalization, Sozialverhalten, Tiermodell, Kommunikation, Autism Spectrum Disorder, Neurobiologie

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by persistent deficits in social communication and interaction across multiple contexts, and restricted, repetitive patterns of behavior; frequently comorbid with intellectual disability (ID). Several studies highlight immense contribution of genetic factors to disease etiology. Particularly, the SHANK family of postsynaptic proteins has emerged as promising candidates, considering that mutations in SHANK1, SHANK2, and SHANK3 genes have repeatedly been reported in individuals with ASD. Animal models provide excellent translational tools to discover disease pathogenesis underlying behavioral and neurobiological abnormalities. This dissertation aimed at understanding these mechanisms by using the Shank1 knockout mouse model for ASD, with an in-depth and longitudinal focus on each diagnostic symptom. Specifically, ASD-like phenotypes were investigated throughout development and across different social contexts. While social behavior was only moderately affected in mice lacking SHANK1 (Study I), evidence for communication deficits and repetitive behavior throughout development and/or across different social contexts were demonstrated in these animals (Study II&III). In conjunction with ASD – ID comorbidity, deletion of Shank1 resulted in severe cognitive impairments (Study I). Highlighting the pivotal role of the hippocampus in this mechanism, elevated levels of learning-associated brain-derived neurotrophic factor were found in the hippocampi of Shank1 mutants. This increase in protein expression was paralleled by alterations in epigenetic regulation (Study I). Overall, results of the studies presented here indicate that SHANK1 is involved in ASD-relevant deficits across species. These findings further extend the knowledge on social communication and interaction, repetitive behaviors, and cognitive phenotypes displayed by the Shank1 mouse model for ASD in an age- and sex-dependent manner, underscoring the importance of social context in ASD research.

Bibliographie / References

  1. Carbonetto S. 2014. A blueprint for research on Shankopathies: A view from research on autism spectrum disorder. Dev Neurobiol 74:85-112.
  2. Ebert DH, Greenberg ME. 2013. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493:327-37.
  3. Durkin MS, Maenner MJ, Newschaffer CJ, Lee L-C, Cunniff CM, Daniels JL, Kirby RS et al. 2008. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol 168:1268-76.
  4. Abrahams BS, Geschwind DH. 2008. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341-55.
  5. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Bentley DR, Chakravarti A, Clark AG et al. 2015. A global reference for human genetic variation. Nature 526:68-74.
  6. Epstein I, Tushev G, Will TJ, Vlatkovic I, Cajigas IJ, Schuman EM. 2014. Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil. Philos Trans R Soc L B Biol Sci 369:20130137.
  7. Lewis MH, Tanimura Y, Lee LW, Bodfish JW. 2007. Animal models of restricted repetitive behavior in autism. Behav Brain Res 176:66-74.
  8. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M. 1995. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63.
  9. Kanner L. 1943. Autistic disturbances of affective contact. Nerv Child 2:217-250.
  10. Louhivuori V, Vicario A, Uutela M, Rantamäki T, Louhivuori LM, Castrén E, Tongiorgi E et al. 2011. BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse. Neurobiol Dis 41:469-480.
  11. Cowansage KK, LeDoux JE, Monfils M-H. 2010. Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr Mol Pharmacol 3:12-29.
  12. Connolly AM, Chez M, Streif EM, Keeling RM, Golumbek PT, Kwon JM, Riviello JJ et al. 2006. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biol Psychiatry 59:354-63.
  13. Gillberg C, Cederlund M, Lamberg K, Zeijlon L. 2006. Brief report: “the autism epidemic”. The registered prevalence of autism in a Swedish urban area. J Autism Dev Disord 36:429-35.
  14. Lim S, Naisbitt S, Yoon J, Hwang JI, Suh PG, Sheng M, Kim E. 1999. Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J Biol Chem 274:29510-8.
  15. Gogolla N, LeBlanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK. 2009. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1:172-181.
  16. Matson JL, Cervantes PE. 2013. Comorbidity among persons with intellectual disabilities. Res Autism Spectr Disord 7:1318-1322.
  17. Jorde LB, Hasstedt SJ, Ritvo ER, Mason-Brothers A, Freeman BJ, Pingree C, McMahon WM et al. 1991. Complex segregation analysis of autism. Am J Hum Genet 49:932-8.
  18. Cook Jr EH, Scherer SW. 2008. Copy-number variations associated with neuropsychiatric conditions. Nature 455:919-923.
  19. Crawley JN. 2004. Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 10:248-58.
  20. American Psychiatric Association. 2013. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. American Psychiatric Publishing, Inc.
  21. Asperger H. 1944. Die „Autistischen Psychopathen” im Kindesalter. Arch Psychiatr Nervenkr 117:76-136.
  22. Grabrucker AM. 2013. Environmental factors in autism. Front Psychiatry 3:1-13.
  23. Lotter V. 1966. Epidemiology of autistic conditions in young children - 1. Prevalence. Soc Psychiatry 1:124-135.
  24. Amiet C, Gourfinkel-An I, Bouzamondo A, Tordjman S, Baulac M, Lechat P, Mottron L et al. 2008. Epilepsy in Autism is Associated with Intellectual Disability and Gender: Evidence from a Meta-Analysis. Biol Psychiatry 64:577-582.
  25. Mannion A, Leader G. 2014. Epilepsy in autism spectrum disorder. Res Autism Spectr Disord 8:354-361.
  26. Christianson AL, Chester N, Kromberg JGR. 1994. Fetal Valproate Syndrome: Clinical and Neuro-developmental Features in Two Sibling Pairs. Dev Med Child Neurol 36:361-369.
  27. Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M et al. 2012. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 8:e1002521.
  28. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. 1995. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92:8856-60.
  29. Lai M-C, Lerch JP, Floris DL, Ruigrok AN V, Pohl A, Lombardo M V, Baron-Cohen S. 2017. Imaging sex/gender and autism in the brain: Etiological implications. J Neurosci Res 95:380-397.
  30. Almeida LEF, Roby CD, Krueger BK. 2014. Increased BDNF expression in fetal brain in the valproic acid model of autism. Mol Cell Neurosci 59:57-62.
  31. Correia CT, Coutinho AM, Sequeira AF, Sousa IG, Lourenço Venda L, Almeida JP, Abreu RL et al. 2010. Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes Brain Behav 9:841-8.
  32. Dykens EM, Lense M. 2011. Intellectual Disabilities and Autism Spectrum Disorder: A Cautionary Note In Autism Spectrum Disorders Oxford University Press, p. 263-269.
  33. Baxter MG. 2010. “I've seen it all before”: explaining age-related impairments in object Cann M. 1998. Human genome diversity. Life Sci:443-446.
  34. Kogan JH, Frankland PW, Silva AJ. 2000. Long-term memory underlying hippocampusdependent social recognition in mice. Hippocampus 10:47-56.
  35. Kouser M, Speed HE, Dewey CM, Reimers JM, Widman AJ, Gupta N, Liu S et al. 2013. Loss of Predominant Shank3 Isoforms Results in Hippocampus-Dependent Impairments in Behavior and Synaptic Transmission. J Neurosci 33:18448-18468.
  36. Croen LA, Najjar D V, Fireman B, Grether JK. 2007. Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med 161:334-40.
  37. Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET. 2010. Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders. J Autism Dev Disord 40:1423-1430.
  38. Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F et al. 2014. Metaanalysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Lepeta K, Lourenco M V., Schweitzer BC, Martino Adami P V., Banerjee P, Catuara-Solarz S, de La Fuente Revenga M et al. 2016. Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students. J Neurochem 138:785-805.
  39. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G et al. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39:25-7.
  40. Kandel ER. 2000. Nerve cells and behavior In E. Kandel, J. Schwartz, & T. Jessell, eds. Principles of neural science McGraw-Hill New York, NY, p. 19-35.
  41. Gauthier J, Spiegelman D, Piton A, Lafrenière RG, Laurent S, St-Onge J, Lapointe L et al. 2009. Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet Part B Neuropsychiatr Genet 150B:421-424.
  42. Barnard CJ, Hurst JL, Aldhous P. 1991. Of mice and kin: the functional significance of kin bias in social behaviour. Biol Rev Camb Philos Soc 66:379-430.
  43. Ferguson JN, Aldag JM, Insel TR, Young LJ. 2001. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21:8278-85.
  44. Kim E, Sheng M. 2004. PDZ domain proteins of synapses. Nat Rev Neurosci 5:771-81.
  45. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. 2013. Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism. JAMA 309:1696.
  46. Baron-Cohen S, Scott FJ, Allison C, Williams J, Bolton P, Matthews FE, Brayne C. 2009. Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry 194:500-509.
  47. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA et al. 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471-5.
  48. Filice F, Vörckel KJ, Sungur AÖ, Wöhr M, Schwaller B. 2016. 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.
  49. Catarino T, Ribeiro L, Santos SD, Carvalho AL. 2013. Regulation of synapse composition by protein acetylation: the role of acetylated cortactin. J Cell Sci 126:149-162.
  50. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185-188.
  51. Arakawa H, Blanchard DC, Arakawa K, Dunlap C, Blanchard RJ. 2008. Scent marking behavior as an odorant communication in mice. Neurosci Biobehav Rev 32:1236-1248.
  52. Mao W, Watanabe T, Cho S, Frost JL, Truong T, Zhao X, Futai K. 2015. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur J Neurosci 41:1025-35.
  53. Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. 2000. Social amnesia in mice lacking the oxytocin gene. Nat Genet 25:284-8.
  54. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H. 2003. Structure-stability-function relationships of dendritic spines. Trends Neurosci 26:360-368.
  55. Kandel ER, Siegelbaum SA. 2000. Synaptic integration In E. Kandel, J. Schwartz, & T. Jessell, eds. Principles of neural science McGraw-Hill New York, NY, p. 209-228.
  56. Elwood RW, Keeling F. 1982. Temporal organization of ultrasonic vocalizations in infant mice. Dev Psychobiol 15:221-7.
  57. Ey E, Torquet N, Le Sourd AM, Leblond CS, Boeckers TM, Faure P, Bourgeron T. 2013. The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations. Behav Brain Res 256:677-689.
  58. Landry SH, Loveland K a. 1989. The effect of social context on the functional communication skills of autistic children. J Autism Dev Disord 19:283-99.
  59. Guilmatre A, Huguet G, Delorme R, Bourgeron T. 2014. The emerging role of SHANK genes in neuropsychiatric disorders. Dev Neurobiol 74:113-22.
  60. Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H. 2010. The Genetics of Autism Spectrum Disorders and Related Neuropsychiatric Disorders in Childhood. Am J Psychiatry 167:1357-1363.
  61. Ehret G, Haack B. 1982. Ultrasound recognition in house mice: Key-Stimulus configuration and recognition mechanism. J Comp Physiol 148:245-251.
  62. Crawley JN. 2007. What's Wrong With My Mouse? Hoboken, NJ, USA: John Wiley & Sons, Inc.
  63. Lamb JA. 2011. Whole Genome Linkage and Association Analyses In D. Amaral, D. Geschwind, & G. Dawson, eds. Autism Spectrum Disorders. Oxford University Press, p. 669-689.
  64. Baron-Cohen S, Lombardo M V, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer R. 2011. Why are autism spectrum conditions more prevalent in males? PLoS Biol 9:e1001081.

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