Nothing Special   »   [go: up one dir, main page]

Skip to main content

Genetic Animal Models for Autism Spectrum Disorder

  • Chapter
  • First Online:
Social Behavior from Rodents to Humans

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 30))

Abstract

Autism spectrum disorder (ASD) affects approximately 1 % of the human population and has a strong genetic component. Hence, the recent discovery of major “ASD genes” has subsequently resulted in the generation of several genetic animal models of ASD. Careful analysis of behavioral phenotypes and characterization of the underlying neurobiological mechanisms in these models should further help us to identify novel therapeutic targets and develop more effective strategies in the future to ameliorate or even reverse core symptoms and comorbidities of ASD. In this review, we will focus on the mutant mouse as animal model and outline how to characterize both behavioral and neurobiological phenotypes in this organism. We will further discuss a selection of major ASD mutant mouse lines. Our conclusions will finally address the current goals and perspectives in the field to obtain a more comprehensive and possibly also converging picture of ASD pathogenesis, which could be most useful for the desired bench-to-bedside strategy of translational medicine for this complex disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Auerbach BD, Osterweil EK, Bear MF (2011) Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480(7375):63–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baudouin SJ, Gaudias J, Gerharz S, Hatstatt L, Zhou K, Punnakkal P, Tanaka KF, Spooren W, Hen R, De Zeeuw CI, Vogt K, Scheiffele P (2012) Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 338(6103):128–132

    Article  CAS  PubMed  Google Scholar 

  • Bhakar AL, Dolen G, Bear MF (2012) The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci 35:417–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bourgeron T (2015) From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci 16(9):551–563

    Article  CAS  PubMed  Google Scholar 

  • Bozdagi O, Tavassoli T, Buxbaum JD (2013) Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism 4(1):9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU, Heintz N, Crawley JN (2008) Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res 1(3):147–158

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang Q, Khare G, Dani V, Nelson S, Jaenisch R (2006) The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49(3):341–348

    Article  CAS  PubMed  Google Scholar 

  • Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY (2010) Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468(7321):263–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen JA, Penagarikano O, Belgard TG, Swarup V, Geschwind DH (2015) The emerging picture of autism spectrum disorder: genetics and pathology. Annu Rev Pathol 10:111–144

    Article  CAS  PubMed  Google Scholar 

  • Davis PE, Peters JM, Krueger DA, Sahin M (2015) Tuberous sclerosis: a new frontier in targeted treatment of autism. Neurotherapeutics 12(3):572–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimaki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Study DDD, Consortium UK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515(7526):209–215

    Google Scholar 

  • Dolen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56(6):955–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ehninger D (2013) From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches. Neuropharmacology 68:97–105

    Article  CAS  PubMed  Google Scholar 

  • El-Kordi A, Winkler D, Hammerschmidt K, Kastner A, Krueger D, Ronnenberg A, Ritter C, Jatho J, Radyushkin K, Bourgeron T, Fischer J, Brose N, Ehrenreich H (2013) Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism. Behav Brain Res 251:41–49

    Article  CAS  PubMed  Google Scholar 

  • Etherton M, Foldy C, Sharma M, Tabuchi K, Liu X, Shamloo M, Malenka RC, Sudhof TC (2011) Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc Natl Acad Sci USA 108(33):13764–13769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ey E, Yang M, Katz AM, Woldeyohannes L, Silverman JL, Leblond CS, Faure P, Torquet N, Le Sourd AM, Bourgeron T, Crawley JN (2012) Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4. Genes Brain Behav 11(8):928–941

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315(5815):1143–1147

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Jiang YH, Ehlers MD (2013) Modeling autism by SHANK gene mutations in mice. Neuron 78(1):8–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kas MJ, Modi ME, Saxe MD, Smith DG (2014) Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents. Psychopharmacology 231(6):1147–1165

    Article  CAS  PubMed  Google Scholar 

  • Kleijer KT, Schmeisser MJ, Krueger DD, Boeckers TM, Scheiffele P, Bourgeron T, Brose N, Burbach JP (2014) Neurobiology of autism gene products: towards pathogenesis and drug targets. Psychopharmacology 231(6):1037–1062

    Article  CAS  PubMed  Google Scholar 

  • Koekkoek SK, Yamaguchi K, Milojkovic BA, Dortland BR, Ruigrok TJ, Maex R, De Graaf W, Smit AE, VanderWerf F, Bakker CE, Willemsen R, Ikeda T, Kakizawa S, Onodera K, Nelson DL, Mientjes E, Joosten M, De Schutter E, Oostra BA, Ito M, De Zeeuw CI (2005) Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome. Neuron 47(3):339–352

    Article  CAS  PubMed  Google Scholar 

  • Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemiere N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T (2014) Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet 10(9):e1004580

    Article  PubMed  PubMed Central  Google Scholar 

  • Lyst MJ, Bird A (2015) Rett syndrome: a complex disorder with simple roots. Nat Rev Genet 16(5):261–275

    Article  CAS  PubMed  Google Scholar 

  • McGraw CM, Samaco RC, Zoghbi HY (2011) Adult neural function requires MeCP2. Science 333(6039):186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472(7344):437–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, Sonnenblick LI, Gruver R, Almajano J, Bragin A, Golshani P, Trachtenberg JT, Peles E, Geschwind DH (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147(1):235–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penagarikano O, Geschwind DH (2012) What does CNTNAP2 reveal about autism spectrum disorder? Trends Mol Med 18(3):156–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penagarikano O, Lazaro MT, Lu XH, Gordon A, Dong H, Lam HA, Peles E, Maidment NT, Murphy NP, Yang XW, Golshani P, Geschwind DH (2015) Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med 7(271):271ra8

    Google Scholar 

  • Pohodich AE, Zoghbi HY (2015) Rett syndrome: disruption of epigenetic control of postnatal neurological functions. Hum Mol Genet

    Google Scholar 

  • Radyushkin K, Hammerschmidt K, Boretius S, Varoqueaux F, El-Kordi A, Ronnenberg A, Winter D, Frahm J, Fischer J, Brose N, Ehrenreich H (2009) Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav 8(4):416–425

    Article  CAS  PubMed  Google Scholar 

  • Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, Fowler SC, Malenka RC, Sudhof TC (2014) Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell 158(1):198–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santini E, Klann E (2014) Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal 7(349):re10

    Google Scholar 

  • Schmeisser MJ (2015) Translational neurobiology in Shank mutant mice–model systems for neuropsychiatric disorders. Ann Anat 200:115–117

    Article  PubMed  Google Scholar 

  • Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, Kuebler A, Janssen AL, Udvardi PT, Shiban E, Spilker C, Balschun D, Skryabin BV, Dieck S, Smalla KH, Montag D, Leblond CS, Faure P, Torquet N, Le Sourd AM, Toro R, Grabrucker AM, Shoichet SA, Schmitz D, Kreutz MR, Bourgeron T, Gundelfinger ED, Boeckers TM (2012) Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486(7402):256–260

    CAS  PubMed  Google Scholar 

  • Silverman JL, Yang M, Lord C, Crawley JN (2010) Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11(7):490–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455(7215):903–911

    Article  PubMed  PubMed Central  Google Scholar 

  • Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Sudhof TC (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318(5847):71–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83(5):1131–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, Steinberg J, Crawley JN, Regehr WG, Sahin M (2012) Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488(7413):647–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verpelli C, Schmeisser MJ, Sala C, Boeckers TM (2012) Scaffold proteins at the postsynaptic density. Adv Exp Med Biol 970:29–61

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Pati S, Pozzo-Miller L, Doering LC (2015) Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes. Front Cell Neurosci 9:55

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wohr M, Scattoni ML (2013) Behavioural methods used in rodent models of autism spectrum disorders: current standards and new developments. Behav Brain Res 251:5–17

    Article  PubMed  Google Scholar 

  • Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, Ha S, Chung C, Jung ES, Cho YS, Park SG, Lee JS, Lee K, Kim D, Bae YC, Kaang BK, Lee MG, Kim E (2012) Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486(7402):261–265

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael J. Schmeisser .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland AG

About this chapter

Cite this chapter

Schroeder, J.C., Reim, D., Boeckers, T.M., Schmeisser, M.J. (2015). Genetic Animal Models for Autism Spectrum Disorder. In: Wöhr, M., Krach, S. (eds) Social Behavior from Rodents to Humans. Current Topics in Behavioral Neurosciences, vol 30. Springer, Cham. https://doi.org/10.1007/7854_2015_407

Download citation

Publish with us

Policies and ethics