Skip to main content

Treatment Approaches in Rodent Models for Autism Spectrum Disorder

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

Abstract

Recent years have seen an impressive amount of research devoted to the developing of therapies to treat autism spectrum disorder (ASD). This work has been largely based on rodent models, employing a multitude of genetic and environmental manipulations. Unfortunately, the task of identifying suitable treatments for ASD is extremely challenging, due to a variety of problems specific to the research in this field. Here, we first discuss these problems, including (I) the presence of a large variety of rodent models (often without universal consensus on their validity), (II) the difficulties in choosing the most appropriate behavioural markers to assess the efficacy of possible treatments, (III) the limited knowledge we still have of the neurobiological bases of ASD pathology and of its aetiology, and (IV) the complexity of ASD itself, including a highly heterogeneous group of disorders sometimes with markedly different symptoms (therefore unlikely to be treated with the same approaches). Second, we give a critical overview of the most relevant advances in designing treatments for ASD, focusing on the most commonly used animal model, the laboratory mouse. We include pharmacological and non-pharmacological approaches, underlining their specific advantages, but also their current limitations especially in relation to the problems discussed before. Finally, we highlight the theoretical (e.g. the combination of multiple rather than single treatments) and methodological (e.g. use of single-gene mouse models) approaches that seem more promising to us, suggesting various strategies that can be adopted to simplify the complex field of research on treatments for ASD.

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

Access this chapter

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

References

  • Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee S, Riordan M, Bhat MA (2014) Genetic aspects of autism spectrum disorders: insights from animal models. Front Cell Neurosci 8:58

    Article  PubMed  PubMed Central  Google Scholar 

  • Bey AL, Jiang YH (2014) Overview of mouse models of autism spectrum disorders. Curr Protoc Pharmacol/Editorial Board, S.J. Enna, 66:5.66.1–5.66.26

    Google Scholar 

  • Budimirovic DB, Kaufmann WE (2011) What can we learn about autism from studying fragile X syndrome? Dev Neurosci 33:379–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crawley JN (2004) Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 10:248–258

    Article  PubMed  Google Scholar 

  • Crawley JN (2007) Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol 17:448–459

    Article  PubMed  Google Scholar 

  • Crusio WE (2015) Key issues in contemporary behavioral genetics. Curr Opin Behav Sci 2:89–95

    Article  Google Scholar 

  • Crusio WE, Goldowitz D, Holmes A, Wolfer D (2009) Standards for the publication of mouse mutant studies. Genes Brain Behav 8:1–4

    Article  CAS  PubMed  Google Scholar 

  • Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, Bourgeron T (2013) Progress toward treatments for synaptic defects in autism. Nat Med 19:685–694

    Article  CAS  PubMed  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 56:955–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dufour-Rainfray D, Vourc’h P, Tourlet S, Guilloteau D, Chalon S, Andres CR (2011) Fetal exposure to teratogens: evidence of genes involved in autism. Neurosci Biobehav Rev 35:1254–1265

    Article  CAS  PubMed  Google Scholar 

  • Ellegood J, Crawley JN (2015) Behavioral and neuroanatomical phenotypes in mouse models of autism. Neurother J Am Soc Exp Neurother 12:521–533

    Article  CAS  Google Scholar 

  • Gerlai R (1996) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci 19:177–181

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Liencres C, Juckel G, Tas C, Friebe A, Brune M (2014) Emotional contagion in mice: the role of familiarity. Behav Brain Res 263:16–21

    Article  PubMed  Google Scholar 

  • Gross C, Berry-Kravis EM, Bassell GJ (2012) Therapeutic strategies in fragile X syndrome: dysregulated mGluR signaling and beyond. Neuropsychopharmacol Official Publ Am Coll Neuropsychopharmacol 37:178–195

    Article  CAS  Google Scholar 

  • Happe F, Ronald A, Plomin R (2006) Time to give up on a single explanation for autism. Nat Neurosci 9:1218–1220

    Article  CAS  PubMed  Google Scholar 

  • Hebert B, Pietropaolo S, Meme S, Laudier B, Laugeray A, Doisne N, Quartier A, Lefeuvre S, Got L, Cahard D, Laumonnier F, Crusio WE, Pichon J, Menuet A, Perche O, Briault S (2014) Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule. Orphanet J Rare Dis 9:124

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Krueger DD, Bear MF (2011) Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 62:411–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Langford DJ, Crager SE, Shehzad Z, Smith SB, Sotocinal SG, Levenstadt JS, Chanda ML, Levitin DJ, Mogil JS (2006) Social modulation of pain as evidence for empathy in mice. Science 312:1967–1970

    Article  CAS  PubMed  Google Scholar 

  • Lofthouse N, Hendren R, Hurt E, Arnold LE, Butter E (2012) A review of complementary and alternative treatments for autism spectrum disorders. Autism Res Treat 2012:870391

    PubMed  PubMed Central  Google Scholar 

  • Lonetti G, Angelucci A, Morando L, Boggio EM, Giustetto M, Pizzorusso T (2010) Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol Psychiatry 67:657–665

    Article  PubMed  Google Scholar 

  • Markram K, Markram H (2010) The intense world theory—a unifying theory of the neurobiology of autism. Frontiers Hum Neurosci 4:224

    Article  Google Scholar 

  • McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN (2008) Autism-like behavioral phenotypes in BTBR T+ tf/J mice. Genes Brain Behav 7:152–163

    Article  CAS  PubMed  Google Scholar 

  • McOmish CE, Burrows EL, Hannan AJ (2014) Identifying novel interventional strategies for psychiatric disorders: integrating genomics, ‘enviromics’ and gene-environment interactions in valid preclinical models. Br J Pharmacol 171:4719–4728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyza KZ, Defensor EB, Jensen AL, Corley MJ, Pearson BL, Pobbe RL, Bolivar VJ, Blanchard DC, Blanchard RJ (2013) The BTBR T+ tf/J mouse model for autism spectrum disorders-in search of biomarkers. Behav Brain Res 251:25–34

    Article  CAS  PubMed  Google Scholar 

  • Modi ME, Young LJ (2012) The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies. Horm Behav 61:340–350

    Article  CAS  PubMed  Google Scholar 

  • Moy SS, Nadler JJ, Magnuson TR, Crawley JN (2006) Mouse models of autism spectrum disorders: the challenge for behavioral genetics. Am J Med Genet C Semin Med Genet 142C:40–51

    Article  CAS  PubMed  Google Scholar 

  • Myers SM, Johnson CP (2007) Management of children with autism spectrum disorders. Pediatrics 120:1162–1182 (American Academy of Pediatrics Council on Children)

    Google Scholar 

  • Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7:697–709

    Article  CAS  PubMed  Google Scholar 

  • Oddi D, Crusio WE, D’Amato FR, Pietropaolo S (2013) Monogenic mouse models of social dysfunction: implications for autism. Behav Brain Res 251:75–84

    Article  CAS  PubMed  Google Scholar 

  • Oddi D, Subashi E, Middei S, Bellocchio L, Lemaire-Mayo V, Guzman M, Crusio WE, D’Amato FR, Pietropaolo S (2015) Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome. Neuropsychopharmacol Official Publ Am Coll Neuropsychopharmacol 40:1113–1122

    Article  Google Scholar 

  • Pardo CA, Eberhart CG (2007) The neurobiology of autism. Brain pathol 17:434–447

    Article  CAS  PubMed  Google Scholar 

  • Patterson PH (2011) Maternal infection and immune involvement in autism. Trends Mol Med 17:389–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pietropaolo S, Goubran MG, Joffre C, Aubert A, Lemaire-Mayo V, Crusio WE, Laye S (2014) Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice. Psychoneuroendocrinology 49:119–129

    Article  CAS  PubMed  Google Scholar 

  • Pietropaolo S, Guilleminot A, Martin B, D’Amato FR, Crusio WE (2011) Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice. PLoS ONE 6:e17073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rapin I (1991) Autistic children: diagnosis and clinical features. Pediatrics 87:751–760

    CAS  PubMed  Google Scholar 

  • Restivo L, Ferrari F, Passino E, Sgobio C, Bock J, Oostra BA, Bagni C, Ammassari-Teule M (2005) Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc Natl Acad Sci USA 102:11557–11562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reynolds S, Urruela M, Devine DP (2013) Effects of environmental enrichment on repetitive behaviors in the BTBR T+ tf/J mouse model of autism. Autism Res Official J Int Soc Autism Res 6:337–343

    Article  Google Scholar 

  • Ruhela RK, Prakash A, Medhi B (2015) An urgent need for experimental animal model of autism in drug development. Ann Neurosci 22:44–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanders J, Mayford M, Jeste D (2013) Empathic fear responses in mice are triggered by recognition of a shared experience. PLoS ONE 8:e74609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scattoni ML, Crawley J, Ricceri L (2009) Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci Biobehav Rev 33:508–515

    Article  PubMed  Google Scholar 

  • Servadio M, Vanderschuren LJ, Trezza V (2015) Modeling autism-relevant behavioral phenotypes in rats and mice: do ‘autistic’ rodents exist? Behav Pharmacol 26:522–540

    Article  CAS  PubMed  Google Scholar 

  • Silverman JL, Crawley JN (2014) The promising trajectory of autism therapeutics discovery. Drug Discovery Today 19:838–844

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terranova ML, Laviola G, de Acetis L, Alleva E (1998) A description of the ontogeny of mouse agonistic behavior. J Comp Psychol 112:3–12

    Article  CAS  PubMed  Google Scholar 

  • Tordjman S, Davlantis KS, Georgieff N, Geoffray MM, Speranza M, Anderson GM, Xavier J, Botbol M, Oriol C, Bellissant E, Vernay-Leconte J, Fougerou C, Hespel A, Tavenard A, Cohen D, Kermarrec S, Coulon N, Bonnot O, Dawson G (2015) Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives. Frontiers Pediatr 3:1

    Article  Google Scholar 

  • Watanabe S (2011) Empathy and reversed empathy of stress in mice. PLoS ONE 6:e23357

    Article  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 

  • Woo CC, Donnelly JH, Steinberg-Epstein R, Leon M (2015) Environmental enrichment as a therapy for autism: a clinical trial replication and extension. Behav Neurosci 129:412–422

    Article  PubMed  PubMed Central  Google Scholar 

  • Woo CC, Leon M (2013) Environmental enrichment as an effective treatment for autism: a randomized controlled trial. Behav Neurosci 127:487–497

    Article  PubMed  Google Scholar 

  • Zhang Y, Bonnan A, Bony G, Ferezou I, Pietropaolo S, Ginger M, Sans N, Rossier J, Oostra B, LeMasson G, Frick A (2014) Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice. Nat Neurosci 17:1701–1709

    Article  CAS  PubMed  Google Scholar 

  • Zoghbi HY, Bear MF (2012) Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect biol 4(3):a009886

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susanna Pietropaolo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Pietropaolo, S., Crusio, W.E., D’amato, F.R. (2015). Treatment Approaches in Rodent 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_433

Download citation

Publish with us

Policies and ethics