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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355
Banerjee S, Riordan M, Bhat MA (2014) Genetic aspects of autism spectrum disorders: insights from animal models. Front Cell Neurosci 8:58
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
Budimirovic DB, Kaufmann WE (2011) What can we learn about autism from studying fragile X syndrome? Dev Neurosci 33:379–394
Crawley JN (2004) Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 10:248–258
Crawley JN (2007) Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol 17:448–459
Crusio WE (2015) Key issues in contemporary behavioral genetics. Curr Opin Behav Sci 2:89–95
Crusio WE, Goldowitz D, Holmes A, Wolfer D (2009) Standards for the publication of mouse mutant studies. Genes Brain Behav 8:1–4
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
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
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
Ellegood J, Crawley JN (2015) Behavioral and neuroanatomical phenotypes in mouse models of autism. Neurother J Am Soc Exp Neurother 12:521–533
Gerlai R (1996) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci 19:177–181
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
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
Happe F, Ronald A, Plomin R (2006) Time to give up on a single explanation for autism. Nat Neurosci 9:1218–1220
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
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
Krueger DD, Bear MF (2011) Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 62:411–429
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
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
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
Markram K, Markram H (2010) The intense world theory—a unifying theory of the neurobiology of autism. Frontiers Hum Neurosci 4:224
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
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
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
Modi ME, Young LJ (2012) The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies. Horm Behav 61:340–350
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
Myers SM, Johnson CP (2007) Management of children with autism spectrum disorders. Pediatrics 120:1162–1182 (American Academy of Pediatrics Council on Children)
Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7:697–709
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
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
Pardo CA, Eberhart CG (2007) The neurobiology of autism. Brain pathol 17:434–447
Patterson PH (2011) Maternal infection and immune involvement in autism. Trends Mol Med 17:389–394
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
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
Rapin I (1991) Autistic children: diagnosis and clinical features. Pediatrics 87:751–760
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
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
Ruhela RK, Prakash A, Medhi B (2015) An urgent need for experimental animal model of autism in drug development. Ann Neurosci 22:44–49
Sanders J, Mayford M, Jeste D (2013) Empathic fear responses in mice are triggered by recognition of a shared experience. PLoS ONE 8:e74609
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
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
Silverman JL, Crawley JN (2014) The promising trajectory of autism therapeutics discovery. Drug Discovery Today 19:838–844
Silverman JL, Yang M, Lord C, Crawley JN (2010) Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11:490–502
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
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
Watanabe S (2011) Empathy and reversed empathy of stress in mice. PLoS ONE 6:e23357
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
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
Woo CC, Leon M (2013) Environmental enrichment as an effective treatment for autism: a randomized controlled trial. Behav Neurosci 127:487–497
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
Zoghbi HY, Bear MF (2012) Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect biol 4(3):a009886
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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
DOI: https://doi.org/10.1007/7854_2015_433
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-47427-4
Online ISBN: 978-3-319-47429-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)