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Autism - Animal Models

Animal models of autism spectrum disorders (ASDs) are aimed at mimicking the core features (impaired communication, impaired social interaction, restricted interests and repetitive behaviors) associated with the disorder. A good animal model must assimilate, (i) face validity (close similarity to the core features of the disease), (ii) construct validity (biological dysfunction that leads to the disease,), and (iii) predictive validity (responsiveness to therapeutic strategies that alter the symptoms of the disease). Maximum face, construct, and predictive validities can be observed in a candidate animal model (Banerjee et al, 2014).

There are several vertebrate and invertebrate models of autism. Some of the well-known animal models of autism are described below.

I. Vertebrate models

  • a. Rodents

    There is a broad range of mouse and rat models exhibiting the cognitive and behavioral abnormalities associated with ASD. The most popular rodent models of ASD include, (i) mutant animals (knockouts), (ii) models generated by prenatal or neonatal environmental challenges that increase the risk of ASD, and (iii) models with neonatal lesions of brain regions that are anomalous in autistic individuals. However, the mouse models have limitations in compiling the broad phenotypic spectrum of ASD.

    There are several comprehensive test batteries to evaluate the social interaction, social communication, and repetitive behaviors in rodent models, thereby examining the various hypotheses implicated in autism. The tests include, (i) home cage observation, social approach and avoidance tasks, and resident-intruder interaction to assess social interaction, (ii) ultrasonic vocalizations in pups to examine early development and communication, (iii) home cage observation, open field tasks and novel object tests to evaluate restricted interests, repetitive behavior and stereotypy, (iv) elevated plus maze and light-dark transition test to assess anxiety, (v) prepulse inhibition of startle responses to evaluate sensory reactivity, (vi) balance beam, climbing pole, and rotarod performance to examine motor skills, and (vi) spatial learning and memory tasks such as Morris water maze, hidden platform, radial arm maze and T-maze (Moy et al, 2006).

    Several gene-specific knockout and transgenic models, especially of mice, have been generated based on genetic studies. These include mice and/or rat with targeted mutations in autism-associated genes, such as the synaptic cell adhesion proteins [e.g. Itgb3 (Carter et al, 2011), Nlgn1 (Hoy et al, 2013), Nlgn2 (Wohr et al, 2013), Nlgn3 (Rothwell et al, 2014), Nlgn4 (Ju et al, 2014), Nrxn1 (Blundell et al, 2010), Cntnap2 (Penagarikano et al, 2011), Shank3 (Yang et al, 2012)], the signaling and developmental proteins [e.g. En2 (Sgado et al, 2013), Met (Martins et al, 2011), Foxp2 (Shu et al, 2005), Pten (Lugo et al, 2014)], and the neurotransmitters and receptors [(Avpr1 (Bielsky et al, 2005), Cadps2 (Sadakata et al, 2013), Gabrb3 (DeLorey et al, 2011), Oxtr (Pobbe et al, 2012), Slc6a4 (Veenstra-VanderWeele et al, 2012)]. There have also been models of prenatal toxicity [(5-methoxytryptamin (Janusonis et al, 2004), valproic acid (Kim JW et al, 2014)], neonatal infection (Borna virus; Pletnikov et al, 2002) and early lesion of the brain regions involved in autism [cerebellum (Bobee et al, 2000), amygdala (Diergaarde et al, 2004)].

    There have been several mouse models for the syndromic forms of ASD. These include, Angelman syndrome (Ube3a; Pignatelli et al, 2014; Meng et al, 2013), Phelan-McDermid syndrome (Shank3; Yang et al, 2012; Peca et al, 2011), Rett syndrome (Mecp2; De Felice et al, 2014; Oginsky et al, 2014), Tuberous sclerosis (Tsc1 and Tsc2; Tsai et al, 2012; Meikle et al, 2007; Reith et al, 2013; Ehninger et al, 2008), Timothy syndrome (Cacna1c; Bader et al, 2011; Splawski et al, 2004), Fragile X syndrome (Fmr1; Ronesi et al, 2012; Nimchinsky et al, 2001) and Smith-Lemli Opitz syndrome (Dhcr7; Korade et al, 2013; Correa-Cerro et al, 2006).

    Prairie voles have also been used as rodent models of ASD. Due to their ability to form lifelong social bonds, they have been used to study impaired social behavior, which is a core feature of autism (McGraw and Young, 2010).

  • b. Non-human primates (NHP)

    NHPs can serve as excellent ASD models owing to their remarkable similarity with human behavior and the high level of homology in the neural circuits that evoke social responses.

    Ablation studies of NHPs have been useful in elucidating the functions of various brain regions (Goursaud and Bachevalier, 2007; Bauman et al, 2008; Kazama and Bachevalier, 2009; Kazama et al, 2012). There have also been some behavioral outcome models (e.g. isolate rearing; Harlow and Suomi, 1971) and etiology models (e.g. prenatal risk factors; Bauman et al, 2014). However, the lack of genetic knockout models, together with ethical considerations, pose serious limitations in NHP research.

  • c. Zebrafish

    Zebrafish can be considered as excellent models to validate new genes of interest owing to their rapid oogenesis and embryogenesis, and high fecundity; this allows for the rapid experimental assays of several genes simultaneously. Moreover, due to the transparency of their externally developing embryos, it is possible to visualize the growth and development of cells and tissues in live embryos.

    Although the zebrafish is a good model for genetic aspects (Kalueff et al, 2014), it is difficult to assess the behavioral phenotypes associated with ASD (Blaser and Vira, 2014; Kim L et al, 2014).

  • d. Songbirds

    Songbirds resemble humans in vocal learning. They have a striking similarity in the developmental time window for learning, and a homologous underlying neural circuitry (Panaitof, 2012).

    Studies have shown that CNTNAP2, a well known autism candidate gene which is enriched in human language-related neural circuits, might also be involved in the vocal communication of songbirds (Panaitof et al, 2010).

  • II. Invertebrate models

    There is an amazing genetic conservation between humans and certain invertebrates. The fruit fly Drosophila is one such classic invertebrate model. Drosophila has orthologs for human genes such as NRXN1, NLGN1 and NLGN2, which have been implicated in ASD. They have been valuable in understanding the basic functions of several novel autism candidate genes (Morales et al, 2002; Cukier et al, 2008; Wu et al, 2008).

    The nematode Caenorhabditis elegans has also made effective contributions towards understanding the biological processes underlying ASD (Calahorro and Ruiz-Rubio, 2011; Hu et al, 2012; Bessa et al, 2013). C. elegans has orthologs for ASD-related genes such as NLGNs, NRXNs, and SHANK (Calahorro et al, 2009; Calahorro 2014)




    Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW, Bett GC, Tsien RW, Rasmusson RL, Shamloo M: Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci USA 2011, 108: 15432-7.

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

    Bauman MD, Toscano JE, Babineau BA, Mason WA, Amaral DG: Emergence of stereotypies in juvenile monkeys (Macaca mulatta) with neonatal amygdala or hippocampus lesions. Behav Neurosci 2008, 122:1005-15.

    Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Patterson PH: Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry 2014, 75:332-41.

    Bessa C, Maciel P, Rodrigues AJ: Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders. Mol Neurobiol 2013, 48:465-89.

    Bielsky IF, Hu SB, Young LJ: Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice. Behav Brain Res 2005, 164:132-136.

    Blaser RE, Vira DG: Experiments on learning in zebrafish (Danio rerio): a promising model of neurocognitive function. Neurosci Biobehav Rev 2014, 42:224-31.

    Blundell J, Blaiss CA, Etherton MR, Espinosa F, Tabuchi K, Walz C, Bolliger MF, Südhof TC, Powell CM: Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 2010, 30:2115-29.

    Bobée S, Mariette E, Tremblay-Leveau H, Caston J: Effects of early midline cerebellar lesion on cognitive and emotional functions in the rat. Behav Brain Res 2000, 112:107-17.

    Calahorro F, Alejandre E, Ruiz-Rubio M: Osmotic avoidance in Caenorhabditis elegans: synaptic function of two genes, orthologues of human NRXN1 and NLGN1, as candidates for autism. J Vis Exp 2009, (34): 1616.

    Calahorro F, Ruiz-Rubio M: Caenorhabditis elegans as an experimental tool for the study of complex neurological diseases: Parkinson's disease, Alzheimer's disease and autism spectrum disorder. Invert Neurosci 2011, 11:73-83.

    Calahorro F: Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human. Invert Neurosci 2014 (Epub).

    Carter MD, Shah CR, Muller CL, Crawley JN, Carneiro AM, Veenstra-VanderWeele J: Absence of preference for social novelty and increased grooming in integrin 3 knockout mice: initial studies and future directions. Autism Res 2011, 4:57-67.

    Correa-Cerro LS, Wassif CA, Kratz L, Miller GF, Munasinghe JP, Grinberg A, Fliesler SJ, Porter FD: Development and characterization of hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy. Hum Mol Genet 2006, 15:389-51.

    Cukier HN, Perez AM, Collins AL, Zhou Z, Zogbhi HY, Botas J: Genetic modifiers of MeCP2 function in Drosophila. PLoS Genet 2008, 4:e1000179.

    De Felice C, Della Ragione F, Signorini C, Leoncini S, Pecorelli A, Ciccoli L, Scalabrì F, Marracino F, Madonna M, Belmonte G, Ricceri L, De Filippis B, Laviola G, Valacchi G, Durand T, Galano JM, Oger C, Guy A, Bultel-Poncé V, Guy J, Filosa S, Hayek J, D'Esposito M: Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiol Dis 2014, 68: 66-77.

    DeLorey TM, Sahbaie P, Hashemi E, Li WW, Salehi A, Clark DJ: Somatosensory and sensorimotor consequences associated with the heterozygous disruption of the autism candidate gene, Gabrb3. Behav Brain Res 2011, 216:36-45.

    Diergaarde L, Gerrits MA, Stuy A, Spruijt BM, van Ree JM: Neonatal amygdala lesions and juvenile isolation in the rat: differential effects on locomotor and social behavior later in life. Behav Neurosci 2004, 118:298-305.

    Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowsky DJ, Ramesh V, Silva AJ: Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 2008, 14:843-8.

    Goursaud AP, Bachevalier J: Social attachment in juvenile monkeys with neonatal lesion of the hippocampus, amygdala and orbital frontal cortex. Behav Brain Res 2007,176:75-93.

    Harlow HF, Suomi SJ: Social recovery by isolation-reared monkeys. Proc Natl Acad Sci USA 1971, 68:1534-38.

    Hoy JL, Haeger PA, Constable JR, Arias RJ, McCallum R, Kyweriga M, Davis L, Schnell E, Wehr M, Castillo PE, Washbourne P: Neuroligin1 drives synaptic and behavioral maturation through intracellular interactions. J Neurosci 2013, 33:9364-84.

    Hu Z, Hom S, Kudze T, Tong XJ, Choi S, Aramuni G, Zhang W, Kaplan JM: Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans. Science. 2012 Aug 24;337(6097):980-4.

    Janusonis S, Gluncic V, Rakic P: Early serotonergic projections to Cajal-Retzius cells: relevance for cortical development. J Neurosci 2004, 24:1652-9.

    Ju A, Hammerschmidt K, Tantra M, Krueger D, Brose N, Ehrenreich H: Juvenile manifestation of ultrasound communication deficits in the neuroligin-4 null mutant mouse model of autism. Behav Brain Res 2014, 270:159-64.

    Kalueff AV, Stewart AM, Gerlai R. Zebrafish as an emerging model for studying complex brain disorders. Trends Phramacol Sci 2014, 35:63-75.

    Kazama A, Bachevalier J: Selective aspiration or neurotoxic lesions of orbital frontal areas 11 and 13 spared monkeys' performance on the object discrimination reversal task. J Neurosci 2009, 29:2794-804.

    Kazama AM, Heuer E, Davis M, Bachevalier J: Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques. Behav

    Neurosci 2012, 126:392-403.

    Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, Choi CS, Kim KC, Gonzales EL, You JS, Choi DH, Lee J, Han SH, Yang SM, Cheong JH, Shin CY, Bahn GH: Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic Acid-induced animal model of autism. PLoS One 2014, 9:e104927.

    Kim L, He L, Maaswinkel H, Zhu L, Sirotkin H, Weng W: Anxiety, hyperactivity and stereotypy in a zebrafish model of fragile X syndrome and autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 2014 (Epub).

    Korade Z, Folkes OM, Harrison FE: Behavioral and serotonergic response changes in the Dhcr7-HET mouse model of Smith-Lemli-Opitz syndrome. Pharmacol Biochem Behav 2013, 106:101-8.

    Lugo JN, Smith GD, Arbuckle EP, White J, Holley AJ, Floruta CM, Ahmed N, Gomez MC, Okonkwo O: Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. Front Mol Neurosci 2014, 7:27.

    Martins GJ, Shahrokh M, Powell EM: Genetic disruption of Met signaling impairs GABAergic striatal development and cognition. Neuroscience 2011, 176:199-209.

    McGraw LA, Young LJ: The prairie vole: an emerging model organism for understanding the social brain. Trends Neurosci 2010, 33:103-9.

    Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, Jensen FE, Kwiatkowski DJ: A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 2007, 27:5546-58.

    Meng L, Person RE, Huang W, Zhu PJ, Costa-Mattioli M, Beaudet AL: Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model. PLoS Genet 2013, 9:e1004039.

    Morales J, Hiesinger PR, Schroeder AJ, Kume K, Verstreken P, Jackson FR, Nelson DL, Hassan BA: Drosophila fragile X protein, DFXR, regulates neuronal morphology and function in the brain. Neuron 2002, 34:961-72.

    Moy SS, Nadler JJ, Magnuson TR, Crawley JN: Mouse models of autism spectrum disorders: the challenge for behavioral genetics. Am J Med Genet C Semin Med Genet 2006, 15;142C:40-51.

    Nimchinsky EA, Oberlander M, Svoboda K: Abnormal development of dendritic spines in FMR1 knock-out mice. J Neurosci 2001, 21:5139-46.

    Oginsky MF, Cui N, Zhong W, Johnson CM, Jiang C: Alterations in the cholinergic system of brainstem neurons in a mouse model of Rett syndrome. Am J Physiol Cell Physiol 2014, (Epub)

    Panaitof SC, Abrahams BS, Dong H, Geschwind DH, White SA: Language-related Cntnap2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds. J Comp Neurol 2010, 518:1995-2018.

    Panaitof SC: A songbird animal model for dissecting the genetic bases of autism spectrum disorder. Dis Markers 2012, 33:241-9.

    Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TL, Lascola CD, Feng G: Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 2011, 472:437-42.

    Peñagarikano 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: Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 2011, 147:235-46.

    Pignatelli M, Piccinin S, Molinaro G, Di Menna L, Riozzi B, Cannella M, Motolese M, Vetere G, Catania MV, Battaglia G, Nicoletti F, Nisticò R, Bruno V: Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome. J Neurosci 2014, 34:4558-66.

    Pletnikov MV, Moran TH, Carbone KM: Borna disease virus infection of the neonatal rat: Developmental brain injury model of autism spectrum disorders. Frontiers in bioscience : a journal and virtual library 2002, 7: d593–d607.

    Pobbe RL, Pearson BL, Defensor EB, Bolivar VJ, Young WS 3rd, Lee HJ, Blanchard DC, Blanchard RJ: Oxytocin receptor knockout mice display deficits in the expression of autism-related behaviors. Horm Behav 2012, 61:436-44.

    Reith RM, McKenna J, Wu H, Hashmi SS, Cho SH, Dash PK, Gambello MJ: Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis 2013, 51:93-103.

    Ronesi JA, Collins KA, Hays SA, Tsai NP, Guo W, Birnbaum SG, Hu JH, Worley PF, Gibson JR, Huber KM: Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 2012, 15: 431-40.

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

    Sadakata T, Shinoda Y, Oka M, Sekine Y, Furuichi T: Autistic-like behavioral phenotypes in a mouse model with copy number variation of the CAPS2/CADPS2 gene. FEBS Lett 2013, 587:54-9.

    Sgadò P, Provenzano G, Dassi E, Adami V, Zunino G, Genovesi S, Casarosa S, Bozzi Y: Transcriptome profiling in engrailed-2 mutant mice reveals common molecular pathways associated with autism spectrum disorders. Mol Autism 2013, 4:51.

    Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD: Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci U S A 2005, 102:9643-8.

    Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT: Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004, 119:19-31.

    Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, Steinberg J, Crawley JN, Regehr WG, Sahin M: Autistic-like behavior and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 2012, 488:647-51.

    Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA, Shah CR, Cohen J, Mannangatti P, Jessen T, Thompson BJ, Ye R, Kerr TM, Carneiro AM, Crawley JN, Sanders-Bush E, McMahon DG, Ramamoorthy S, Daws LC, Sutcliffe JS, Blakely RD: Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc Natl Acad Sci U S A 2012, 109:5469-74.

    Wöhr M, Silverman JL, Scattoni ML, Turner SM, Harris MJ, Saxena R, Crawley JN: Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. Behav Brain Res 2013, 251:50-64.

    Yang M, Bozdagi O, Scattoni ML, Wöhr M, Roullet FI, Katz AM, Abrams DN, Kalikhman D, Simon H, Woldeyohannes L, Zhang JY, Harris MJ, Saxena R, Silverman JL, Buxbaum JD, Crawley JN: Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci 2012, 32:6525-41.