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).

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• 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)

 

 

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