Rodent models of Autism Spectrum Disorder: strenghts and limitations

Abstract

Autism Spectrum Disorder (ASD) is a psychiatric disease that arises from a complex interplay between genetic and environmental background. Its symptomology comprises social interaction deficits, communication impairments and repetitive behaviours. However, ASD is currently diagnosed based on behavioural phenotypic traits, rather than neurobiological defects. Animal models have been used to gain insight into the aetiology of the disorder, in order to find a ‘gold standard’ to drive the diagnosis, and to search for treatments. Throughout history, lesion models, genetic models and models manipulating environmental influences have been developed. The effects on the behaviour of the animals are measured using a set of behavioural phenotyping assays. The question arises whether these models are validated through their behavioural symptoms or because of their resemblance with the mechanism that causes ASD. Furthermore, when using the phenotyping strategies, one should take into account the natural behaviour of the animals, thereby evaluating the ecological validity with respect to the human disorder. In this thesis, various types of models for ASD are critically reviewed for their use to mimic the complexity of the developmental biology of the disorder. Face, construct and predictive validity of these models are evaluated, as well as the behavioural phenotyping assays that are applied. Future directions point towards a multi-model approach, in which the body as one functioning system is emphasized. Animal models are always a compromise between mimicking the complexity of the actual disorder and designing practical experiments. However, these experiments should be designed in a way that the animal is minimally restricted in performing its natural behaviour. Combining knowledge, we narrow down the funnel towards not only a gold standard model, but also a gold standard behavioural phenotyping strategy, thereby increasing the translational capacity of the animal model.