Exploring the Validity of Valproic Acid Animal Model of Autism

Abstract

The valproic acid (VPA) animal model of autism spectrum disorder (ASD) is one of the most widely used animal model in the field. Like any other disease models, it can't model the totality of the features seen in autism. Then, is it valid to model autism? This model demonstrates many of the structural and behavioral features that can be observed in individuals with autism. These similarities enable the model to define relevant pathways of developmental dysregulation resulting from environmental manipulation. The uncovering of these complex pathways resulted to the growing pool of potential therapeutic candidates addressing the core symptoms of ASD. Here, we summarize the validity points of VPA that may or may not qualify it as a valid animal model of ASD.

Keywords: animal model; autism spectrum disorder; construct validity; face validity; predictive validity; social communication deficit.

Fig. 1. The validity of VPA animal model at a glance. Construct validity constitutes the similarity of the etiological factors underlying the disorder between the animal and the human disease that it models. VPA induces ASD both in human and animals. The etiological mechanism may involve changes in epigenetic marks, expression level of genetic determinants as well as brain lesion. The recapitulated disease endophenotypes or biologic markers are assessed for face validity, which shows consistency with human ASD phenotypes. Finally, predictive validity evaluates the treatment response (and disease mechanisms as well as target predictive capability) of the model either to assess its sameness with the human response or to measure its ability to identify drugs beneficial to human. In VPA animal model, known drugs and many drug candidates has been assessed for the applicability as potential therapeutics. MOA, mechanism of action; POC, proof of concept.

Fig. 2. Heterogeneity of ASD etiology and symptoms necessitate multiple models. ASD is portrayed as continuous spectrums of several traits including core and comorbid symptoms, which is schematically represented as sunlight through the prism. Regardless of the extreme heterogeneity, we may re-group ASD patients into several categories with shared symptoms and molecular changes in the future, which we like to call "Rainbow" of ASD. In this sense, we might need multiplicity of animal models, which represents one or two groups of ASD more closely than others, possibly with some overlap with other models. The VPA animal model of ASD will be a representative member of "Rainbow" of animal models for ASD, which might be helpful for the development of group-specific drugs against the devastating disorder.