When Genetic and Environmental Factors Meet in Modelling Autism
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, characterised by deficits in verbal and non-verbal communication, social interaction and repetitive behaviours (APA, 2013). The aetiology of ASD is mostly unknown, with continued research identifying a multitude of genetic and non-genetic factors. However, it is the interaction between environmental factors and the genetic background of an individual which leads to the development of ASD. There is an urgent need for improved animal models of ASD to further our understanding of the aetiology and particularly its pathophysiology, as this will aid in the development of much needed pharmaceutical treatments to alleviate the impact of adverse symptoms for individuals with ASD. Current animal models of ASD examine the genetic (e.g. serotonin transporter knock out rats) or the environmental (e.g. prenatal exposure to Valproate) contributions to the disorder, and very rarely a combination of the two. This thesis aimed to improve the Valproate (VPA) induced ASD animal model with a genetic × environmental interaction approach, as well as optimising chronic administration of the VPA to pregnant rats. To this aim, a non-invasive method of delivering VPA was used, which allowed genetically normal rats to voluntarily consume VPA throughout pregnancy. The prenatal exposure to VPA led to ASD-like behaviours in the offspring (communication delays, increased social behaviour, and social aversion). Next, rats with a genetic deficit in SERT (SERT+/-) exposed to VPA throughout gestation, with an optimised administration method using gelatine pellets, which allowed for voluntary non-invasive consumption, and a more accurate administration of increased VPA doses. Overall, the chronic prenatal exposure to VPA in SERT+/- rats led to a mild ASD-like phenotype, with rats exhibiting communication delays, abnormal play behaviour, disrupted social preference, and to some extent increased anxiety-like behaviour. The brains of the adult offspring were examined for neuronal changes in the GABA interneurons in brain regions associated with social behaviour (amygdala and hippocampus). However, no significant effects of prenatal VPA exposure, genotype, or sex were found. Thus, the variations GABAergic system is unlikely to underlie the earlier identified behavioural alterations. Ultimately, this thesis has furthered the VPA induced ASD animal model with a genetic × environmental interaction approach, as well as optimising the chronic administration method for pregnant rats.