Novel zebrafish models for autism spectrum disorder

Autism spectrum disorder (ASD) refers to a group of complex neurodevelopment disorders influenced by multiple genes and environmental factors. ASD is characterized by repetitive and stereotyped behaviour together with deficits in social communication and interaction. The lack of knowledge regarding the underlying genetics and neurobiology of this disorder has hindered the discovery of novel drugs. The aim of this project is to investigate the function of two ASD candidate genes, reelin (reln) and ywhaz, to gain insights into the neurological basis of ASD and improve drug treatments. To this end, we have used reln and ywhaz mutant lines to investigate the function of ASD-candidate genes in zebrafish. The first results chapter focuses on reln, the archetypal ASD candidate gene. reln-/- exhibits an impaired behavioural phenotype which resembles specific symptoms of ASD and it provides significant insights into the relationship between Reln activity and the role of the serotoninergic system in ASD. The second chapter describe the generation of a stable zebrafish ywhaz-/- mutant line using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein-9 nuclease (CRISPR/Cas9) technique. The third chapter focuses on the characterisation of ywhaz-/-, highlighting the importance of functional ywhaz signalling in the adult brain, and shedding light on the role of both the serotoninergic and dopaminergic system in ASD. ywhaz-/- reveal an impaired behaviour which resembles some of the defects occurring in ASD and it can be rescued by fluoxetine and quinpirole treatment. In summary, both the mutant lines analysed in this project can be considered suitable models to analyse some defects which occur in ASD, in particularly cerebellar defects. This study supports the idea that damage of certain cerebellar areas can result in the core symptoms of ASD.