Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

Abstract

Autism spectrum disorders (ASDs) are a highly variable and complex set of neurological disorders that alter neurodevelopment and cognitive function, which usually presents with social and learning impairments accompanied with other comorbid symptoms like hypersensitivity or hyposensitivity, or repetitive behaviors. Autism can be caused by genetic and/or environmental factors and unraveling the etiology of ASD has proven challenging, especially given that different genetic mutations can cause both similar and different phenotypes that all fall within the autism spectrum. Furthermore, the list of ASD risk genes is ever increasing making it difficult to synthesize a common theme. The use of rodent models to enhance ASD research is invaluable and is beginning to unravel the underlying molecular mechanisms of this disease. Recently, zebrafish have been recognized as a useful model of neurodevelopmental disorders with regards to genetics, pharmacology and behavior and one of the main foundations supporting autism research (SFARI) recently identified 12 ASD risk genes with validated zebrafish mutant models. Here, we describe what is known about those 12 ASD risk genes in human, mice and zebrafish to better facilitate this research. We also describe several non-genetic models including pharmacological and gnotobiotic models that are used in zebrafish to study ASD.

Fish as model systems to study epigenetic drivers in human self-domestication and neurodevelopmental cognitive disorders

“…Thus, the use of fish models to study neurodevelopmental cognitive disorders exhibiting (self-)domestication-related features has already a sound basis on previous research. Indeed, zebrafish has been used as a model for the three disorders studied here, SCZ [96], WS [97] and ASD [98]. Our findings that homologue genes were differentially methylated in both human disorders and early fish domesticates provides further evidence for the use of fish as models to study the epigenomic regulation implicated in self-domestication-related human phenotypes, which has proven to be key source of the human uniqueness [5].…”

Impaired dendritic spine development in a zebrafish model of Fragile X

“…In addition to confirming similarities between spine morphogenesis in zebrafish larvae and mammals, these findings establish the larval zebrafish as a valuable animal model to study cellular mechanisms underlying spine defects in neurodevelopmental disorders. Although in this study we have focused on a zebrafish model of Fragile X, there are currently more than a dozen validated zebrafish lines with mutations in paralogs of ASD risk genes (Rea and Van Raay, 2020). The ability to conduct automated, high-resolution brain imaging in living zebrafish larvae (Early et al, 2018; Pardo-Martin et al, 2010) will enable future studies to monitor PyrN spine morphology and dynamics with increased throughput.…”

Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders

“…For chemical treatments, the glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, the dopamine D1 receptor antagonist SCH23390, and the epilepsy and bipolar disorder drug valproic acid have been used to evoke ASD-like symptoms in rodents [ 203 ] and have also been applied to zebrafish for modeling ASD [ 204 , 205 ]. For genetic modeling analogous to rodent ASD models which were established by overexpressing ASD-risk genes such as kctd13 , bbs7 , and cep290 , or by knocking down/knocking out dyrk1a , coro1a , fam57ba , gdpd3 , hirip3 , kif22 , maz , ppp4ca , shank3 , fmr1 , and cntnap2 , zebrafish ASD models have been successfully generated by targeting a similar set of ASD-susceptibility genes using genetic manipulations (reviewed in [ 126 , 206 ]).…”