Behavioral and molecular insights into anxiety in ube3a and fmr1 zebrafish models of autism spectrum disorders

Angelman syndrome and Fragile X syndrome are neurodevelopmental disorders (NDDs) caused by mutations in the UBE3A and FMR1 genes, respectively. However, they share common features such as cognitive and motor deficits, anxiety, and impaired social behavior. In this study, we utilized zebrafish as an animal model to investigate the anxiety-like effects of mutations in these genes across larval and adult stages, employing two widely used behavioral assays: the light-dark test (LDT) and the novel tank diving test (NTT). We conducted detailed analyses of anxiety-like behaviors and exploration patterns in ube3a and fmr1 mutant fish, comparing both genotypes to their respective wild-type (WT) counterparts. Importantly, we analyzed RNA sequencing data from both larvae and adults to better understand the molecular pathways associated with the anxiety profiles of these genotypes. Our results show that larval ube3a mutants did not exhibit significant difference in the LDT compared to the WT; however, they showed significant reductions in distance travelled, velocity, and light-zone exploration during adult stages. In contrast, fmr1 mutants exhibited reduced locomotor activity in the LDT at larval age and hyperactivity and lower anxiety-like behaviors in adulthood. We identify key genes implicated in these behaviors and shared pathways that warrant further investigation for the development of therapies addressing ASD. Ultimately, our results highlight the importance of using different behavioral assays, such as the LDT and NTT, combined with omics approaches like RNA sequencing, to discern the distinct behavioral phenotypes caused by genetic mutations and to create opportunities for better understanding NDDs.