The goal of this project is to investigate genes that increase risk for autism spectrum disorder (ASD) by characterizing mutant zebrafish. There are hundreds of genes implicated in ASD in humans, but many have unknown functions, and it is not clear whether they are involved in common neurodevelopmental mechanisms. While zebrafish are not expected to display features of ASD or accurately phenocopy the human syndrome, they are an ideal model for uncovering the neurobiological roles of conserved genes. This vertebrate shares over 70 percent of its genes with humans, has similar neural cell types, and larvae fit in individual wells of 96-well plates. Furthermore, their brains are transparent, enabling straightforward visualization of brain development and neural activity.
Summer Thyme’s lab uses zebrafish behavioral assays to test for changes such as increased sensory responsiveness and blunted social interactions, which relate to core characteristics of ASD. A compelling reason to characterize zebrafish models of neurodevelopmental conditions is the possibility of conducting drug screens in future studies. Drugs discovered in zebrafish are in clinical trials for multiple conditions, including for seizure suppression in people with Dravet syndrome. Defining phenotypes for these zebrafish models sets the stage for the discovery of new compounds that alleviate core ASD symptoms and those of co-occurring conditions.
In Aim 1, Thyme’s team plans to survey the development, whole-brain activity and structure, and behavior1 of 24 zebrafish mutants representing 16 human ASD risk genes. They have already generated this mutant collection, and it includes 22 protein truncation alleles and two patient-specific point mutations.
In Aim 2, the researchers plan to explore sleep abnormalities and seizure threshold, as these phenotypes relate to conditions that co-occur with ASD. This will involve challenging the mutants to various stresses, such as sleep deprivation and low levels of convulsant .
In Aim 3, they plan to define molecular mechanisms that underly phenotypes that they have already uncovered through their preliminary studies for three alleles generated for one ASD risk gene that encodes a transcription factor.
In future work, and as they establish mutant phenotypes in this screen (Aim 1), the lab plans to collect transcriptomic data for other ASD risk genes. Ultimately, the group may discover that these diverse genetic factors impact shared underlying pathways, which are ideal targets for rational drug development.