Neurodevelopmental disorders (NDDs) affect 1 in 10 children born in the United States and the incidence of some NDDs, such as autism spectrum disorder is increasing at an alarming rate. Because many NDD- associated genetic variants are neither necessary nor sufficient to cause NDDs, it is increasingly postulated that environmental factors interact with genetic susceptibilities to determine NDD risk. However, identifying specificenvironmental risk factors for NDD remains a significant challenge. I propose to use a zebrafish model to test the hypothesis that NDD-associated mutations in the mTOR-signaling pathway interact with environmental chemicals that sensitize the ryanodine receptor (RyR), such as polychlorinated biphenyls (PCBs) to exacerbate adverse neurodevelopmental outcomes. The following aims have been created to test this hypothesis: 1) Demonstrate that developmental exposure to RyR-active PCBs modulates neuronal connectivity in the developing zebrafish in an RyR-dependent manner as determined by quantification of dendritic arborization and synaptic density; 2) Assess the role of mTOR signaling in mediating PCB effects on neurodevelopment in zebrafish; and 3) Model a specific gene-environment interaction relevant to NDDs by developing a zebrafish line with a human NDD-linked mutation in mTOR signaling and determine whether this mutation exacerbates the neurotoxicity of RyR-active PCBs. Successful completion of these aims will provide novel mechanistic insights regarding gene-environment interactions that influence NDD risk and will provide an experimental platform to develop higher throughput assays to screen for additional environmental risk factors that affect early neurodevelopment.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
