Redox signaling during neurodevelopment and sensitivity to oxidative stress

Project Summary: Genetic susceptibilities and environmental insults together shape risk of developmental disorders. Identifying convergent pathways among diverse risk factors is critical to developing therapeutic targets. One such candidate pathway is oxidative stress. However, the role of oxidation-reduction (redox) signaling in neurodevelopment is poorly understood. We will address this gap by characterizing redox signaling during normal forebrain neurodevelopment in mice and its response to environmental exposures. Using a genetically encoded redox sensitive fluorescent biosensor, we will determine the redox state of developing neurons at critical developmental timepoints. Embryos will then be exposed to the known oxidant herbicide paraquat and acetaminophen to determine the sensitivity of neuron subclasses to oxidative stress during different developmental stages. A commonly used antipyretic in pregnancy, acetaminophen metabolites deplete cellular antioxidants, making cells more susceptible to oxidative stress. The response of developing neurons to redox modifying compounds like paraquat and acetaminophen are of substantial clinical and