Grant: Project Grant

Pannexin-1 (Panx1) channels are non-selective heptameric homomeric channels that are permeable to ions and small molecules, including ATP. They have well-described roles in inflammation and cell death under several paradigms. As ATP release channels, Panx1 are intimately linked to activation of the purinergic system, effecting several downstream signalling pathways such as Ca2+ influx and reactive oxygen species (ROS) generation. This grant is founded on our exciting discovery that brain injuries in adolescent mice have unique sex-specific effects on microglia density/phenotype, synaptic density, and neuronal activity, which are regulated, in part, by microglial Panx1. Given that adolescence have high rates of mild traumatic brain injuries (often from sports) there is a need to understand how these injuries affect the brain in order to design novel therapeutic approaches tailored to personal outcomes. Here, we propose Panx1-mediated ATP release causes reactive oxygen species generation in microglia to drive sex-specific microglia remodelling, resulting in synaptic alterations that drive aberrant neuronal activity controlling injury symptoms. Here, we use several specific hypothesis to test the general hypothesis that Panx1-mediated activation of purinergic cell death pathways initiates adolescent sex-specific microglia remodelling following injury that negatively impacts neuronal communication. Understanding how injury in the adolescent brain affects communication between microglia and neurons will help identify novel mechanisms of how the adolescent brain responds to injury, determine if microglia contribute to sex-specific outcomes in this demographic, and identify new targets for personalized treatments that aid in injury recovery.