Targeting Neuron-Microglia Interactions at the Margin of Glioma

PROJECT SUMMARY/ABSTRACT Recent studies have revealed that crosstalk between glioma cells and the brain microenvironment is a crucial regulator of cancer initiation and progression. A vast majority of glioma patients suffer from seizures, and this pathological neuronal activity has been proposed to contribute to increased glioma growth and proliferation. While some have hypothesized that neurons may be directly altering glioma cell activity, this proposal investigates whether a more prominent consequence of pathological neuronal activity is to cause activation of microglia, whose pro-inflammatory response contributes to glioma growth. This proposal will investigate glioma-induced changes in neuronal and microglial activity and whether neuronal activity, microglia, and glioma cells are mechanistically linked in driving cancer progression. Microglia have been separately implicated in both epileptogenesis and glioma growth. Neurons communicate directly with microglia through secreted purines, such as ATP, acting on microglial purinergic receptors. This ATP binding causes microglial activation, and activated microglia have been shown to stimulate glioma cell growth, enhance invasiveness and migration of glioma cells, and cause angiogenesis. P2RX7 is a well-studied purinergic receptor present on microglia, shown in preliminary data to be highly expressed in the tumor microenvironment. In aim 1, I will use whisker stimulation with simultaneous in-vivo imaging of neuronal and microglial calcium activity to determine if the presence of glioma causes pathological stimulus-evoked responses in neurons and microglia. In aim 2, I will utilize electroconvulsive seizure (ECS) induction to determine the effect of seizures, a known instance of pathological neuronal activity, on microglial expression of inflammatory cytokines as well as on glioma growth. In both aims I will administer Brilliant Blue G (BBG), a selective P2RX7 inhibitor with known CNS penetrance to interrogate if these effects are mediated through purinergic signaling between neurons and microglia.