The regulation and function of lipid metabolism in astrocytes

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Background: Neuron-astrocyte communication is essential for the brain to function. An exciting area in neurobiology is investigating the role of fatty acid metabolism in neuron-astrocyte coupling. While neurons have a low capacity to metabolize fatty acids, astrocytes readily metabolize fatty acids in response to neuronal activity. What is the result of this increased fatty acid metabolism in astrocytes? Mitochondrial oxidation of fatty acids produces ATP. ATP can be packaged into vesicles and secreted by astrocytes where it functions as a gliotransmitter by modulating neuronal activity. The main goal of this research program is to investigate the role of fatty acid metabolism in brain function. To work towards this goal, our immediate objective is to uncover the function and mechanisms of increased fatty acid metabolism in astrocytes in response to neural activity. Specific Aims: 1. How do astrocytes alter fatty acid metabolism in response to neural activity? We discovered that astrocytes increase fatty acid metabolism in response to neuronal activity, however the mechanisms that mediate this response are unknown. We will determine the signal transduction pathways used by astrocytes to increase fatty acid metabolism in response to neural activity (glutamate). 2. What is the contribution of fatty acid metabolism to ATP-positive vesicle formation? Mitochondrial metabolism of fatty acids or carbohydrates generate ATP. ATP produced in astrocytes can be used directly in the cytosol or loaded into vesicles for release. We will now determine the contribution of fatty acid metabolism in the formation of ATP-positive vesicles in astrocytes. 3. How does fatty acid metabolism in astrocytes influence ATP release? Astrocytes increase fatty acid metabolism in response to increased neural activity but it is unclear whether this results in increased ATP release. We will now determine the effects of fatty acid metabolism on vesicular ATP secretion. Proposed Methods: We will use primary cultured astrocytes as our model system. Our experiments will involve a combination of quantitative fluorescence microscopy [including super-resolution and live-cell total internal reflection (TIRF) microscopy], Western blotting, and biochemical detection of ATP from astrocyte-conditioned medium. Significance of Research: Neuron-astrocyte communication is integral to brain function. Yet the contribution of fatty acid metabolism in coupling neuron and astrocytes is unknown. This research program aims to uncover how astrocytes utilize fatty acids in order to communicate with neurons and influence their activity. Ultimately, this program will uncover important insights into the function of astrocytes in the brain and how they support proper neuronal function.