Grant: Discovery Grants Program - Individual

Long-term goals: The long-term vision of my program is to understand how microglia, the brain-resident immune cells, function during development and how they influence neuronal activity to achieve normal brain functions. Overview: Microglia are the macrophages (a type of immune cell) of the central nervous system (CNS; the brain and the spinal cord). During the embryonic (early development) and the postnatal stages (after birth), microglia play an important role in phagocytosis or `nibbling' of the weaker connections (synapses) between the developing neurons. This process of `synaptic pruning' is important for normal functioning of the brain. But the mechanisms that drive these microglia functions are not understood. It is now recognized that immune cells use different metabolic pathways such as glycolysis and oxidative phosphorylation to perform specific functions. Microglia also undergo metabolic changes during inflammation. However, metabolic pathways within microglia and their importance during synaptic pruning are not known. Short term objectives: The short-term objectives are to identify metabolic pathways important for synaptic pruning by microglia during development. Hypothesis: We hypothesize that microglia use glycolysis for efficient synaptic pruning. To address this, we will: Aim 1. Investigate different metabolic pathways within microglia during development. Using embryonic and postnatal mouse brain samples, we will study key metabolic enzymes and proteins in different brain regions to generate a microglia `metabolic map'. We expect microglia to increase glycolytic pathways during the critical stages of synaptic pruning. Aim 2. Establish importance of glycolysis for microglial functions. We will perform knockdowns of glycolytic enzymes and their mediators in microglia cultures to study phagocytosis of synapses by these cells. We believe microglia with decreased glycolysis will exhibit reduced phagocytosis of synaptic material in cultures. Aim 3. Investigate a novel upstream inducer of glycolysis in microglia. Our earlier studies have shown extracellular matrix metalloproteinase inducer (EMMPRIN), a membrane glycoprotein, to drive glycolysis within macrophages. To understand its functions, we will generate mice to genetically delete EMMPRIN from microglia. We hypothesize microglia in EMMPRIN knockout mice to have reduced glycolysis, altered synaptic pruning and neurobehavioral deficits. Anticipated outcomes: Our studies will be the first to identify and confirm specific metabolic pathways for their roles in synaptic pruning by microglia. Significance: Our work will highlight novel signaling mechanisms by which microglia execute synaptic pruning and guide brain development. This study will also unravel potential basis for sexual dimorphism in synaptic pruning during brain development.