Role of microglial ion channels in neuroprotection

Microglia are a special type of immune cell that live in the brain. In healthy people, microglia take on a neuroprotective surveillance role. Microglia have highly mobile branches, which are constantly scanning the brain for signs of injury or disease. Microglia respond to brain infection, inflammation and trauma and get activated to mount an immune response. They migrate to the site of infection or insult, proliferate and release factors to attract other cells. Microglia have a number of ion channels in their cell membrane. The flow of ions including calcium, sodium and potassium can regulate behaviours in microglia, including proliferation, migration and phagocytosis. In this project, we will study the expression and function of two cation channels that are very common on microglia: the P2X7 receptor and the voltage-gated sodium channel (VGSC). P2X7 has been shown to help microglia to become activated and VGSCs have been shown to regulate microglial migration. However, the combined effect of these ion channels on microglial physiology, activation and motility has not been studied before. The aim of this project is to test the hypothesis that P2X7 receptors and VGSCs jointly regulate the membrane potential (Vm), which in turn, regulates microglial behaviour via voltage-dependent signalling. We will use a range of sophisticated microscopy approaches, e.g. confocal and multiphoton microscopy, to explore the expression and functional activity of these ion channels in microglia. We will modulate ion channel expression using pharmacological and genetic (knockout mice, RNAi, CRISPR) techniques. Importantly, we will measure channel activity and Vm using a combination of whole cell patch clamp recording of isolated cells and brain slices, and Vm and ion-sensitive dyes. We will also study the effects of ion channel activity and Vm on downstream signalling and microglial behaviour using molecular biology approaches, e.g. western blotting and in vivo imaging of GFP-expressing microglia. The project will therefore expose the student to a range of cutting-edge cell biology techniques in labs that are leading in this
field. As microglia play a key role in normal brain physiology and in a number of diseases, this project is expected to provide novel mechanistic insights into an important, and relatively understudied brain cell type.

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