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Project Summary

Microglia as the brain’s innate immune cells continuously survey the CNS with their highly motile processes. This enables them to specifically interact with neurons and other cells in a highly dynamic manner, which is critical for neural development and function. The role of microglia for neuronal function in the adult brain is less clear, but there is mounting evidence that microglial dysfunction contributes to many neurological diseases4. We have recently discovered that the two-pore domain potassium channel THIK-1 regulates microglial ramification, surveillance and the release of pro-inflammatory interleukin-1ß. In contrast, directed motility of microglia to damaged tissue is independent of THIK-1 but requires P2Y12 receptor signaling. Thus, the P2Y12/THIK-1 signaling complex is associated with key microglial functions that are likely to affect microglia-neurons interactions, but their relevance to neural development and function has not yet been examined. This project will explore the role of microglial surveillance in neural function by electrophysiological analyses during development and in adulthood (Aim 1), since microglial surveillance may be crucial to establish physiological interactions with neurons. Given their involvement in cell activation and cytokine release, we will also study what role THIK-1 channels and their functionally coupled P2Y12 receptors play in disease-affected activated microglia. This will be studied in development by inducing microglia activation via maternal immune activation (Aim 2), and in adulthood by exposure of brain slices to an acute inflammatory activation stimulus evoked by bacterial lipopolysaccharide (LPS) in the presence and absence of hypoxia (Aim 3).