Nanoscale Surveillance of the Brain by Microglia via cAMP-Regulated Filopodia

Abstract

Summary: Microglia, the brain’s immune cells, maintain homeostasis and sense pathological changes by continuously surveying the parenchyma with highly motile large processes. Here, we demonstrate that microglia also use thin actin-dependent filopodia that allow fast nanoscale sensing within discrete regions. Filopodia are distinct from large processes by their size, speed, and regulation mechanism. Increasing cyclic AMP (cAMP) by activating norepinephrine Gs-coupled receptors, applying nitric oxide, or inhibiting phosphodiesterases rapidly increases filopodia but collapses large processes. Alternatively, Gi-coupled P2Y12 receptor activation collapses filopodia but triggers large processes extension with bulbous tips. Similar control of cytoskeletal dynamics and microglial morphology by cAMP is observed in ramified primary microglia, suggesting that filopodia are intrinsically generated sensing structures. Therefore, nanoscale surveillance of brain parenchyma by microglia requires localized cAMP increases that drive filopodia formation. Shifting intracellular cAMP levels controls the polarity of microglial responses to changes in brain homeostasis and alters the scale of immunosurveillance. : Brain surveillance by microglia requires a motile and ramified morphology. Bernier et al. demonstrate that fine filopodia extend from the tip of large processes in a cAMP-dependent manner. The differential regulation of filopodia versus large processes establishes a dual-scale surveillance behavior of microglia. Keywords: microglia, immune surveillance, filopodia, cyclic AMP, THIK-1, actin, cytoskeletal dynamics, norepinephrine, nitric oxide, phosphodiesterase