Microglia, the resident immune cells of the brain, are very sensitive to changes in their environment, and respond rapidly to brain injury. Purinergic receptor signalling is crucially involved in communication between microglia and their surrounding cells. It enables microglia to find damaged cells, to which they send out highly branched and motile processes, and also triggers their transformation into activated, phagocytotic cells. We have previously described that microglia also respond to subtle mechanical changes evoked by flow of the extracellular solution, which hyperpolarises the membrane potential by about -30mV. Here, we analyse the underlying signalling cascade and show that the mechanical stimulus evokes ATP release into the extracellular space. By pulling whole-cell patch-clamped microglial cells out of the slice and isolating them we show that ATP release occurs from the microglial cell itself, which is independent of extra- and intracellular calcium levels. The resulting rise in extracellular nucleotide levels then activates P2Y₁₂ purinergic receptors, which trigger an outwardly-rectifying and slowly inactivating potassium current through a calcium independent G_i/o-mediated pathway. Pharmacological analysis suggests that this current is mediated by a TWIK-related spinal cord potassium channel (TRESK, a two-pore domain potassium channel). Using 2-photon imaging of isolectin B4 labelled microglia, we have observed that the microglia-derived ATP increases the motility of their processes, enabling them to scan the local brain area more efficiently, and thus may facilitate microglial detection of tissue damage in pathological conditions such as brain concussion or trauma.

Supported by the Wellcome Trust, ERC and a Marie Curie fellowship