Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K + channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y 12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y 12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y 12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1β from activated microglia, consistent with K + loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity.
The two-pore domain channel THIK-1 is the main K + channel in “resting” microglia
Tonic activity of THIK-1 maintains the microglial resting potential
Blocking THIK-1 reduces microglial ramification, surveillance, and IL-1β release
Surveillance depends on THIK-1, not P2Y 12; chemotaxis depends on P2Y 12, not THIK-1
Microglia survey the brain for invading micro-organisms, remove dying neurons, and prune synapses during development. We show that maintenance of the microglial resting potential by THIK-1 K + channels is essential for maintaining microglial ramification, surveillance, and interleukin-1β release.