Neuron
Volume 97, Issue 2, 17 January 2018, Pages 299-312.e6
Journal home page for Neuron

Article
Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1

https://doi.org/10.1016/j.neuron.2017.12.002Get rights and content
Under a Creative Commons license
open access

Highlights

  • 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 P2Y12; chemotaxis depends on P2Y12, not THIK-1

Summary

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 P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 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.

Keywords

microglia
potassium channel
ATP
surveillance
inflammasome
interleukin-1β
ramification
THIK-1

Cited by (0)

6

These authors contributed equally

7

Lead Contact