Abstract
SummaryMicroglia 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.
Highlights
Microglia continuously extend and retract their fine processes in the healthy brain (Nimmerjahn et al, 2005; Davalos et al, 2005)
By patch clamping microglia in brain slices and imaging their movements in brain slices and in vivo, we demonstrate that the two motility modes of microglia—directed process movement to a damage site and ceaseless surveillance of the brain—are differentially controlled by P2Y12 activation and by membrane potential
By characterizing the membrane current activated by P2Y12 receptors, we show for the first time that the microglial resting potential is maintained by a two-pore domain K+ channel that we identify as THIK-1 (TWIK-related Halothane-Inhibited K+ channel), the product of the Kcnk13 gene (Rajan et al, 2001), and demonstrate that this channel is tonically active even without ATP or ADP present to activate
Summary
Microglia continuously extend and retract their fine processes in the healthy brain (Nimmerjahn et al, 2005; Davalos et al, 2005). Synapses that are to be pruned become tagged with complement molecules and are removed by microglia (in the dorsal lateral geniculate nucleus; Schafer et al, 2012; Stevens et al, 2007) Disruption of this system leads to altered wiring of the CNS, generating an excess of excitatory synapses that promotes epilepsy (Chu et al, 2010) and neuropsychiatric disorders (Zhan et al, 2014), while during ischemia the interaction of microglia with synapses is markedly prolonged and may lead to a loss of synapses (Wake et al, 2009). In the healthy brain, microglia preferentially contact neurons with high levels of activity and decrease their firing rate (Li et al, 2012) All of these functions presumably depend on microglia sensing their environment by repeatedly extending and retracting their processes, but the factors regulating microglial surveillance are unknown
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