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

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          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 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.

          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 P2Y 12; chemotaxis depends on P2Y 12, not THIK-1

          Abstract

          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.

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          Most cited references43

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          The Microglial Sensome Revealed by Direct RNA Sequencing

          Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.
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            The P2Y12 receptor regulates microglial activation by extracellular nucleotides.

            Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
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              Dendritic organization in the neurons of the visual and motor cortices of the cat.

              D SHOLL (1953)
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                Author and article information

                Contributors
                Journal
                Neuron
                Neuron
                Neuron
                Cell Press
                0896-6273
                1097-4199
                17 January 2018
                17 January 2018
                : 97
                : 2
                : 299-312.e6
                Affiliations
                [1 ]Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
                [2 ]Institute of Neurophysiology, Charité – Universitätsmedizin, 10117 Berlin, Germany
                [3 ]CERN and Département de physique nucléaire et corpusculaire, University of Geneva, 1211 Geneva 4, Switzerland
                [4 ]National Institute of Neuroscience, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan
                [5 ]Department of Anesthesiology, Baylor College of Medicine, 434D Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
                Author notes
                []Corresponding author christian.madry@ 123456charite.de
                [∗∗ ]Corresponding author d.attwell@ 123456ucl.ac.uk
                [6]

                These authors contributed equally

                [7]

                Lead Contact

                Article
                S0896-6273(17)31125-X
                10.1016/j.neuron.2017.12.002
                5783715
                29290552
                1c3621a9-e2c6-4932-a958-4a8cfc498397
                © 2017 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 July 2017
                : 6 November 2017
                : 30 November 2017
                Categories
                Article

                Neurosciences
                microglia,potassium channel,atp,surveillance,inflammasome,interleukin-1β,ramification,thik-1
                Neurosciences
                microglia, potassium channel, atp, surveillance, inflammasome, interleukin-1β, ramification, thik-1

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