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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 references42

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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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            Dendritic organization in the neurons of the visual and motor cortices of the cat.

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              Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo.

              Microglia are the primary immune cells in the brain. Under physiological conditions, they typically stay in a "resting" state, with ramified processes continuously extending to and retracting from surrounding neural tissues. Whether and how such highly dynamic resting microglia functionally interact with surrounding neurons are still unclear. Using in vivo time-lapse imaging of both microglial morphology and neuronal activity in the optic tectum of larval zebrafish, we found that neuronal activity steers resting microglial processes and facilitates their contact with highly active neurons. This process requires the activation of pannexin-1 hemichannels on neurons. Reciprocally, such resting microglia-neuron contact reduces both spontaneous and visually evoked activities of contacted neurons. Our findings reveal an instructive role for neuronal activity in resting microglial motility and suggest the function for microglia in homeostatic regulation of neuronal activity in the healthy brain. Copyright © 2012 Elsevier Inc. All rights reserved.
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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/).

                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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