publication . Article . 2018

Microglial ramification, surveillance and interleukin-1beta release are regulated by the two-pore domain K+ channel THIK-1

Attwell, D.; Madry, C.; Kyrargyri, V.; Arancibia-Carcamo, I. L.; Jolivet, R.; Kohsaka, S.; Bryan, R.;
Open Access English
  • Published: 17 Jan 2018
  • Publisher: Elsevier
  • Country: United Kingdom
Abstract
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, ramifica...
Subjects
free text keywords: microglia; potassium channel; ATP; surveillance; inflammasome; interleukin-1β; ramification; THIK-1
Related Organizations
Funded by
WT| Novel aspects of neurotransmitter signalling and its regulation by transporters in health and disease.
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 075232
  • Funding stream: Neuroscience and Mental Health
,
WT| The development, plasticity and pathology of myelinated CNS axons.
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 099222
  • Funding stream: Neuroscience and Mental Health
,
SNSF| Phases incommensurables, structures désordonnées, diffusion diffuse
Project
  • Funder: Swiss National Science Foundation (SNSF)
  • Project Code: 2000-046666
  • Funding stream: Project funding | Project funding (Div. I-III)
,
EC| BRAINENERGYCONTROL
Project
BRAINENERGYCONTROL
Quantifying control of brain energy supply by the neuron-glia-vasculature unit
  • Funder: European Commission (EC)
  • Project Code: 274384
  • Funding stream: FP7 | SP3 | PEOPLE
,
NIH| EDHF in the Cerebral Circulation
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01NS046666-05
  • Funding stream: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Download from
UCL Discovery
Article . 2018
77 references, page 1 of 6

Bernardino, L., Balosso, S., Ravizza, T., Marchi, N., Ku, G., Randle, J.C., Malva, J.O., and Vezzani, A. (2008). Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: a crucial role of P2X7 receptor-mediated IL-1beta release. J. Neurochem. 106, 271-280. [OpenAIRE]

Bialas, A.R., Presumey, J., Das, A., van der Poel, C.E., Lapchak, P.H., Mesin, L., Victora, G., Tsokos, G.C., Mawrin, C., Herbst, R., and Carroll, M.C. (2017).

Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 546, 539-543.

Bischofberger, J., Engel, D., Li, L., Geiger, J.R.P., and Jonas, P. (2006). Patchclamp recording from mossy fiber terminals in hippocampal slices. Nat. [OpenAIRE]

Protoc. 1, 2075-2081.

Bohlen, C.J., Bennett, F.C., Tucker, A.F., Collins, H.Y., Mulinyawe, S.B., and Barres, B.A. (2017). Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759-773.e8. [OpenAIRE]

Boucsein, C., Zacharias, R., Fa€rber, K., Pavlovic, S., Hanisch, U.K., and Kettenmann, H. (2003). Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur. J. Neurosci. 17, 2267-2276. [OpenAIRE]

Bradley, A., Anastassiadis, K., Ayadi, A., Battey, J.F., Bell, C., Birling, M.-C., Bottomley, J., Brown, S.D., Bu€rger, A., Bult, C.J., et al. (2012). The mammalian gene function resource: the International Knockout Mouse Consortium. [OpenAIRE]

Mamm. Genome 23, 580-586.

Brown, S.D., and Moore, M.W. (2012). The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping. Mamm.

Genome 23, 632-640.

(2014). Identification of a unique TGF-b-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131-143.

Charolidi, N., Schilling, T., and Eder, C. (2015). Microglial Kv1.3 channels and P2Y12 receptors differentially regulate cytokine and chemokine release from brain slices of young adult and aged mice. PLoS ONE 10, e0128463.

(2010). Enhanced synaptic connectivity and epilepsy in C1q knockout mice.

Proc. Natl. Acad. Sci. USA 107, 7975-7980.

77 references, page 1 of 6
Abstract
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, ramifica...
Subjects
free text keywords: microglia; potassium channel; ATP; surveillance; inflammasome; interleukin-1β; ramification; THIK-1
Related Organizations
Funded by
WT| Novel aspects of neurotransmitter signalling and its regulation by transporters in health and disease.
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 075232
  • Funding stream: Neuroscience and Mental Health
,
WT| The development, plasticity and pathology of myelinated CNS axons.
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 099222
  • Funding stream: Neuroscience and Mental Health
,
SNSF| Phases incommensurables, structures désordonnées, diffusion diffuse
Project
  • Funder: Swiss National Science Foundation (SNSF)
  • Project Code: 2000-046666
  • Funding stream: Project funding | Project funding (Div. I-III)
,
EC| BRAINENERGYCONTROL
Project
BRAINENERGYCONTROL
Quantifying control of brain energy supply by the neuron-glia-vasculature unit
  • Funder: European Commission (EC)
  • Project Code: 274384
  • Funding stream: FP7 | SP3 | PEOPLE
,
NIH| EDHF in the Cerebral Circulation
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01NS046666-05
  • Funding stream: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Download from
UCL Discovery
Article . 2018
77 references, page 1 of 6

Bernardino, L., Balosso, S., Ravizza, T., Marchi, N., Ku, G., Randle, J.C., Malva, J.O., and Vezzani, A. (2008). Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: a crucial role of P2X7 receptor-mediated IL-1beta release. J. Neurochem. 106, 271-280. [OpenAIRE]

Bialas, A.R., Presumey, J., Das, A., van der Poel, C.E., Lapchak, P.H., Mesin, L., Victora, G., Tsokos, G.C., Mawrin, C., Herbst, R., and Carroll, M.C. (2017).

Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 546, 539-543.

Bischofberger, J., Engel, D., Li, L., Geiger, J.R.P., and Jonas, P. (2006). Patchclamp recording from mossy fiber terminals in hippocampal slices. Nat. [OpenAIRE]

Protoc. 1, 2075-2081.

Bohlen, C.J., Bennett, F.C., Tucker, A.F., Collins, H.Y., Mulinyawe, S.B., and Barres, B.A. (2017). Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759-773.e8. [OpenAIRE]

Boucsein, C., Zacharias, R., Fa€rber, K., Pavlovic, S., Hanisch, U.K., and Kettenmann, H. (2003). Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur. J. Neurosci. 17, 2267-2276. [OpenAIRE]

Bradley, A., Anastassiadis, K., Ayadi, A., Battey, J.F., Bell, C., Birling, M.-C., Bottomley, J., Brown, S.D., Bu€rger, A., Bult, C.J., et al. (2012). The mammalian gene function resource: the International Knockout Mouse Consortium. [OpenAIRE]

Mamm. Genome 23, 580-586.

Brown, S.D., and Moore, M.W. (2012). The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping. Mamm.

Genome 23, 632-640.

(2014). Identification of a unique TGF-b-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131-143.

Charolidi, N., Schilling, T., and Eder, C. (2015). Microglial Kv1.3 channels and P2Y12 receptors differentially regulate cytokine and chemokine release from brain slices of young adult and aged mice. PLoS ONE 10, e0128463.

(2010). Enhanced synaptic connectivity and epilepsy in C1q knockout mice.

Proc. Natl. Acad. Sci. USA 107, 7975-7980.

77 references, page 1 of 6
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