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Synapse development is regulated by microglial THIK-1 K+ channels

Izquierdo, P; Shiina, H; Hirunpattarasilp, C; Gillis, G; Attwell, D; (2021) Synapse development is regulated by microglial THIK-1 K+ channels. Proceedings of the National Academy of Sciences of the United States of America , 118 (42) , Article e2106294118. 10.1073/pnas.2106294118. Green open access

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Abstract

Microglia are the resident immune cells of the central nervous system. They constantly survey the brain parenchyma for redundant synapses, debris, or dying cells, which they remove through phagocytosis. Microglial ramification, motility, and cytokine release are regulated by tonically active THIK-1 K+ channels on the microglial plasma membrane. Here, we examined whether these channels also play a role in phagocytosis. Using pharmacological blockers and THIK-1 knockout (KO) mice, we found that a lack of THIK-1 activity approximately halved both microglial phagocytosis and marker levels for the lysosomes that degrade phagocytically removed material. These changes may reflect a decrease of intracellular [Ca2+]i activity, which was observed when THIK-1 activity was reduced, since buffering [Ca2+]i reduced phagocytosis. Less phagocytosis is expected to result in impaired pruning of synapses. In the hippocampus, mice lacking THIK-1 expression had an increased number of anatomically and electrophysiologically defined glutamatergic synapses during development. This resulted from an increased number of presynaptic terminals, caused by impaired removal by THIK-1 KO microglia. The dependence of synapse number on THIK-1 K+ channels, which control microglial surveillance and phagocytic ability, implies that changes in the THIK-1 expression level in disease states may contribute to altering neural circuit function.

Type: Article
Title: Synapse development is regulated by microglial THIK-1 K+ channels
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2106294118
Publisher version: https://doi.org/10.1073/pnas.2106294118
Language: English
Additional information: Copyright © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Keywords: microglia, phagocytosis, synaptic pruning
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10136728
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