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

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 play a role in phagocytosis. Using pharmacological blockers and THIK-1 knockout (KO) mice, we found that lack of THIK-1 activity reduced microglial phagocytosis, which may result in impaired pruning of synapses. In hippocampus, mice lacking THIK-1 expression had an increased number of glutamatergic synapses during development. This resulted from an increased number of presynaptic terminals, due to impaired removal by THIK-1 KO microglia. In microglia in brain slices from fresh human biopsies, modulating THIK-1 function had effects similar to those in rodents: blocking THIK-1 rapidly reduced microglial process ramification and increased synaptic density. The dependence of synapse number on THIK-1 K + channels, which control microglial surveillance and phagocytic ability, implies that changes in THIK-1 expression level over the lifespan or in disease states may contribute to altering neural circuit function.

Significance

Microglia are the brain’s resident immune cells, surveying it with motile processes, which can remove pathogens but also prune unnecessary junctions between the neurons (synapses). A potassium channel, THIK-1, in the microglial membrane allows efflux of potassium from these cells, and thereby regulates their membrane voltage as well as their process motility and release of inflammatory mediators. Here, using THIK-1-blocking drugs and THIK-1-deficient mice, we demonstrate that THIK-1 controls removal of synaptic material by microglia, which reduces the number of functional synapses. We also show that blocking THIK-1, as some anaesthetics do, affects microglial structure and increases the number of synapses in living brain slices from both rodents and humans, and could thus alter network function in the brain.
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