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.
Highlights
Microglia are the primary immune cells in the brain parenchyma, accounting for 5 to 12% of all cells, with a high density in the hippocampus [1]
Using pharmacology and THIK-1 KO mice, we demonstrated that microglial phagocytosis is controlled by THIK-1 (Fig. 1)
The requirement of THIK-1 for phagocytosis may in part be due to its role in enhancing microglial ramification and surveillance, which will increase the probability of a microglial cell encountering a target to phagocytose
Summary
Microglia are the primary immune cells in the brain parenchyma, accounting for 5 to 12% of all cells, with a high density in the hippocampus [1] Their functions are controlled by a plethora of ion channels and receptors on their plasma membrane [2]. Microglia can internalize and degrade targets that they have previously detected and contacted This process, referred to as phagocytosis, occurs throughout life in both physiological and pathological conditions. Microglia are more than mere cleaners of the brainparenchyma These cells are key for normal brain development [7], and their processes interact with various neuronal compartments. Microglial THIK-1 K+ channels maintain ramification of microglial processes and their surveillance of the brain [3], which could promote the elimination of synapses during development by phagocytosis (or trogocytosis) [12]. Because developmental mechanisms are thought to be reactivated during aging and disease [22,23,24,25,26], understanding these mechanisms
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