Microglia as hunters or gatherers of brain synapses

Over a decade ago, it was discovered that microglia, the brain’s immune cells, engulf synaptic material in a process named microglial pruning. This term suggests that microglia actively sculpt brain circuits by tagging and phagocytosing unwanted synapses. However, live imaging studies have yet to demonstrate how microglial synapse elimination occurs. To address this issue, we propose a new conceptual framework distinguishing between two potential mechanisms of synapse elimination, culling and scavenging. During culling, microglia may use a contractile ring to sever the neuronal plasma membrane, removing the unwanted synapse. During scavenging, synapse elimination is neuronal-driven, and the neuronal plasma membrane fission machinery sheds off synapses that are later phagocytosed by microglia. We will discuss the current limitations of studying microglial synapse elimination and evaluate evidence supporting either culling or scavenging. Discerning between these mechanisms is essential for determining the therapeutic value of phagocytosis modulators in diseases with altered brain connectivity.