Resting Microglia Directly Monitor the Functional State of Synapses<i>In Vivo</i>and Determine the Fate of Ischemic Terminals

TLDR

Glial cells, particularly resting microglia, are known to influence neuronal circuit plasticity by dynamically extending and retracting processes, yet the specific structures they sample and how they interact with synapses in vivo remain unclear. This study aims to elucidate how resting microglia detect synaptic functional states and contribute to circuit remodeling after ischemic injury, with the goal of informing microglia‑targeted therapies for brain injury. Using in vivo two‑photon imaging of fluorescently labeled neurons and microglia, the authors observed that resting microglial processes make brief (≈5 min) direct contacts with synapses roughly once per hour. These contacts are activity‑dependent, decrease with reduced neuronal activity, and after transient cerebral ischemia become prolonged (≈1 h) and often precede presynaptic bouton loss, demonstrating that microglia monitor synaptic function and can drive synaptic turnover.

Abstract

Recent studies have identified the important contribution of glial cells to the plasticity of neuronal circuits. Resting microglia, the primary immune effector cells in the brain, dynamically extend and retract their processes as if actively surveying the microenvironment. However, just what is being sampled by these resting microglial processes has not been demonstrated in vivo , and the nature and function of any interactions between microglia and neuronal circuits is incompletely understood. Using in vivo two-photon imaging of fluorescent-labeled neurons and microglia, we demonstrate that the resting microglial processes make brief (∼5 min) and direct contacts with neuronal synapses at a frequency of about once per hour. These contacts are activity-dependent, being reduced in frequency by reductions in neuronal activity. After transient cerebral ischemia, the duration of these microglia–synapse contacts are markedly prolonged (∼1 h) and are frequently followed by the disappearance of the presynaptic bouton. Our results demonstrate that at least part of the dynamic motility of resting microglial processes in vivo is directed toward synapses and propose that microglia vigilantly monitor and respond to the functional status of synapses. Furthermore, the striking finding that some synapses in the ischemic areas disappear after prolonged microglial contact suggests microglia contribute to the subsequent increased turnover of synaptic connections. Further understanding of the mechanisms involved in the microglial detection of the functional state of synapses, and of their role in remodeling neuronal circuits disrupted by ischemia, may lead to novel therapies for treating brain injury that target microglia.