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

Division of Homeostatic Development, National Institute of Physiological Sciences, Okazaki 444-8585, Japan.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2009; 29(13):3974-80. DOI: 10.1523/JNEUROSCI.4363-08.2009
Source: PubMed


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 (approximately 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 (approximately 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.

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Available from: Hiroaki Wake, Feb 26, 2014
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    • "There have been reports of sex differences in microglial colonization and function in rodent development that begin at or shortly after birth but are absent at E17 (Schwarz et al., 2012). Glial function is increasingly understood to play a prominent role in brain development and learning by influencing synaptic plasticity and our findings of sex-specific differences of microglial populations are consistent with previous studies (Tremblay et al., 2010; Wake et al., 2009). Given that sex differences in glia are not evident at E17 suggests a mechanism of propagated insult whereby the acute neuronal injury continues until such a time that sex differences can influence outcomes. "
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    • "Speculatively, these changes in the morphology of Iba1 + microglia may therefore be linked to potential loss of neuropil in the ACC and S2 cortices, leading to a volume decrease. This hypothesis is consistent with recent evidence that microglia are critical mediators of activity-dependent synaptic remodelling and plasticity in the healthy brain (Boonstra et al., 2011; Cazorla et al., 2014; Kettenmann et al., 2013; Wake et al., 2009; Zatorre et al., 2012). In contrast, increases in "
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    • "Following focal traumatic brain injury the processes rapidly converge on the site of injury (without cell body movements) and shield the healthy tissue from the injured one [16] [17]. Subsequently, the same technical approach allowed discovering that fine microglial processes make direct contacts with neuronal synapses that in the intact brain are retracted within a time scale of a few minutes, whereas, following transient cerebral ischemia, they are kept for much longer time (about one hour) and are frequently followed by the disappearance of the presynaptic terminal [18]. Soon after that, another major breakthrough was the demonstration that the physiologically occurring synaptic pruning during postnatal development requires the active involvement of microglia that phagocyte synaptic material: this process is mediated by the fractalkine receptor Cx3cr1 and plays a major role in normal brain developmental wiring [19]. "
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