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: 6.75). 05/2009; 29(13):3974-80. DOI: 10.1523/JNEUROSCI.4363-08.2009
Source: PubMed

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 (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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    • "In their ramified, non-activated state, microglia exhibit small somas and elaborate, highly motile processes (Nimmerjahn et al., 2005). This high degree of motility facilitates the interaction of microglial bulbous endings with numerous physiological processes in the central nervous system, ranging from response to cellular damage (Davalos et al., 2005; Wake et al., 2009) to a role in synaptic pruning and response to neuronal activity (Paolicelli et al., 2011; Schafer et al., 2012; Dissing-Olesen et al., 2014; Eyo et al., 2014). The normal ramified morphology of microglia is dependent on the immune-privileged environment of the brain parenchyma and is difficult to reproduce in vitro, as serum and other factors present in the culture media cause immunological activation and subsequent changes in cell morphology and activity. "
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    Frontiers in Molecular Neuroscience 05/2015; 8. DOI:10.3389/fnmol.2015.00012 · 4.08 Impact Factor
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    • "ments , par - ticularly pre - synaptic axon terminals and post - synaptic dendritic Frontiers in Neuroanatomy | www . frontiersin . org 7 April 2015 spines . Microglial contacts with synaptic elements have been observed in vivo with two - photon microscopy , showing dura - tions varying between 5 and 30 min , as well as in fixed tissue using TEM ( Wake et al . , 2009 ; Tremblay et al . , 2010 ; Sogn et al . , 2013 ) ."
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