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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    • "Likewise, reduction of basal activity in the visual cortex in vivo by several independent approaches, including binocular eye enucleation, retinal TTX injection and reduction of body temperature, had no effect on basal velocity of microglial processes (Wake et al., 2009). However, with a simultaneous visualization of neurons and microglia,Wake et al. (2009), showed a reduced frequency of microglia-synapse contacts. Since this effect resulted from the aforementioned manipulations of neuronal activity, apart from TTX application, neuronal activity could at least modulate microglia-synapse interaction. "
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    ABSTRACT: Microglia, the resident immune cells of the central nervous system (CNS), were traditionally believed to be set into action only in case of injury or disease. Accordingly, microglia were assumed to be inactive or resting in the healthy brain. However, recent studies revealed that microglia carry out active tissue sampling in the intact brain by extending and retracting their ramified processes while periodically contacting synapses. Microglial morphology and motility as well as the frequency and duration of physical contacts with synaptic elements were found to be modulated by neuronal activity, sensory experience and neurotransmission; however findings have not been straightforward. Microglial cells are the most morphologically plastic element of the CNS. This unique feature confers them the possibility to locally sense activity, and to respond adequately by establishing synaptic contacts to regulate synaptic inputs by the secretion of signaling molecules. Indeed, microglial cells can hold new roles as critical players in maintaining brain homeostasis and regulating synaptic number, maturation and plasticity. For this reason, a better characterization of microglial cells and cues mediating neuron-to-microglia communication under physiological conditions may help advance our understanding of the microglial behavior and its regulation in the healthy brain. This review highlights recent findings on the instructive role of neuronal activity on microglial motility and microglia-synapse interactions, focusing on the main transmitters involved in this communication and including newly described communication at the tripartite synapse.
    Preview · Article · Jan 2016 · Frontiers in Integrative Neuroscience
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    • "In vivo two-photon microscopy (TPM) is an emerging technique for studying of the progression of biological processes in tissue beyond the depth range of conventional confocal microscopy and resolution beyond photoacoustic imaging, magnetic resonance imaging, or fluorescence molecular tomography. TPM has been successfully used as a research tool to understand temporal dynamics of injury and disease (Bell et al., 2010; Davalos et al., 2005; Kozai et al., 2012b; Masamoto et al., 2012; Wake et al., 2009) For example, in vivo TPM has been previously used to map the BBB prior to implant insertion (Kozai et al., 2010). This mapping technique identified regions in the cortex where large blood vessels penetrate into the cortex as well as regions densely filled with small capillaries, which are only wide enough to allow a single blood cell to pass at time. "
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    ABSTRACT: Background: Two-photon microscopy has enabled the visualization of dynamic tissue changes to injury and disease in vivo. While this technique has provided powerful new information, in vivo two-photon chronic imaging around tethered cortical implants, such as microelectrodes or neural probes, present unique challenges. New Method: A number of strategies are described to prepare a cranial window to longitudinally observe the impact of neural probes on brain tissue and vasculature for up to 3 months. Results: It was found that silastic sealants limit cell infiltration into the craniotomy, thereby limiting light scattering and improving window clarity over time. In contrast, low concentration hydrogel sealants failed to prevent cell infiltration and their use at high concentration displaced brain tissue and disrupted probe performance. Comparison with Existing Method(s): The use of silastane sealants allows for a suitable imaging window for long term chronic experiments and revealed new insights regarding the dynamic leukocyte response around implants and the nature of chronic BBB leakage in the sub-dural space. Conclusion: The presented method provides a valuable tool for evaluating the chronic inflammatory response and the performance of emerging implantable neural technologies
    Full-text · Article · Oct 2015 · Journal of Neuroscience Methods
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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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