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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    • "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
    Journal of Neuroscience Methods 10/2015; DOI:10.1016/j.jneumeth.2015.10.007 · 2.05 Impact Factor
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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. "
    Dataset: BBIpaper

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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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    ABSTRACT: Neuroinflammation is increasingly implicated in the pathogenesis of Schizophrenia (SCZ). In addition, there is increasing evidence for a relationship between the dose and duration of antipsychotic drug (APD) treatment and reductions in grey matter volume. The potential contribution of microglia to these phenomena is however not yet defined. Adult rats were treated with a common vehicle, haloperidol (HAL, 2mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) for 8 weeks via an osmotic mini-pump implanted subcutaneously. Microglial cells, identified by their Iba-1 immunoreactivity, were quantified in four regions of interest chosen based on previous neuroimaging data: the hippocampus, anterior cingulate cortex, corpus striatum, and secondary somatosensory cortex. Those cells were also analysed according to their morphology, providing an index of their activation state. Chronic APD treatment resulted in increased density of total microglia in the hippocampus, striatum, and somatosensory cortex, but not in the ACC. Importantly, in all brain regions studied, both APD tested led to a dramatic shift towards an amoeboid, reactive, microglial morphology after chronic treatment compared to vehicle-treated controls. These data provide the first in vivo evidence that chronic APD treatment at clinically relevant doses leads to microglial proliferation and morphological changes indicative of activated microglia in the naïve rat brain. Although caution needs to be exerted when extrapolating results from animals to patients, these data suggest a potential contribution of antipsychotic medication to markers of brain inflammation. Further investigation of the links between antipsychotic treatment and the immune system are warranted. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
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