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

By H. Wake, A. Moorhouse, S. Jinno, S. Kohsaka, J. Nabekura. Journal of Neuroscience, 2009

1,565 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/3c5a8898f5b50b80eb8228e2e1153b4d5a820a34

How researchers see this paper

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In Cellular and Molecular Neuroscience

1. M. Pekny
2. M. Sofroniew
3. M. Pekna
4. Alexei Verkhratsky
5. Beth Stevens
6. E. Hol
7. O. Butovsky
8. Guang Yang

In Developmental Neuroscience

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. E. Hol
5. O. Butovsky
6. B. Barres
7. Beth Stevens
8. Marie-Eve Tremblay

In Neurology

1. M. Sofroniew
2. R. Ransohoff
3. B. Barres
4. M. Pekny
5. Alexei Verkhratsky
6. Beth Stevens
7. M. Pekna
8. E. Hol

Citations in the corpus

• Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. (2016, background): “Recently, increasing evidence shows that microglia not only function as dynamic immune surveillants but also can impact neural development and the maintenance of neuronal cell function in both healthy and pathological conditions (Michell-Robinson et al., 2015; Nimmerjahn et al., 2005; Wake et al., 2”
• Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis (2011, background): “Recent in vivo time-lapse imaging of microglia especially challenged the view of ‘resting’ and ‘activated’ microglia (Davalos et al., 2005; Nimmerjahn et al., 2005; Wake et al., 2009).”
• Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012, neutral): “However, recent studies suggest that microglia may play a role in synaptic remodeling and plasticity in the healthy brain (Davalos et al., 2005; Nimmerjahn et al., 2005; Paolicelli et al., 2011; Schafer et al., 2012; Tremblay et al., 2010a; Wake et al., 2009).”
• Microglia: Dynamic Mediators of Synapse Development and Plasticity (2015, background): “Pioneering in vivo imaging studies revealed that the processes of microglia are highly motile and are continually extending, retracting, and interacting with synapses [20–23].”
• Microglial M1/M2 polarization and metabolic states (2016, background): “Similar to macrophages, microglia mount an immune response to pathogens, monitor for tissue changes and maintain tissue homeostasis by clearing pathogens, dying cells, debris or aberrant proteins (Gehrmann et al., 1995; Bruce-Keller, 1999; Stevens et al., 2007; Wake et al., 2009; Nagamoto-Combs et a”
• Astrocytes: a central element in neurological diseases (2016, background): “The synaptic assembly also includes a microglial cell process that frequently senses the synapse status [114, 229, 242].”
• Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, background): “As activated microglia are thought to mediate synaptic stripping (Blinzinger and Kreutzberg, 1968; Wake et al., 2009), we sought to determine whether microglial elimination could affect dendritic spine number in 5xfAD mice.”
• Origin and Functions of Tissue Macrophages (2014, background): “During the aging process, microglia acquire an irregular shape, occupy smaller territories, and form inclusions containing apparent synaptic elements, suggesting that dysfunction develops in macrophage degradative pathways with age (Tremblay et al., 2012; Wake et al., 2013).”
• The complement system: an unexpected role in synaptic pruning during development and disease. (2012, background): “…studies in the mouse cortex have revealed that microglial dynamics and interactions with neuronal compartments change in response to neural activity and experience (Davalos et al. 2005, Nimmerjahn et al. 2005, Wake et al. 2009, Tremblay et al. 2010), but the underlying mechanisms remain elusive.”