Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner

By Dorothy P. Schafer, Emily K. Lehrman, Amanda G Kautzman, Ryuta Koyama, Alan R. Mardinly, R. Yamasaki, R. Ransohoff, Michael E. Greenberg, B. Barres, Beth Stevens. Neuron, 2012

3,753 citations recorded by the source corpus.

SUMMARY Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/4a4c722dcbce64ef7af28d1871c153d9356ff7ac

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. C. Eroglu
5. E. Hol
6. N. J. Allen
7. B. Barres
8. Irving L. Weissman

In Neurology

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

Citations in the corpus

• Microglia regulate the number of neural precursor cells in the developing cerebral cortex (2013, background): “Recent work has shown that microglia participate in synaptic pruning in the developing postnatal brain (Paolicelli et al., 2011; Schafer et al., 2012), and phagocytose newborn neurons in the subgranular zone of the adult hippocampus (Sierra et al., 2010).”
• Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment (2014, background): “Microglia, the brain-resident macrophages, prune synapses during development (Paolicelli et al., 2011; Schafer et al., 2012).”
• Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States (2018, background): “mediate adaptive synaptic remodeling in the healthy developing and adult brain (Schafer et al., 2012; Stevens et al., 2007); (3) TLRs are expressed in neurons, where they play roles in regulating developmental and adult neuroplasticity (Okun et al.”
• The role of glia in the spinal cord in neuropathic and inflammatory pain. (2015, background): “Additionally, a number of inappropriate synaptic connections are made between neurons during development, and microglia play an important role in the regulation of these contacts via the process of synaptic pruning—the phagocytosis of both pre- and postsynaptic elements in a complement cascade-depen”
• Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. (2016, background): “Microglia, as one of the major neural cells that contribute to the brain’s development, act to help sculpt neural circuits and are active in synaptic pruning and the support neurogenesis (Paolicelli et al., 2011; Schafer et al., 2012; Xavier et al., 2015).”
• Microglial brain region-dependent diversity and selective regional sensitivities to ageing (2016, background): “Key findings include that (1) transcriptional networks controlling microglial bioenergetic and immunoregulatory functions contribute prominently to heterogeneity in the young adult, (2) immunophenotypic variation suggests a more immune vigilant state of cerebellar microglia, (3) networks of gene co-”
• An environment-dependent transcriptional network specifies human microglia identity (2017, background): “As microglia participate in the developmental refinement of synaptic networks (28) and elaborate neuromodulatory factors for adult motor learning (29), alterations in the brain microenvironment may lead to pathogenic programs of gene expression in microglia.”
• Microglia promote learning-dependent synapse formation through BDNF (2013, background): “In addition, the microglia themselves express activated TrkB, and BDNF released from microglia has been shown to increase their proliferation (Spencer-Segal et al., 2011).”
• Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation (2016, positive): “Several previous studies indicate that complement-mediated synaptic pruning by microglia plays a critical role in the refinement of neural circuits during early postnatal development and in the normal aging process (Schafer et al., 2012; Shi et al., 2015; Stephan et al., 2013; Stevens et al., 2007).”