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      Microglial Interactions with Synapses Are Modulated by Visual Experience

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      PLoS Biology

      Public Library of Science

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Microglia, the brain's immune cells, show unique interactions with nearby synaptic elements under non-pathological conditions that are sensitive to changes in sensory experience.

          Abstract

          Microglia are the immune cells of the brain. In the absence of pathological insult, their highly motile processes continually survey the brain parenchyma and transiently contact synaptic elements. Aside from monitoring, their physiological roles at synapses are not known. To gain insight into possible roles of microglia in the modification of synaptic structures, we used immunocytochemical electron microscopy, serial section electron microscopy with three-dimensional reconstructions, and two-photon in vivo imaging to characterize microglial interactions with synapses during normal and altered sensory experience, in the visual cortex of juvenile mice. During normal visual experience, most microglial processes displayed direct apposition with multiple synapse-associated elements, including synaptic clefts. Microglial processes were also distinctively surrounded by pockets of extracellular space. In terms of dynamics, microglial processes localized to the vicinity of small and transiently growing dendritic spines, which were typically lost over 2 d. When experience was manipulated through light deprivation and reexposure, microglial processes changed their morphology, showed altered distributions of extracellular space, displayed phagocytic structures, apposed synaptic clefts more frequently, and enveloped synapse-associated elements more extensively. While light deprivation induced microglia to become less motile and changed their preference of localization to the vicinity of a subset of larger dendritic spines that persistently shrank, light reexposure reversed these behaviors. Taken together, these findings reveal different modalities of microglial interactions with synapses that are subtly altered by sensory experience. These findings suggest that microglia may actively contribute to the experience-dependent modification or elimination of a specific subset of synapses in the healthy brain.

          Author Summary

          Microglia are important players in immune responses to brain injury. In the event of pathological insults, microglia rapidly become activated and acquire the ability to release various inflammatory molecules that influence neuronal survival as well as synaptic function and plasticity. Similarly to macrophages in other areas of the body, activated microglia can engulf, or phagocytose, cellular debris and are believed to eliminate synapses. In the absence of pathological insult, microglia are more quiescent, but still, these immune surveillants continually sample their surrounding environment and contact neighboring cells and synapses. To further explore the roles of microglia at synapses under non-pathological conditions, we used quantitative electron microscopy and two-photon in vivo imaging to characterize the interactions between quiescent microglia and synaptic elements in the visual cortex of juvenile mice. We also examined the “activity-dependent” processes involved by preventing light exposure in a group of mice. We show surprising changes in microglial behavior during alterations in visual experience, such as increased phagocytosis of synaptic elements and interaction with subsets of structurally dynamic and transient synapses. These observations suggest that microglia may participate in the modification or elimination of synaptic structures, and therefore actively contribute to learning and memory in the healthy brain.

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          Most cited references 39

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          Transient and persistent dendritic spines in the neocortex in vivo.

          Dendritic spines were imaged over days to months in the apical tufts of neocortical pyramidal neurons (layers 5 and 2/3) in vivo. A fraction of thin spines appeared and disappeared over a few days, while most thick spines persisted for months. In the somatosensory cortex, from postnatal day (PND) 16 to PND 25 spine retractions exceeded additions, resulting in a net loss of spines. The fraction of persistent spines (lifetime > or = 8 days) grew gradually during development and into adulthood (PND 16-25, 35%; PND 35-80, 54%; PND 80-120, 66%; PND 175-225, 73%), providing evidence that synaptic circuits continue to stabilize even in the adult brain, long after the closure of known critical periods. In 6-month-old mice, spines turn over more slowly in visual compared to somatosensory cortex, possibly reflecting differences in the capacity for experience-dependent plasticity in these brain regions.
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            Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling.

            The internalization of various cargo proteins and lipids from the mammalian cell surface occurs through the clathrin and lipid-raft endocytic pathways. Protein-lipid and protein-protein interactions control the targeting of signalling molecules and their partners to various specialized membrane compartments in these pathways. This functions to control the activity of signalling cascades and the termination of signalling events, and therefore has a key role in defining how a cell responds to its environment.
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              Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse.

              An activity-dependent form of synaptic plasticity underlies the fine tuning of connections in the developing primary visual cortex of mammals such as the cat and monkey. Studies of the effects of manipulations of visual experience during a critical period have demonstrated that a correlation-based competitive process governs this plasticity. The cellular mechanisms underlying this competition, however, are poorly understood. Transgenic and gene-targeting technologies have led to the development of a new category of reagents that have the potential to help answer questions of cellular mechanism, provided that the questions can be studied in a mouse model. The current study attempts to characterize a developmental plasticity in the mouse primary visual cortex and to demonstrate its relevance to that found in higher mammals. We found that 4 d of monocular lid suture at postnatal day 28 (P28) induced a maximal loss of responsiveness of cortical neurons to the deprived eye. These ocular dominance shifts occurred during a well-defined critical period, between P19 and P32. Furthermore, binocular deprivation during this critical period did not decrease visual cortical responses, and alternating monocular deprivation resulted in a decrease in the number of binocularly responsive neurons. Finally, a laminar analysis demonstrated plasticity of both geniculocortical and intracortical connections. These results demonstrate that an activity-dependent, competitive form of synaptic plasticity that obeys correlation-based rules operates in the developing primary visual cortex of the mouse.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                November 2010
                November 2010
                2 November 2010
                : 8
                : 11
                Affiliations
                Department of Neurobiology and Anatomy and Center for Visual Science, University of Rochester, Rochester, New York, United States of America
                University of Pennsylvania, United States of America
                Author notes

                The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: MET AKM. Performed the experiments: MET. Analyzed the data: MET. Contributed reagents/materials/analysis tools: RLL. Wrote the paper: MET AKM.

                Article
                10-PLBI-RA-6592R3
                10.1371/journal.pbio.1000527
                2970556
                21072242
                Tremblay et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 16
                Categories
                Research Article
                Cell Biology/Neuronal and Glial Cell Biology
                Immunology/Immune Response
                Neuroscience
                Neuroscience/Neurodevelopment
                Neuroscience/Neuronal and Glial Cell Biology
                Neuroscience/Sensory Systems
                Cell Biology/Extra-Cellular Matrix

                Life sciences

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