Though microglia, the housekeeping cells of the central nervous system, have been implicated in the clearance of amyloid-β (see ARF related news story), they have also long been thought to be passive bystanders, only springing into action when there is a problem. But in an exposé in the April 15 Sciencexpress, Fritjof Helmchen and colleagues at the Max-Planck-Institute, Heidelberg, Germany, show that glia are far from passive. In pictures and time-lapse movies taken transcranially and in vivo, Helmchen and colleagues show that the cells are in constant motion, probing and surveying their environment. One dramatic video, for example, shows how rapidly a parenchymal inclusion can be sucked up and transported to the soma of a microglia (see below).

First author Axel Nimmerjahn and colleagues used two-photon microscopy to peer into the brain tissue of living mice (see ARF related news story on the use of the microscope). To ensure they were viewing the right cells, the authors used transgenic animals that expressed enhanced green fluorescent protein under control of a chemokine receptor (CX3CR1), which is only expressed in microglia. Using time-lapse images, taken for hours at a time, Nimmerjahn and colleagues were able to capture the glial daily routine.

The first thing the authors noticed was that glial cell bodies don’t move very much. Only about 5 percent seemed to shift position, and only by around 1-2 micrometers per hour. This is perhaps to be expected. But cell processes were another matter. The authors found that these were remarkably active and mobile (see movies 1 and 2).

Movie 1. Glia are far from static
This two-photon time-lapse video (images taken at 1-minute intervals) shows that in a resting microglia, processes are far from static. The green color indicates new processes, red indicates old. Link to quicktime movie at Science magazine.

 

Movie 2. Sending out feelers
High-resolution time-lapse video shows that glia repeatedly probe the parenchyma (images taken every 15 seconds). Link to quicktime movie at Science magazine.

Of particular interest to AD researchers are time-lapse images showing how glial processes suck up inclusion bodies and transport them to the cell soma (see movie 3). The images suggest that glia might be able to remove intraneural aggregates of Aβ in the same manner, though in this case, the nature of the inclusion is not known.

Movie 3. Engulfing inclusions
Images taken at 80-second intervals show how rapidly an inclusion body (bottom center) is transported to the glial soma (top center). Link to quicktime movie at Science magazine.

The authors also found that glia can rapidly mobilize in response to an acute trauma. When Nimmerjahn and colleagues used a highly localized laser beam to poke a hole in a capillary, nearby glia rushed to the site of injury (see movie 4). The speed of this migration was on the order of 2 micrometers per minute, which contrasts to the 1-2 micrometers per hour seen under normal conditions.

Movie 4. Glial paramedics
Images taken every 60 seconds show that when a small blood vessel (red) is opened with a focused laser beam (represented by the flash of yellow), glia (green) rush to the scene to deal with the hemorrhage (blood is labeled with Texas red dextran). Link to quicktime movie at Science magazine.

The authors conclude that microglial cells are highly dynamic structures, and they suggest that the “ongoing structural changes of resting microglial cells presumably serve an immune surveillance function.” They also write that “early formation of spherical-shaped inclusions suggests immediate phagocytic engulfment and removal of damaged tissue or leaked blood components.” That phagocytic activity, plus the cells rush to shield tissue leaks in the blood-brain barrier, fits with the idea that glia perform a protective role in the brain. The need for continual surveillance by these highly dynamic cells may also help explain why glial mutations can have such a dramatic impact on neurons and can even lead to neurodegeneration of wild-type motor neurons (see ARF related news story on the importance of glia in amyotrophic lateral sclerosis).—Tom Fagan.

Reference:
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Sciencexpress. 14 April, 2005. Abstract

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  1. Nimmerjahn et al. have used the two-photon imaging technique to demonstrate the dynamic action of microglial cells in vivo. They were provided with a green fluorescent microglia cell line by S. Jung and D.R. Littman. In their elegantly illustrated paper, they provide living proof, by time-lapse imaging, of the way microglial cells are behaving in living brain. In the resting state, they are not at rest, but are continuously extending and retracting their processes over periods of minutes, sampling the extracellular environment, and generally patrolling their immediate environment. When the environment was disturbed, they immediately responded. This was done by either laser damage to microvessels, in which case the microglia moved to seal the leak, or with LPS injections from a micropipette, in which case the microglia engulfed the pipette tip. The three figures in the paper are supplemented by 12 short movies online. The movies need to be watched to grasp the full significance of the paper. This paper follows up a previous demonstration of the dynamic actions of astrocytes using a comparable technique, but in which case it was mouse astrocytes that were transfected with fluorescent green (Mulligan et al., 2004). The most interesting experiment in this fascinating series is yet to come. That will be when neurons are transfected with fluorescent green and we will be able to witness the formation and retraction of synapses in real time.

    References:

    . Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature. 2004 Sep 9;431(7005):195-9. PubMed.

Comments on Primary Papers for this Article

  1. This is really a breakthrough for Alzheimer's diesease research. I think this technique can be used for a variety of in vivo studies, e.g. to see how immune cells interact with target cells.

    View all comments by Jun Xu

References

News Citations

  1. Microglia Aid and Abet Aβ Toxicity and Clearance
  2. Window to the Brain Shows Dystrophic Neurites Shrinking
  3. ALS—Is It the Neurons or the Glia?

Paper Citations

  1. . Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005 May 27;308(5726):1314-8. PubMed.

External Citations

  1. Link to quicktime movie at Science magazine
  2. Link to quicktime movie at Science magazine
  3. Link to quicktime movie at Science magazine
  4. Link to quicktime movie at Science magazine

Further Reading

Papers

  1. . Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005 May 27;308(5726):1314-8. PubMed.

News

  1. Astrocytes May Hold Key to Adult Neurogenesis
  2. ALS—Is It the Neurons or the Glia?

Primary Papers

  1. . Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005 May 27;308(5726):1314-8. PubMed.