Trends in Neurosciences
Research FocusLike cops on the beat: the active role of resting microglia
Introduction
Every tissue appears to employ its own specialized watchdogs to keep order and remove dysfunctional debris. These must also deal with potentially infectious agents, and be able to signal for help from the professional immune system of T and B lymphocytes, natural killer cells, and other circulating white blood cells such as dendritic cells, macrophages and granulocytes.
The brain and spinal cord parenchyma, the CNS proper, are no different. They feature microglia – a specific subpopulation of cells related to monocytes and dendritic cells that acts as a first line of defence against neural infection [1]. These specialized cells are professionals that remove dead cells and other debris such as degenerating axons and myelin, and they have a pivotal role in the early recruitment of T cells following even minor injury [2]. They also exhibit surface expression of immunoglobulin, and receptors for complement and apoptotic-cell surface markers 3, 4, 5, in line with their local surveillance role. In the normal brain, these resting microglia are highly ramified, with an elaborate tertiary and quaternary branch structure, and each stakes claim to an area of the brain 30–50 μm wide that rarely overlaps with the branches of even nearby sister cells.
However, this intricate branching poses a perceptual problem for the ability of microglia to survey the surrounding tissue. Most neurons, astrocytes and oligodendroglia also exhibit highly ramified structures. However, these ramifications are usually fixed, owing to physical connections between the branches and their appropriate targets, be they neurite terminals, myelin sheaths or, in the case of astrocyte endfeet, the basal membranes of cerebral blood vessels. Are the microglial branches also fixed in space? If so, their surveillance role would be severely restricted to a passive sensing of the molecules or cellular structures that came into contact with them.
Section snippets
The creeping branches
Two recently published papers, by Nimmerjahn et al. [6], and Davalos et al. [7], now show that these ‘resting’ microglia are capable of, and engage in, surprisingly extensive movements in the mature and uninjured adult brain. Both studies employed the CX3CR1::EGFP mice [8], in which brain microglia selectively express enhanced green fluorescent protein (EGFP) under control of the fractalkine receptor (CX3CR1) promoter; trans-cranial two-photon laser-scanning microscopy was used to obtain
Physiological signals
But what drives and attracts the movement of these microglial branches? For example, does it reflect the neuronal or synaptic activity? Cessation of axonal and synaptic activity using the Na+-channel blocker tetrodotoxin (TTX) had no significant effect on the microglial activity [6] (Figure 1a). Enhancing synaptic activity using the GABA-receptor blocker bicuculline (50 μM) did have a slight stimulating effect (+14%) [6]. However, bicuculline also elicits seizure activity; thus, the
Concluding remarks
So what are the direct mediators of surveillance in the resting microglia – are they nucleotides, or hypothetical chemokines and adhesion molecules rapidly activated on the astrocyte surface (Figure 1b), or possibly combinations of both? At the moment, this is not entirely clear. The study by Davalos et al. [7] indicates that nucleotides such as ATP are essential for the injury-mediated response, which is associated with release of cytoplasmic contents. However, the fact that our brains are
Acknowledgements
I thank Milan Makwana for his valuable help with Figure 1, and Donald Peebles and Giles Kendall for reading the manuscript.
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