Scientific Understanding of Consciousness
Synapses Pruned by Microglia
Nature, 485, 570–572 (31 May 2012)
Microglia seem to be crucial for pruning back neurons during development.
Nature News Feature
'Resting' microglia are anything but. Their delicate branches snake through densely packed brain tissue, constantly extending and shrinking and re-growing. “They're very dynamic, much more than any other cell in the adult brain,” says a biophysicist at the Salk Institute in La Jolla, California. He calculated that the cells' concerted movements could survey the entire brain every couple of hours. But it was unclear why the microglia were moving so much.
A flurry of studies during the past two years have investigated microglia's influence in adult and developing brains. The results are overturning the idea that microglia are passive immune sentinels. Several groups have proposed that these shape-shifting cells not only eat up invaders and damaged tissue, but also trim away weak synapses, between neurons. This pruning process occurs on a large scale in the developing brain, and it is known to be important in learning and memory. Neurodevelopmental disorders such as autism and schizophrenia are often associated with faulty pruning.
But many questions remain. No one knows how microglia 'talk' to neurons or other cells, or whether their functions are limited to certain brain regions.
Neurons account for only about 10% of the cells in the human brain. The balance is made up by different types of glia, which surround and support neurons and influence neuronal signalling. Oligodendrocytes, for example, create fatty sheaths that encase long neuronal branches and help to speed up electrical impulses. Astrocytes surround synapses and have been shown to affect neuronal signalling by controlling the mix of chemical messengers at neuronal junctions.
Microglia are quite different from their neighbours. Unlike neurons and other glial cells, they begin in the embryonic yolk sac as immune-cell progenitors, just as the macrophages that patrol the bloodstream for foreign invaders. During prenatal development — within eight embryonic days in a mouse — microglia migrate to the brain, where they become its dedicated immune cells. Researchers assume that the brain needs microglia because the blood–brain barrier seals it off not only from toxins, pathogens and some drugs in the bloodstream, but also from the immune cells circulating there.
Microglia spring into action in most brain diseases, engulfing pathogens, dead cells and misfolded proteins. They also clear away synapses that have been damaged by injury. It is not a big intellectual leap, then, to suppose that microglia have similar roles in the healthy brain. One researcher thinks microglia cells are probably extremely important for synapse remodelling and plasticity in development.
The activity of microglia is imaged in the visual cortex of young mice. In rodents and in people, this region is known for its plasticity: the animal begins life with a large number of synapses, and then the ones that are not activated by light input from the eyes are gradually pruned away. The research study showed that microglia seem to interact with small synapses that disappear within a couple of days.
Microglia are active in another highly plastic region of the developing mouse brain — the hippocampus, which is important for learning and memory. Researchers examined young mice lacking the fractalkine receptor protein, which is expressed only by microglia and which binds fractalkine, a protein present on neurons. The mutant mice have an abundance of weak and immature synapses in the hippocampus. By the time the mutant mice are adults, the number of synapses normalizes, but some other synaptic problems remain.
The speculation is that a very close signalling is going on between neurons and microglia, back and forth, that coordinates which synapses they prune.
Researchers have showed that pruning in the area of the thalamus called the lateral geniculate nucleus, or LGN — depends on certain proteins in the complement cascade, part of the innate immune system that helps to clear out pathogens and unwanted cells. The researchers reported that complement proteins are expressed by immature neuronal cells and are more likely to show up around immature synapses than elsewhere during key periods of brain development. Mice that lack complement proteins show a mess of unrefined neural connections.
Research results suggested that the complement system was responsible for tagging weak synapses for pruning. But how could this tagging lead to synapse removal? An obvious hypothesis is that it works exactly the same way as the immune system. In the bloodstream, complement proteins tag harmful bacteria, signalling for macrophage cells to come along and eat them. Microglia are both the brain's resident macrophages and the only brain cells that express the complement receptor.
Researchers designed an assay for imaging the LGN using a previously developed mutant mouse whose microglia glow bright green under ultraviolet light. The researchers' colourful pictures, showing fragments of red and blue synapses in the microglia, suggested that the cells selectively engulf the weakest synapses.
It is unclear whether neuronal activity influences the complement-tagging process. Other immune-system players — the molecules of the major histocompatibility complex — are necessary for synaptic pruning, influenced by neuronal activity and likely to show up near complement proteins. There probably is a way to connect all of these observations.
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