Gleeful Brain’s Glia
When I was at Caltech (1968-1973), the Nobel laureate neurophysiologists I spoke with, such as Roger Sperry, told me “there are roughly ten billion, 10 to the power of 10, brain cells in your head.” Back then, neurons were thought to be doing memory, thought, and consciousness alone. Glia (Greek for “glue”) were demoted to a supporting role regulating a neuron’s environment, helping it to grow, and being the physical scaffolding. When I studied Brain Science in graduate school, the experts told me “there are roughly ten billion brain cells in your head, of which a hundred billion, 10 to the power of 11, are glial cells.” Ever since then, I’ve wondered: “Glial cells? WTF?”
Roger Wolcott Sperry (20 August 1913-17 April 1994) was one of the neurobiologists and neuropsychologists who most influenced my cognitive science research. Roger was the Nobel laureate who, together with David Hunter Hubel and Torsten Nils Wiesel, won the 1981 Nobel Prize in Medicine for his work with split-brain research. Another thing he said, which experiments suggest is right, was: “The cells and fibers of the brain must carry some kind of individual identification tags, presumably cytochemical in nature, by which they are distinguished one from another almost, in many regions, to the level of the single neurons.”
Kerri Smith, in a recent issue of Nature, reviewed partial answers to the question: “Do the billions of non-neuronal cells in the brain send messages of their own?” She summarizes these things that experts today think that they know about your brain.
¥ The human brain is made of approximately an equal numbers of glia and neurons, 85 billion of each.
¥ Some glia, called astrocytes, have thousands of bushy tendrils snuggling close to the synapses, those active junctions between neurons.
¥ Any given astrocyte can make as many as 30,000 connections with cells around it.
¥ Andrea Volterra says that, if glia are involved in signaling, then processing in the brain turns out to be an order of magnitude more complex than previously expected. Andrea examines astrocytes at the University of Lausanne in Switzerland.
¥ According to Andrea, neuroscientists, who have long focused on the neuron, would have to rethink everything.
¥ Our knowledge about astrocytes is so sketchy that people tend to generalize findings in different circuits or different brain areas, says Volterra.
¥ In the past year or so, several papers have highlighted the urgency of this rethinking.
¥ Chemical transmitters released by neurons cause an uptick in the level of calcium inside astrocytes, which spurs them to release transmitters of their own.
¥ These in turn can amplify or suppress signaling between neurons.
¥ Transmitter molecules released from astrocytes can influence the strength of their connections over time.
¥ Astrocytes activated at one synapse might communicate with other synapses and astrocytes with which they make contact.
¥ The consequences of this “gliotransmission” could be profound.
¥ Because of the enormous neural complexity that gliotransmission would indicate, some people don’t want astrocytes to be involved at all, according to glial neuroscientist Phil Haydon, at Tufts University in Boston.
¥ Neuroscientist David Attwell, at University College London, explains that emotions in the community are intense. If someone tells you that everything you’ve done is wrong, it feels as if you’ve wasted your life.
¥ Dmitri Rusakov at University College London and Stphane Oliet at the University of Bordeaux in France support the gliotransmission hypothesis.
¥ They wrote that the chemical D-serine, released from astrocytes, activates the NMDAR, or N-methyl-D-aspartate receptor on the surface of neurons, influencing their behavior. Communication through NMDARs is presumed important in learning and memory, since it can help to enhance signals between synapses, thus helping memories to form.
¥ Two months ago, Justin Lee at the Korea Institute of Science and Technology in Seoul, published evidence that astrocytes in the human cerebellum release the neurotransmitter GABA (gamma-aminobutyric acid).
¥ Unlike the work of other labs, suggesting that that astrocytes release chemicals packaged within tiny bubbles called vesicles, Lee’s experiments indicate that the cells are transmitting the chemicals directly through an ion channel in their membranes.
¥ When Justin Lee’s researchers blocked the channel, called Bestrophin-1, GABA levels dropped, implying that glia release GABA through this outlet.
¥ McCarthy’s group, including postdoc Cendra Agulhon, studied two mouse lines: one in which calcium signaling in astrocytes had been given a boost, and another in which it had been completely obliterated.
¥ In a March 2010 paper in Science, these researchers concluded that astrocytes couldn’t possibly be releasing chemicals to signal to neurons.
¥ McCarthy would love to see gliotransmission, he says. Yet the evidence both for and against it still needs to be verified.
¥ Glial biologist Richard Robitaille, at the University of Montreal in Canada, says that measuring the effect of astrocytes will require more subtle experimental approaches.
¥ Maiken Nedergaard, a glial biologist at the University of Rochester in New York, suggests that maybe these arguments are culturally induced. Neuroscientists have been trained in “neurocentric” labs, so everyone thought that astrocytes work like neurons.
¥ But astrocytes seem to function very differently.
¥ Astrocytes use a different “language.”
¥ Astrocytes employ a different way of getting input and output than neurons.
¥ Astrocytes might work on a totally different timescale from neurons, hints Rusakov. One thousand times slower.
¥ Standard techniques for measuring neuronal responses won’t work on astrocytes.
¥ Techniques of imaging calcium in cells are poor at measuring slow fluctuations or increases in the outer reaches of astrocytes, in part because calcium dyes simply don’t penetrate there.
R. Douglas Fields, in a Scientific American blog entry, calls this new frontier of neuroscience “The Other Brain,” because scientists are only now, after a century of neuron research, starting to explore it. New findings revolutionize fundamental concepts of information processing in the brain. This might lead to new treatments for diseases ranging from Alzheimer’s disease to brain cancer to spinal cord injury or even chronic pain. The data overturns a century-old paradigm about how the brain works.
Bottom line: many scientists are gleeful about glia. Others are acting as if an atom bomb is going off in their brain cells. Not only neuroscientists are waiting to see what happens next. Anyone with a brain should care. Of course, that’s what my astroglial network told me say.
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