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Thursday, February 22, 2001 Key Brain Cells Emerge From the Shadows Experiments indicate that glia, once thought to play merely a supportive role, are vital in properly forging the web of contacts between neurons. The finding opens a new line of research into head injuries and Alzheimer's. By ROSIE MESTEL, Times Medical Writer The brain is a miraculous organ, but for decades neuroscientists have written off 90% of its cells as--well, rather boring. Neurons, they knew, were the exciting cells of the brain--the ones sending electrical signals flitting here and there, helping to forge memories, move limbs, frame thoughts. But the cells making up the bulk of the brain were deemed just about as sexy as the sound of their name: glia. The jobs of glia, when even known, were important but humdrum: supporting and insulating neurons, nourishing them, soaking up chemicals that might harm them. But today glia are hot. New findings from a Stanford research team show that they're needed for properly forging and maintaining the intricate web of contacts between neurons. Such contacts, called synapses, allow neurons to communicate with each other and are crucial for brain function. Glia, in other words, aren't just supporting actors in the workings of the brain: They're central players. The discovery should help neuroscientists understand how synapses are made, strengthened or broken. (Brains forge a billion such synapses per microliter of tissue.) Number and size of the synapses dictate much of brain function, not least how memories are forged or forgotten. "Whatever it is that glia are doing will give us a clue to what regulates the number of synapses and how big they are," said Dr. Chuck Stevens, neuroscientist at the Salk Institute in La Jolla and an investigator with the Howard Hughes Medical Institute. The discovery also opens up a new line of inquiry into brain damage and diseases such as Alzheimer's. It's possible--though still unproved--that malfunctioning glia lie behind at least some of these maladies. "Any number of diseases could be glial diseases--but we just don't know it yet," Stevens said. Formerly Considered the Brain's 'Glue' The cells' very name comes from the Greek word for "glue"--because they used to be thought of as cells that just glued the brain together. Then, over the years, other roles for glia were unearthed. One major kind of glial cell wraps itself around nerve fibers and creates an insulation that allows electric signals to travel more quickly. In multiple sclerosis, this fatty sheath of cells gets destroyed. The other class of glial cell--called an astrocyte, because it's shaped like a tiny star--was thought, until two experiments suggested otherwise, only to feed, guide and protect neurons. In the first, published in Science three years ago, Ben Barres and co- workers at the Stanford University School of Medicine discovered that neurons in a test tube, without glia, send weak, wimpy signals to each other--10 times weaker than when glia are there in the test tube as well. "It was a very, very important paper," said Joshua Sanes, a neuroscientist at Washington University in St. Louis. In the second paper, published last month, Barres' group figured out the reason why. Neurons, on their own, make very few synapses--seven times fewer--and the ones that get made are small and immature. No synapses, no electrical signaling. "We were just in shock when we figured out what was going on," said Barres, associate professor of neurobiology at Stanford. "We were just not used to thinking about glia this way." Given all the fancy things neuroscientists know about the brain, it may seem odd that it took so long to figure out this fundamental fact. The explanation is simple: Separating neurons from glia was a technical nightmare, and, once separated, the neurons had an annoying habit of dying before people had time to perform experiments with them. "It's amazing. You'd work hours to purify these things, make a culture, go away, come back the next day and they'd all be dead," said Barres. Barres' lab has tackled both problems, gently sifting through tiny slices of rat brain to get neurons away from glia, then figuring out how to keep the neurons alive. To get 95% pure cultures of neurons, they first use an enzyme derived from papaya to lightly chew up the glue that sticks brain cells together. Next, they "pan" the mix of separated cells, much as a prospector pans for gold, in specially designed plates. The plates are coated with chemicals to which one type of cell--glia or neuron--sticks. Cells that don't stick stay in the liquid. By selecting stuck cells or floating cells, scientists can select neuron, or glia, as they choose. Barres' lab has also concocted a simple soup of chemicals that keep the neurons alive and kicking when the glia aren't around to nourish them any more. In the most recent experiment, postdoctoral researcher Erik Ullian and co-workers carefully panned their neurons and allowed them to grow and send out thousands of delicate fibers. They stained the cells so the synapses would glow brightly, viewed the cells under a microscope--and noted many fewer synapses than was normal. Only after they'd looked at the cells again and again, in a set of successive experiments, were they absolutely sure they were right. Now Barres' lab is working hard to find out just how glia promote synapse formation. What signals do they send to the neurons? What chemicals do they secrete? Researchers are also thinking about the role glia play in disease. Anything that causes glia to wither and die might cause synapses to wither and die too. Another prime possibility: When brains are injured, or when brains are damaged by conditions such as epilepsy, it's very common for too many glia to grow. These, in turn, could cause extra synapses to grow. And while synapses are important, making too many of them could be dangerous--since neurons, when over-excited, tend to die. Barres' discovery, in fact, creates a whole new avenue for neuroscientists to explore. "We should stop being neuron chauvinists," Barres said. "We should start realizing that everything our brain does is a dialogue between the neurons and the glia." * * * http://www.latimes.com/news/science/science/20010222/t000015850.html ******