By David N. Leff

Ninety percent of the adult human brain consists of glial cells. The other 10 percent are neurons - which do the heavy mental lifting for which the brain is famous. The glia have long been put down as mere scaffolding cells that support the neurons, keeping them well fed with nutrients and managing their waste disposal. In fact, the very word "glia" - Greek for "glue" - suggests their presumed second-rate standing inside your skull.

But now scientists at Stanford University have raised the lowly glia up to something closer to parity with the neurons they serve. Today's Science, dated Jan. 26, 2001, tells the story of their redemption in an article titled: "Control of synapse number by glia." Its senior author is neurobiologist Ben Barres; its lead author is his postdoctoral fellow, Erik Ullian.

"What we found," Barres told BioWorld Today, "is that glia are necessary for the formation of functional synapses between neurons. This came as a huge surprise to us because people have long been thinking that neurons possess all the machinery necessary to form a synapse, and these glia - these astrocytes - are just sitting there and playing presumably passive roles, like preventing neurotransmitters from spilling over from one synapse to another. Whereas, what we're showing is that you have to have the glia there for formation of a functional synapse - essential for our neural circuitry.

"Not only that," Barres added, "it further shows that once a synapse is formed, the glia are needed for its maintenance. And that implies the possibility that glia are also actively building and rebuilding the synapses that underlie learning and memory in the brain."

Synapses are infinitely narrow, nanometer-wide gaps or clefts across which neuronal axons route their electrochemical messages to the next neuron down the signaling line in the central nervous system - or to effector cells in the periphery, such as muscle receptors, which translate their message into action.

To demonstrate the novel notion that glia have a higher calling than just neuronal housekeeping, Ullian turned to the retinal ganglion cell (RGC) of rats. "Retinal ganglion cells," he told BioWorld Today, "are the only relay neurons in the retina of the eye. Unlike other neurons, they don't require glia for survival. RGCs project to an area in the brain's superior colliculus, where the target neurons are. There's an interesting developmental phenomenon that occurs," he noted, "where these RGCs project very early on to touching their target cells, but don't actually form synapses."

Rat's Retina Furnishes Glial Connection

"This means," Ullian explained, "that they're waiting around for some signal, and only then do they form all their synapses. And interestingly, the time that they're setting to form most of their mature synapses is the same time that glia are generated. In the animal's developmental process, it's one of the final steps in establishing the final circuitry for the visual system, which matures a week or so after birth. So what we did was look at both the synapses and the astrocytes - which hadn't been done before."

(In their paper, the co-authors use the terms "glia" and "astrocytes" interchangeably.)

"We purified RGCs," he said, "and cultured them in the presence of glia. We also purified their target neurons, and cultured them in the presence and absence of glia, and found the same binding either for synapses onto the normal target, or RGC-to-RGC synapses. Which meant that the glia produced the signal that expanded the number of synapses. They contributed at least a sevenfold increase in their number. I consider this to be a huge increase," Ullian said, "because it has profound effects on the activities of neurons. It's close to a tenfold increase, from a base of probably - by my count - on the order of five synapses per cell without glia to close to 50 with them.

"When we removed the glia," Ullian added, "neurons started to shed their synapses within a few days."

Having shown the vital role of astrocytes in synaptic management, the co-authors are now trying to drop the second shoe. "We really need to identify the factor - the protein - that these astrocytes are making," Ullian said. "They seem to have a profound regulatory effect on the number of synapses without affecting the health of the neuron. That's what we're trying to do - identify the factor.

"In addition," he added, "It's important that we make sure astrocytes are having the same effect in vivo as we found in vitro. This is difficult, because if we kill off all the astrocytes, we can't expect the animals to live. But there might be more subtle ways to do that, so I think these are the things we really need to undertake now. Once we have the factor," Ullian observed, "we'll be able to ask more sophisticated questions of rats or mice about what's happening."

From Putative Protein To Therapeutic Drugs

"I suppose in the best of all possible worlds," he mused, "we will have identified the protein factor, and then we'll be able to make knockout mice. Perhaps we won't delete the factor everywhere, but knock it out in very specific parts of the brain - for example, in the target area of the RGCs. Then we'll look, by various criteria, at the number of synapses that form, and see what the effect is.

"Once we identify what the factor is," Ullian said, "then we might be able to ask specifically what receptors this protein is interacting with, and maybe develop drugs that can block reactions between it and its target neuron - assuming that it does have a normal classical receptor."

Ben Barres picked up on this clinical aspect. "The potential," he observed, "is for learning and memory, plus very interesting implications for disease processes. Because any brain injury is associated with an enormous glial response - the glial cells multiply in a process called gliosis. That may induce a large increase in unwanted synapses, leading to overstimulation of neurons, which could mean either their death - as occurs in neurodegenerative diseases, such as Alzheimer's or Lou Gehrig's, or to unwanted electrical activity, as for example happens in epilepsy."