Gray Matters

Find your audience. Make a connection. Communicate the message. Like a performer or politician, a nerve cell knows how to make an impression. But is someone pulling the strings behind the scenes?

Evidence is mounting that in controlling the nervous system, the nerve cell, or neuron, may be comparable to the flashy front man. Researchers are learning that a host of other nervous system cells, called glia, have more control than anyone suspected. Neurons, it turns out, would be lost without these costars, which come in a variety of cell types and make up 90 percent of the brain’s cells.

In the 1960s, neuroscientists established that glia nurture and defend neurons, but now scientists are finding that glia also rein in neurons’ impulses, issue them orders, and shape their future moves.

“The exciting thing is that there are more and more ways in which neurons and glial cells are shown to interact,” says Eric A. Newman of the University of Minnesota in Minneapolis.

Investigating glia

Investigation of glia has lagged behind the study of neurons. In the 1800s, a debate simmered about whether the soggy brain tissue in which neurons sat contained other cells. Around 1860, a German neuroanatomist named Otto Friedrich Carl Dieters first discerned that the amorphous gray matter of the brain contained tightly packed cells distinct from the neurons.

Then, Italian cell biologist Camillo Golgi made a major find by misplacing a bit of a brain he was studying in his lab, so the story goes. He unknowingly had dropped the piece into a bath of silver nitrate. By the time he fished it out days later, the chemical had stained the sample’s surface in a spidery pattern of black. The lines were the branching arms of cells, revealed for the first time in their entirety as individual types of neurons and glia with distinctly different structures.

Once recognized, glia were immediately relegated to second-class status in the brain. “It was the neurons that everyone focused on, and the [glia] were left as bit players,” says Ira B. Black, a neuroscientist at the Robert Wood Johnson Medical School in New Jersey.

Although some of the earliest researchers of the brain had inklings of a greater role for glia, most neuroscientists thought of them as the scaffolding on which neurons are draped. One even referred to the star-shaped glia called astrocytes as packing material.

Glia eventually were recognized to be a diverse group of cells with specialized tasks. Oligocytes in the brain and Schwann cells in other parts of the body insulate the nerves, thereby speeding electrical transmission along them. Microglia, the neurons’ bodyguards, engulf and dispose of threatening viruses and bacteria that find their way into the brain.

Astrocytes are the most numerous glia in the brain and have received much of the recent attention. They bloom like delicately branching sea anemones, extending tendrils in all directions toward synapses, the knobby communication connections between neurons. Without astrocytes, researchers find, neurons couldn’t nourish themselves, grow, or transmit signals effectively.

Researchers at Harvard Medical School in Boston, led by Stephen W. Kuffler, in the early 1960s finally confirmed an idea postulated by Golgi—that astrocytes feed neurons. The supporting cells, the scientists discovered, pull glucose from the bloodstream, convert the sugar into lactate, and dole it out to neurons. The researchers also found that using the same connection to the bloodstream, astrocytes protect the brain from toxic agents. The cells press flattened ends of their arms against the surface of capillaries. The oily, waterproof sheathing they form blocks many water-soluble agents from entering the brain and damaging cells.

As brain research focused on chemical processes in the early 1990s, neuroscientists began to recognize more-complex tasks being carried out by astrocytes. The cells’ role is more than nursemaid or protector. Several studies have shown that astrocytes might be engaged in chemical conversations with each other and the neurons. Experiments also showed that these glia influence neurons’ exchange of signals across a synapse.

Recent studies have found that strong ties bind astrocytes to their nerve-cell companions. Through their tendril-like arms, these glia also alter the number of neural synapses and their signaling strength. Astrocytes may even be architects of memory and learning, coaxing neurons to strengthen their connections along well-worn mental pathways. According to an emerging hypothesis about the relationship between nerve synapses and their associated astrocytes, these glia may contribute as much to nerve communication as the neurons do.

Synapse formation

This year scientists added to evidence that this tight relationship between astrocytes and nerve synapses influences synapse formation. When members of Ben A. Barres’ lab at Stanford University School of Medicine grew neurons in astrocyte-free cultures, they found that signals across the synapses of the neurons were sluggish and often failed. With astrocytes, however, the number of signals the neurons sent increased 70-fold. They hypothesized a simple relationship: that astrocytes increase the number of signals—the strength of a neural message—passed between individual synapses.

Investigating further, however, a team led by Erik Ullian in Barres’ lab made a surprising finding. The message strength at any one synapse doesn’t increase when astrocytes are added to neurons in culture, but the number of synapses carrying the message does.

Ullian explains that astrocytes instruct lab-grown nerve cells to sprout numerous synapses. He and his coworkers found that neurons growing with these glia form up to seven times as many synapses as neurons without glia do. “A lot of people were very skeptical when I first started finding these results,” says Ullian. Before this research, remembers Barres, “everyone thought that neurons were the only ones dictating how neurons would form.”

Neural communication

This influence of glia essentially adds more voices and ears to the neural communication system. Ullian suspects this influence shows up in the developing brain as vision is refined, when the first visual signals start coming in from the eyes, for example. This process of strengthening synapses along pathways that have frequent traffic, as when a person practices a skill, might also be a component of learning and memory, he says.

Ullian was able to do his experiments because other scientists had already learned how to grow lab cultures of brain neurons free of other cells. For many years, researchers had had little success growing neurons without glia. It turned out that neurons need certain molecules called trophic factors, such as brain-derived neurotrophic factor (BDNF).

Astrocytes are “little trophic-factor factories,” Black says. The glia secrete the molecules constantly and thereby can extend the life of neurons. Recent experiments show that BDNF increases in astrocytes in the spinal cord after injury, so it may provide a route to repair after nerve damage, Black speculates.

In experiments over the past few years, Black and his colleagues have also found that BDNF from astrocytes ups the firing rate and efficiency of neurons in the hippocampus, a brain area critical to learning and memory. BDNF strengthens the connections between neurons in minutes, he says.

While trophic factors enabled nerve cells from outside the brain and spinal cord to grow on their own in the lab, neurons from the brain and spinal cord—the central nervous system—would still quickly shrivel and die without glia. In the early 1990s, Barres found that neurons of the central nervous system have a second requirement for independent growth: They also need to be electrically active. This was a watershed for neuroscience research. Barres developed a protocol that included a cocktail of trophic factors and a jolt of electrical activity. “Put the two together and—vavoom!—you get [the neurons] surviving,” he says.

This finding might help scientists resolve a frustrating paradox. Brain neurons’ need for electrical stimulation might explain why nerves in the body can regenerate after nerve damage but those in the brain and spinal cord can’t, says Barres. If an injury, such as a broken bone, crushes a nerve in a person’s arm and paralyzes it, the feeling will eventually come back. Nerves outside the brain and spinal cord regrow at the rate of about 1 millimeter a day and mend the damage. But a person paralyzed from a crushed spine can’t currently expect such regeneration. It may be that damaged brain and spinal neurons have trophic factors but are no longer electrically active, says Barres.

Talking back

The view of astrocytes as silent, supporting cells changed considerably in 1994, when physician Maiken Nedergaard of New York Medical College in Valhalla found that astrocytes could talk back to the neurons and thus influence them. She found that the astrocytes can react to signals between neurons with a slow-paced internal surge of calcium. This in turn elicits a surge of calcium within adjacent neurons. Nedergaard suspected that this reaction influences a neuron’s future signaling.

The calcium signal can move from one astrocyte to another through channels that directly connect the interiors of the cells. In recent experiments, Newman and his colleagues observed that a wave of increased calcium concentration propagates through an entire network of astrocytes, seemingly spreading some message. “Astrocytes are a part of the circuit that is responsible for neural processing,” says Newman. ” [These] glial cells participate in a second-to-second neural communication—the ongoing electrical transmission in neurons.”

Soon after Nedergaard’s first calcium-signaling observations, Alfonso Araque and Philip G. Haydon’s group at Iowa State University in Ames discovered that astrocytes can also talk back to neurons, via bursts of glutamate. The astrocytes react when neurons release glutamate, one of their important signaling chemicals, into a synapse. “Initially, we were quite quiet about this because this was going against the dogma,” says Haydon. “[Astrocytes] were very much considered second-class citizens.”

Interestingly, too much glutamate can be toxic to the neurons. Glutamate poisoning underlies some of the brain damage in stroke, for example. One more glia role turns out to be mopping up excess glutamate. This cleanup prepares the synapse for the next nerve signal and protects neurons from toxic effects.

Long-distance signaling

Scientists remain puzzled about why such slow communication goes on among astrocytes while nerves can send the same message much faster. Maybe the astrocyte activity stores memories over a longer period, Nedergaard suggests.

The fast, long-distance signaling of neurotransmission that blazes a trail rapidly might not build a very sturdy mental pathway. In contrast, the slow system of astrocyte communication might maintain a localized route for a memory longer.

“It is possible that calcium signaling initiated by neurons is transmitted from astrocyte to astrocyte in various spatial patterns to store memory information,” says Nedergaard. “Most of us working in the field have the goal of placing astrocytes in the learning and memory process.”

However, questions remain about whether the documented activities of the cells occur in the living human brain. By necessity, studies of live astrocytes are carried out on cultured cells in the laboratory rather than in living tissue.

Araque, Haydon, and their colleagues proposed in 1999 that astrocytes are an unacknowledged third synaptic partner. The team’s vision of a “tripartite synapse” breaks with the classical “neurocentric” view of synapse function, says Barres.

Nevertheless, he supports the idea that glia play many roles. “It’s very hard to find anything the neurons are doing by themselves. Everyone is dependent on everyone else,” he says.