White Matter Matters More than Once Thought


by Brenda Patoine

June, 2007

Two research groups have turned the conventional wisdom about glial cells—that they do not form synapses with neurons—on its head, opening up new avenues of scientific exploration directed at glia. They have reported convincing evidence of synapses that directly link neurons with a type of glial cell in the corpus callosum, the white matter tracts that connect the brain’s hemispheres.

Their work is the latest chapter in a succession of unanticipated results that are challenging the long-held view of glia as the necessary but unremarkable supporting cast to the reigning star of the nervous system, the neuron. The new findings were reported in Nature Neuroscience in March by lead investigators Dwight Bergles of Johns Hopkins University, and Dirk Dietrich of the University Clinic Bonn in Germany.

“The two studies are beautifully done,” says Erik Ullian, who studies glial modulation of neuronal communication in development at University of California, San Francisco. “What is so surprising is that they’ve found these synaptic connections in the white-matter tracts.”

Bergles agrees: “The white matter has always been thought to be involved only in transmitting signals between different brain areas.” He likens the bundles of axons that make up white-matter tracts to “little highways through which you can conduct nerve signals, but there’s no off-ramp.”

“What we’ve shown is that those signals are actually communicating as they come down the axon. They’re carrying information and there are cells that are receiving that information,” Bergles says.

Stem Cell Reservoir?

Bergles worked with mice that had been genetically modified with a fluorescent protein to light up a specific group of glial cells in the white matter. The targeted cells, so-called NG2+ cells, are a type of adult stem cell called precursor cells. They have attracted considerable interest from scientists because of their apparent ability to morph into various types of brain cells, including neurons.

“These cells seem to have an intrinsic multipotent capability,” says Bergles. “That’s why there is tremendous excitement about them, because they might be the largest pool of stem cells within the brain.”

Under certain circumstances, NG2+ cells become oligodendrocytes, the glial cells that make the fatty sheath called myelin that envelops axons to speed the transmission of nerve signals.

The Johns Hopkins researchers recorded the activity of NG2+ cells in brain samples taken from the fluorescent-tagged mice. What they found stunned them: clear synaptic connections between the NG2+ cells and axons running through the corpus callosum.

“We were shocked to see that they were detecting the same type of signaling that was occurring in the gray matter,” Bergles says: rapid release of glutamate that was being picked up by receptors on the surface of the NG2+ cells. Glutamate is one of the brain’s most abundant neurotransmitters involved in neuron-to-neuron communications.

“This type of glutamate release was just not thought to occur within the white matter,” Bergles says. “This study, along with our previous work, suggests that this signaling is ubiquitous among this population of NG2+ cells.”

Questions and Clues

“Like any good study, this one raises many more questions than it answers,” says Ullian. It’s possible, he says, that the synaptic connections “may be required to keep NG2+ cells from proliferating out of control and producing too much myelin, or they may be providing some signal that keeps them in a predifferentiated state.”

 “There are a lot of potential implications,” Bergles adds. “But it’s not clear at all why this mechanism exists and what it’s being used for.”

In laboratory studies, he notes, glutamate has been shown to alter the proliferation of NG2+ cells, clearly influencing the speed at which they divide and their potential to differentiate into other cell types. But, he cautions, “We don’t know yet if glutamate is working that way in the intact brain.”

From a clinical standpoint, further research may provide clues to what goes wrong in demyelinating disorders such as multiple sclerosis, or in cerebral palsy, which is characterized by widespread damage to corpus callosum white matter. It could even help explain affective disorders such as depression and schizophrenia, which are thought to involve deficits in the connectivity and communication between specialized brain regions.

“There are several clues that tell us that after an injury, the brain tries to remyelinate,” says Vittorio Gallo, a glial cell researcher at Children’s National Medical Center in Washington, D.C., who wrote a commentary in Nature Neuroscience accompanying the papers. “It looks like the brain is trying to recapitulate something that happens early in development. If we can understand the developmental mechanism, we can devise strategies to repair the injured adult brain.”