For centuries, neuroscientists have pondered what role glial cells may play in behavior and cognition. Now, with advances in imaging and other techniques, they have started to closely investigate glial function. Two new studies suggest that astrocytes, a star-shaped type of glial cell, may directly participate with synapses to aid long-term potentiation (LTP) and long-term depression (LDP), processes linked to learning and memory.

Tracing glial function

Glial cells outnumber neurons nearly 10 to 1 in the brain, but they have been far more difficult to study. Though researchers have identified different types of glial cells, such as oligodendrocytes, microglia and astrocytes, defining their function was difficult because of their innate properties.

“Neurons work on electrical signals, but astrocytes are not electrically excitable,” says Philip Haydon, a neuroscientist at Tufts University. “It was not until the 1990s that we developed sophisticated imaging and other techniques that could reveal biochemical excitability to help us visualize the dynamic processes in astrocytes.”

Early hypotheses about glial cells were based on their form and structure. “Scientists got their main ideas from the structural elements of the cells,” says Dwight Bergles, a researcher at Johns Hopkins University. “We saw that the glia insulated the neurons and synapses in the brain and provided an interface with the vasculature, so it made sense to assume that glia played a role in delivering nutrients from the bloodstream to the neurons.”

Studies in the past decade were able to demonstrate just that. But work in the past two years has shown that astrocytes do much more than aid in metabolism. Bergles’ and Haydon’s labs, among others, have shown that in a variety of circumstances, glia interact with synaptic connections between neurons.

“When neurons release neurotransmitters, the astrocytes can remove them to help modulate a signal,” says Haydon. “But the more recent insight is that those neurotransmitters can also work on astrocyte receptors to stimulate the release of chemicals from the astrocyte itself.”

Modulating memory?

Astrocytes appear to be “mopping up” and then recycling brain-derived neurotrophic factor (BDNF), suggest Marco Canossa, a neurobiologist at the Italian Institute of Technology of Genoa, and colleagues in a multidisciplinary study in the Oct. 20 issue of the Journal of Cell Biology. This, they say, promotes LTP and LDP—processes that enhance and hinder synaptic transmission, respectively.

Whether LTP or LDP is instigated depends on the form of the BDNF. Pro-BDNF, a precursor form of the protein released by neurons, is believed to promote LDP. A more mature version of the protein, called simply BDNF, is linked to LTP. But researchers were unsure how the protein matured. Some scientists have hypothesized that neurons released pro-BDNF and that was somehow altered in the “synaptic space”—the gap between neuronal connections. Canossa and colleagues wondered if astrocytes, known to clean up some neurotransmitter and neuromodulator proteins, might be involved.

Using immunochemistry, electrophysiology, in vitro cell cultures and advanced microscopy techniques, Canossa’s group examined the spaces between synapses from different perspectives. “We concentrated on the cell membranes,” Canossa says. “And by investigating at this one place, we were able to examine how BDNF and the astrocyte receptors interacted in all these different ways.”

When the group applied an electrophysiological method that mimicked LTP to cells in vitro, they found that neurons secreted both pro-BDNF and mature BDNF. The pro-BDNF did not ripen in the synaptic space, but rather was taken up by the astrocytes. By removing this form of the growth factor, the astrocytes helped promote LTP.

But the group also found something surprising: After the astrocytes took up the pro-BDNF, they recycled it within the cell and then released some of it back into the synaptic cell, prompting LDP. This multitude of interactions suggests that astrocytes play a significant role in regulating synaptic plasticity.

“This makes the role of astrocytes far more important than previously thought,” Canossa says. “They are releasing this neuromodulator back into the synapse, and it changes what happens there. It sheds new light on the complexity of neural-glial interaction”—so much so that Canossa thinks some of these synaptic proteins one day will be reclassified as glial transmitters, to complement the better understood neurotransmitters.

A research renaissance

Canossa and colleagues plan to study whether astrocytes play a similar trafficking role in living animals when they are learning.

“It’s a good question,” he says. “After animals are trained for a specific paradigm like trying to find the platform in a water tank, will we see the same neurotrophin trafficking?”

Haydon’s lab also plans to take a closer look at how astrocytes regulate learning and memory as well as how the proteins expressed by the cells may play a role in certain medical conditions. “In epilepsy, we see dramatic changes to the properties of astrocytes,” he says. “Is that merely a reaction to an abnormal brain or is something else happening?”

In any case, most researchers are enthused that tools are finally available to give glia the attention they deserve. “It’s a very exciting time,” Haydon says. “Those of us who study glia can really start to speculate and finally try to add our pieces to the puzzle of the human brain.”