February 4, 2009

Neurons Little Helpers

Neuroscientist Philip Haydon and his team are finding that brain cells long thought to be bit players have key roles in brain functions—and malfunctions

By Jacqueline Mitchell

Metaphors come easily to Phil Haydon. All the brain’s a stage, and its neurons merely players, he says. But it’s the astrocytes—an abundant, but little understood type of brain cell—that Haydon suggests serve as stagehands, without which the play could not go on.

In addition to memory and learning, Philip Haydon’s research has implications for epilepsy, Alzheimer’s disease, substance abuse and even sleep. Photo: John Soares

As the Annetta and Gustav Grisard Professor and chair of the department of neuroscience at the School of Medicine, Haydon is working to get these backstage cells the recognition they deserve and, in the process, to decode the language of the brain.

Ever since the Italian physicist Luigi Galvani discovered in 1771 that a spark will make a dead frog’s leg twitch, neuroscience has focused on the electrically excitable neuron as the brain cell that deserves top billing. But that narrow attention on the neuron is really an artifact of technical limitations, Haydon says. “We always look under the light,” he says, not off to the darker sides where the less-obvious effects linger.

With an arsenal of high-tech tools, Haydon’s team is now illuminating the electrically inactive brain cells that were largely overlooked by 20th-century neuroscience.

The central nervous system, which includes the brain and the spinal cord, contains two types of cells. The first are neurons, which propagate electrical impulses via electrochemical communication—a stimulated neuron dumps a chemical cocktail of neurotransmitters into the space, called a synapse, between itself and its neighboring neurons. Those chemicals, in turn, provoke an electrical response from the surrounding cells. These actions and reactions happen extremely quickly; it’s how your brain can whisk your hand off a hot stove before you’ve even consciously registered the heat.

Outnumbering neurons ten to one in the human brain, glial cells support and protect the neurons. For decades, researchers thought that’s all these cells—named for the Greek word for “glue”—did.

Suddenly Hearing Both Sides of the Conversation

But a surprising finding in Haydon’s lab, reported in Nature in 1994, began to change that conventional wisdom. Haydon—then at Iowa State University—and his colleagues killed off the neurons in a sample of living brain tissue, expecting to block the release of chemical transmitters.

However, the team was surprised to find some of the chemical transmitters had been released anyway. “It must have been glial,” says Haydon. “So we took a total risk and changed the direction of the lab.” The discovery was the first evidence that glia play a previously unknown role as modulators of synaptic activity. It was as though scientists who had been listening to one end of a telephone call suddenly were able to hear both sides of the conversation.

“Haydon’s group really opened up a whole new line of research,” says Harald Sontheimer, professor of neurobiology at University of Alabama, Birmingham, and director of the Center for Glial Biology in Medicine. “People talked about the possibility that glial cells played a role, but Haydon has brought unprecedented credibility to the field.”

A native of England, Haydon joined the faculty at Iowa State University as an assistant professor in 1986. In 2001, he moved to the University of Pennsylvania in Philadelphia, where he held the position of professor and vice chair of the neuroscience department. He came to Tufts last summer because “it was clear the administration was very serious about building a great neuroscience department that will be recognized for excellence,” he says.

Tufts’ neuroscience department can distinguish itself from its competitors by narrowing its research focus to synapses, brain disorders and neuro-glial interactions, says Haydon, who also plans to deepen collaboration with the departments of psychiatry, neurosurgery and neurology at Tufts Medical Center. “The spirit of cooperation here [at Tufts] is second to none,” he says. “And that is our opportunity and our challenge, to be competitive and driven, while protecting that collegiality.”

The Neurological Pit Crew

Since that serendipitous lab result in the early 1990s, Haydon’s lab has used modern computing, powerful imaging tools and microscopy, and even genetic manipulation, to study these long-unheralded cells. He now focuses on one type of glial cell, called astrocytes, star-shaped cells that are often in close proximity to neuronal synapses.

The team, which includes Stephen J. Moss, a professor of neuroscience who came to Tufts with Haydon from the University of Pennsylvania, can stimulate an astrocyte and ask, “Does its neighbor listen? And if it does, does it talk back?” Their work, and now that of other labs around the world, shows that astrocytes do converse with their neighbors, modulating the strength of signals relayed among neurons by releasing and/or taking up many of the same chemicals that neurons use to communicate with each other.

“The question now is, what does it mean?” says Haydon.

In answer, Haydon offers up another metaphor. Think of your brain as a Formula One race car. It’s a complex machine, and an efficient pit crew—the astrocytes—maintains and enhances its performance. By tinkering with the astrocytes’ genes, causing mutations that Haydon likes to think of as his wrenches, researchers are learning what happens when astrocytes don’t do their job in the brain.

Using imaging technology only available in the last five years or so, Haydon’s group has shown that mice engineered with defective astrocytes have trouble with memory and learning. It’s no surprise to Haydon that astrocytes should play a vital role in higher cognitive functions like these. Humans’ 10:1 ratio of glia to neurons is by far the highest in the animal kingdom. (Contrast that to the nematode worms’ 1:5.)

In addition to memory and learning, Haydon also implicates astrocytes in epilepsy, Alzheimer’s disease, substance abuse and even sleep. The team published a research paper in the journal Neuron in late January that identifies an astrocyte mechanism that controls sleep functions. Their findings could lead to the development of drugs to treat sleep disorders, though that will require more years of research and testing. Similarly, Haydon’s work may have relevance for stroke patients. Because glial cells normally protect and repair neurons, Haydon is attempting to “hijack” those abilities to arrest the damage caused by stroke.

“His team’s recent studies are absolutely stunning,” says Sontheimer. “His findings that glial cells are involved in the wake/sleep cycle were totally unexpected. They’ve made great strides with epilepsy. They’ve elevated an entire field of study.”

In all these disorders, Haydon says, astrocytes appear to be damaged, but whether that damage is the cause or the result of the disorder is still unknown. “We are just beginning to identify the pit crew and how it normally operates. Now we can look at which disorders are the fault of the pit crew,” he says.

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.

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