The Brain’s Underdogs Have Their Day

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[Cartoon from the University of Washington “Neuroscience for Kids” page.]

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In neuroscience, the neurons hog all the attention. Most research is focused on the 100 billion neurons of the brain, the elongated cells that fire electric action potentials and release chemical transmitters to communicate with each other. But the neurons are a minority in the brain, outnumbered 10 to 50 times over by their neglected stepbrothers, the glia. Traditionally, scientists think of glia as the mere support staff to the more fashionable neurons, playing the role of repairmen (microglia), wallpaper installers (oligodendrocytes), or janitors (astrocytes). When scientists go looking for the source of human behavior or disease in the brain, they tend to overlook the glia and go straight for the neurons.

But at the 2011 Chicago Symposium on Translational Neuroscience, held on campus last Friday, it was the glia who had their chance in the spotlight. Subtitled “Glia in Neuronal Health and Disease,” the day-long event steered away from the “glamour cells of the nervous system,” as the program described neurons. Instead, the focus was on mounting evidence concerning how glia play critical roles in sleep, depression, brain development, Lou Gehrig’s disease, and other notable neurological disorders. In a conference dedicated to transferring scientific discovery from the laboratory to the clinic, the talks described several possible new glial targets for treating some of the most common brain disorders.

Appropriately, the morning began with a talk about adenosine, a neurotransmitter known best by its very popular blocker, caffeine. As the audience sipped from cups of adenosine antagonist (coffee), Philip Hayden of the Tufts University School of Medicine described how this small nucleoside, made from ATP released by glial astrocytes, can have a big impact on an organism’s wakefulness and health. Most of Hayden’s discoveries were made using a special genetically-modified mouse, where the astrocyte release machinery was disrupted to reduce adenosine levels in the brain.

In normal mice (and humans), the amount of adenosine in the brain builds up over the course of the day, increasing drowsiness. When someone pulls an all-nighter, the elevated adenosine levels are responsible for the miserable feeling of the next day and the extra-long “catch-up” sleep most people need to recover. But in the mice with disrupted adenosine, there were no effects of sleep deprivation on their subsequent sleep, a sign of reduced “sleep pressure.”

“This is an awesome party pill,” Hayden joked. “You can stay up late at night, and wake up on time the next morning. You’re not getting the homeostatic response to sleep deprivation.”

As often discussed here, sleep disorders are linked with a wide range of diseases, from diabetes to depression to hypertension. Hayden added another sleep co-morbidity to the list: epilepsy. In epileptic mice, interfering with adenosine release also decreased the number of seizures and the damage caused by them, suggesting that astrocytes might be a good target for anti-epileptic drug design and other neuroprotective effects.

“The way we think of the brain is NASCAR racing,” Hayden said. “Though the car and driver are important – they’re the neurons – in the difference between a car winning and coming second, how well the pit crew is changing the engine can really make a difference. We feel the astrocyte is tuning the system and helping to optimize performance.”

Before working as the brain’s pit crew, astrocytes play a critical role in the construction of that complex engine, said Cagla Eröglu of the Duke Institute for Brain Sciences. When neurons are grown in a lab dish, the addition of astrocytes, or the factors secreted by astrocytes, can dramatically increase the number of synapses those neurons form. Eröglu’s lab has joined the hunt for the identity of those factors and the mechanism they use to build the brain’s networks, finding new players with names like Hevin and SPARC and determining the receptor target for an older player, thrombospondin.

In the latter case, the receptor subunit found to interact with thrombospondin is already the accidental target of two drugs, Neurentin and Lyrica, used for treating chronic pain and epilepsy. The coincidental overlap suggests that excessive formation of synapses could actually be a bad thing, producing an over-sensitive pain system or an excitable brain prone to seizure. Learning more about the interaction of glia, their factors, and this receptor could help design new treatments for these conditions, as well as developmental disorders resulting from impaired synapse building.

But while glia can help build the brain, it can also help tear it down. Raymond Roos, the Marjorie and Robert E. Straus Professor of Neurology at the Medical Center, talked about the role of glia cells in neurodegenerative disease, with a focus on amyotrophic lateral sclerosis, or ALS. Described in 1881 by its discoverer, Jean-Martin Charcot, as a “relentless disease,” ALS is marked by a degeneration of motor neurons, which led researchers to look for what goes wrong in this particular cell type. But recent research on familial forms of ALS caused by an inheritable genetic mutation in a protein called SOD1 have expanded the hunt to various types of glia, Roos said.

In experiments, researchers selectively expressed the mutant SOD1 in various brain cell types, and found that its presence in astrocytes or microglia could also alter the course of disease, accelerating its progression. In a reverse experiment, where mutant SOD1 was expressed in motor neurons but normal SOD1 was expressed in surrounding glia, the disease appeared to have been averted.

“Some of these mice lived over 14 months, and had an overwhelming predominance of mutant SOD1 motor neurons,” Roos said. “Mutant SOD1-expressing motor neurons can survive for long periods when surrounded by cells that express wild-type SOD1, and wild-type SOD1-expressing motor neurons can show signs of degeneration if they are near or associated with cells expressing mutant SOD1…The neighborhood is important for these cells and non-neuronal cells play a very important role.”

The important role of glia, in disease or in health, was something neurologists “would not have anticipated in the old days,” Roos said. But in a case of better late than never, the attention of brain researchers is increasingly drifting back to the untapped potential of glia function. The saying that humans only use 10 percent of their brains might be an urban legend, but re-orienting neuroscience to look beyond the 10 percent of brain cells that typically hog the spotlight may open the door to new treatments and understanding.

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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