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Spring 2009, Issue 10

Understanding Astrocytes

Philip HaydonPhilip G. Haydon joined the Department of Neuroscience as a professor and chair in 2008. He studies astrocytes, those glial cells found throughout the central nervous system that were once thought to be merely structural (glia is Greek for glue) but are now thought to participate actively in neural transmission. Haydon is excited about obtaining a deeper understanding of astrocytes, for basic neuroscience as well as potential therapeutics.

Haydon earned his PhD in physiology from the University of Leeds, England, and pursued postdoctoral training in biology at the University of Iowa. As a faculty member at Iowa State University, he was director of the Signal Transduction Training Group and the Laboratory of Cellular Signaling, and he was associate director of the Microanalytical Instrumentation Center. While a member of the Department of Neuroscience at the University of Pennsylvania, Haydon directed the Center for Dynamic Imaging of Nervous System Function and the Silvio O. Conte Center for Studies of the Tripartite Synapse.

The Haydon group is studying neuronal circuits and their role in controlling behavior. They are looking at the mechanisms by which astrocytes regulate synaptic transmission and the role of astrocytes in disorders of the nervous system such as epilepsy and amyloid plaque development, which they study in mouse models of Alzheimer’s disease. The experimental techniques used by the group include molecular genetic manipulations, in vivo and slice electrophysiology, two-photon microscopy, and behavioral studies.

Haydon’s interest in astrocytes began in 1992 with an experiment that seemed to go terribly wrong. The neurotransmitter glutamate appeared in culture dishes that were meant to be the negative controls, that is, devoid of neurons. But these negative control dishes did contain glial cells, which led to the realization that glial cells release glutamate. Another serendipitous event occurred in 2005 with an experiment that did not go as expected. “We introduced a gene [into astrocytes] to perturb a pathway,” says Haydon. “We expected something different. Again, the control raised its ugly head and said your hypothesis is incorrect. And so now we follow the path that the experiment provided.” That path was a new link between astrocytes, adenosine, and sleep.

Astrocytes appear to control sleep pressure—the need to sleep that increases with wakefulness—through their control of the neurotransmitter adenosine in the brain. “The levels of adenosine rise during the day when you’re staying awake, increasing the sleep pressure,” says Haydon. “Then, as you sleep, you discharge the sleep pressure and the levels fall.” Astrocytes release adenosine during wakefulness, increasing sleep pressure. If you block the release of adenosine from astrocytes, not only is sleep pressure dramatically reduced, but memory impairment associated with sleep deprivation is also dramatically reduced. Because adenosine is a signal used by every cell in the body, any potential sleep therapy would have to target astrocytes specifically, perhaps through novel receptors on astrocytes. “There’s a potential to develop drugs that control [astrocyte-released] adenosine, either increasing or decreasing it to impact sleep or the memory process,” says Haydon. “So that’s one avenue that we’re following.”

Although neurons are the main actors in neural transmission, astrocytes appear to fine-tune transmission. Recent studies have revealed their involvement in the cellular form of learning and memory. “One of the foundations of learning and memory is change in synapses, which are the sites of communication between neurons,” explains Haydon. Since changes in synapses are necessary for cellular memory, and astrocytes facilitate this process, changes in astrocytes may lead to changes in cellular memory. When Haydon’s research group introduced into mouse astrocytes a gene that impairs calcium signaling, which is known to be involved in neurotransmitter release by astrocytes, they discovered that the cellular form of learning and memory was impaired. The group is actively pursuing this early-stage research.

The Haydon group also looks at astrocyte involvement in epilepsy. “One of the long-term consequences of traumatic injury to the brain is that it can lead to a delayed development of epilepsy,” says Haydon. “So we’re very interested in understanding the changes in the brain during this latent period following an injury, before a person or an animal becomes epileptic. Our hypothesis is that there are early changes in glial cells [astrocytes] which inadvertently instruct neurons to change permanently, and it’s the permanent change in the neurons that then leads to the epileptic brain.” Adenosine is a natural focus for this early-stage research because it is considered a natural anticonvulsant. Using techniques similar to those used in studies of how adenosine impacts sleep, Haydon’s research group is investigating how changes in astrocyte-released adenosine affect epilepsy. Asks Haydon, “Is it possible that we could increase the adenosine from the glial cell and reduce seizure susceptibility?”

Two-photon microscopy is a technique integral to Haydon’s research. This technology lets you see individual cells and synapses in vivo and allows you to revisit the same location to witness changes over time. Haydon is excited about applying this technology in new investigations into Alzheimer’s disease. Using mouse models of Alzheimer's, researchers will be able to watch changes in synapse structure and amyloid plaque development, with the potential to study the effects of possible therapeutics.

“I'm really interested in talking with people who have more knowledge of translational neuroscience,” says Haydon. He welcomes interested parties to contact him at philip.haydon@tufts.edu.

For more information, please go to http://www.neurosci.tufts.edu/faculty_labs/haydon/haydon.html.

 

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