Summary of Workshop on Astrocyte Function in Health and Disease

Table of Contents (click to jump to sections)

I. Introduction
II. Background
III. Discussion
IV. Recommendations/Conclusions
Participant List

Summary of Workshop on Astrocyte Function in Health and Disease

September 23-25, 2002
Doubletree Hotel, Rockville MD

I. Introduction

This workshop brought together leaders in various aspects of astrocyte biology to discuss current research findings, assess the state of knowledge regarding astrocyte function in the healthy and injured/diseased states, and set a research agenda for the study of astrocyte biology.

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II. Background

Astrocytes are the most abundant cell in the central nervous system and yet, despite current research, our knowledge is surprisingly limited. Over the past decade, research findings have revealed that astrocytes exhibit a wide variety of biological activities. How these activities integrate into complex nervous system functioning, how astrocytes respond to insult or injury in the CNS, and whether these responses promote or inhibit repair in the nervous system is poorly understood. Improved understanding of the function and dysfunction of astrocytes is germane, in fact probably essential, to our understanding of the normal and diseased central nervous system.

III. Discussion

Session A: Defining the Astrocyte and its Diversity

For the past 20 years protein expression has been used to define astrocytes, however, this is a plastic phenomenon; ultimately astrocytes must be defined on the basis of function. A conceptual definition of astrocytes is that they form a structural and functional interface between non-nervous tissues and neurons, where they monitor the integrity of nervous tissue by a complex set of receptors and channels. One future goal is to define the differences between adult oligodendrocyte precursor cells and astrocytes in the mature brain. Another area of controversy is the question of astrocyte heterogeneity. The challenge is to come up with functional subtypes of astrocytes that relate to lineages and development, however, observations on lineages from in vitro studies may not translate to in vivo situations.

Session B: Territories Versus an Integrated Syncytium

The current view is that astrocytes distribute evenly throughout gray matter; cell bodies are separate but cell processes overlap. New advances in light and 3-D microscopic technologies reveal that astrocytes exhibit territorial boundaries and do not overlap. Furthermore, astrocytes have a "bushy" morphology. Most of the astrocytic membrane is found in extensions that ensheathe clusters of dendritic synapses. These membranous extensions, termed microdomains, may form functional units. They contain mitochondria and may be coupled via gap junctions. Important questions regarding the structural organization of astrocytes remain. What regulates and modulates astrocytic microdomains? Do microdomains extend to other astrocytes?

Other important topics include: (1) What is the relationship between brain edema and aquaporins, water selective channels expressed by astrocytes in the vicinity of vessels? (2) Do reactive astrocytes differ physiologically from their counterparts in normal brain? (3) Do reactive astrocytes arise from endogenous astrocytes or from adult progenitor cells?

Session C: Glutamate and Astrocytes

In vitro studies provide evidence that astrocytes can take up glutamate at synapses and release glutamate in a calcium-dependent manner. Studies on mechanisms of glutamate uptake reveal that astrocytes in gray matter do not appear to express ionotropic glutamate receptors however there is evidence that they express glutamate transporters and/or metabotropic glutamate receptors. The transporter GLT-1A is predominantly expressed by astrocytes, while Bergmann Glia predominantly express the transporter, GLAST. Glutamate transporters are electrogenic; when many transporters cycle in unison they create a current that can be measured. Functionally there may be interplay between astrocytic metabotropic glutamate receptors and glutamate transporters in the perisynaptic space. Future research should be aimed at determining in greater detail the properties of glutamate transporters and their regulation in situ.

There is mounting evidence that astrocytes release glutamate via calcium-dependent mechanisms. A variety of mechanisms mediating glutamate release from astrocytes have been proposed. Understanding astrocytic glutamate release under normal physiological conditions versus under pathological conditions remains a priority. Remaining questions include: (1) understanding the functional role of astrocytes in synaptic transmission; (2) understanding the relationship between glial glutamate receptors and glutamate transporters;(3) determining if there is a correlation between types of glutamate receptors and astrocytic subtypes; and (4) understanding the role of astrocytes in synaptic plasticity (5) Understanding astrocytic release of glutamate under normal and pathological conditions.

During lactation, interactions between structural elements of neurons and glia dynamically change in the hypothalamus. This appears to be a reversible process. Normally thin glial processes separate neurons in the SON, however during periods of lactation the glial processes retract, leaving neuronal elements closely juxtaposed. After the lactation cycle the glial processes revert back to their original positions, interspersed among the neuronal elements. This phenomenon of glial process retraction may impact glutamate transmission in the SON during lactation.

Session D: New Approaches to Study Astrocytes

The field needs to move from pharmacology to physiology. To accomplish this we need to be able to image and manipulate astrocytes in vivo. Three aims would help towards this goal: (1) Develop reporters for multiple signaling molecules that are expressible so that they can be used in transgenic animals, (2) Invest in cell-specific promoters and strategies to control where and when genes are expressed, (3) Develop technologies that would cover the full spectrum of imaging from molecule to mind, the goal being to study molecular interactions in vitro and then go in vivo to study those signals simultaneously within astrocytes and neurons.

Session E: Astrocyte Communication Mechanisms: Gap Junctions, Transmitters, and Metabolites

In vitro studies demonstrate that astrocytes propagate calcium waves in culture and this has been proposed to be a mode of glial cell-cell communication however, the extent to which calcium moves between astrocytes under physiological conditions in vivo is not known.

New evidence suggests that hemi-channels (uncoupled gap junction channels) composed of the protein connexin-43, are present on the glial cell surface and can be stimulated to open in response to various physiological stimuli. The regulation of hemi-channel permeability and the function of these channels under normal and pathological conditions warrant further study.

We still don't fully understand nitrogen signaling in the brain despite the fact that there is a lot of ammonium transmitted back and forth between CNS cells. Newly discovered ammonium transporters in the CNS suggest that nitrogen signaling may play a role in astrocyte metabolism.

Brain tumors are unique in that they have a limited space in which to grow. These tumor cells may actually kill normal neighboring cells to make room for tumor growth. Neoplastic transformation of astrocytes appears to be accompanied by glioma cell-mediated toxicity of neighboring normal cells. The mechanisms underlying this toxicity remain to be resolved. Glioma cells are highly migratory and must move through tight interstitial spaces. Mechanisms of glioma-cell migration are poorly understood. Finally, the origin of neoplastic glial cells is unknown. Do glioma cells arise from astrocytes that de-differentiate or from adult progenitor cells?

Other research priorities include: a closer examination of the bi-directional communication between astrocytes and endothelial cells at the blood brain barrier.

Session F: Astrocytes and Brain Ischemia/Hypoglycemia

Following ischemia, the transition of the penumbra to an infarct region occurs when astrocyte function fails. During ischemia glutamate uptake by astrocytes is impaired which could be a major factor contributing to excitotoxicity of neurons. In addition, in vitro studies suggest that astrocytes release glutamate during ischemia, but to date this has not been demonstrated in vivo. During ischemia, astrocytes may also play a significant role in oxidative stress.

Regarding glycogen and brain metabolism, important questions remain: (1) Is astrocyte glycogen rapidly available as a usable fuel source for neurons and axons during periods of high demand? (2) Does astrocyte glycogen have a role in brain function under normal physiological conditions? (3) What might the role of glycogen be in diabetes, especially in children?

Session G: Astrocyte Diversity and New Roles for Astrocytes in Immune Function and Neurological Disease

The following topics were identified as priorities for future research: (1) we need a better understanding of how astrocytes are part of the immune / inflammatory response in in the CNS (2) we need to characterize communication between microglia and astrocytes (3) further studies are needed on proteoglycans and astrocyte inhibition of nerve regeneration following spinal cord injury (5) the role of astrocytes as mediators or amplifiers of chronic pain is an exciting new area that warrants further study.

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IV. Recommendations/Conclusions

Issues for setting an astrocyte research agenda:

• Can distinct subpopulations of astrocytes be defined?
• Do astrocytes communicate via calcium waves in vivo? Are there networks of astrocytes?
• It is important to understand how astrocytes control the development, maintenance, and plasticity of synapses.
• Are astrocytic microdomains functional units? How do they integrate into complex nervous system functioning?
• Do astrocytes release glutamate in vivo and if so, what effect does this have on neurons?
• We need better tools for manipulating astrocyte gene expression in vivo including: better astrocyte-specific promoters that might target subsets of astrocytes to take advantage of heterogeneity; inducible promoters, and better reporters that actually report on different aspects of astrocyte function.

Participant List

*Workshop organizers and Chairs

Christopher Anderson, Ph.D. (University of California, San Franciso)
Gregory Arcuino (New York Medical College)
Praveen Ballabh (New York Medical College)
Ben Barres, M.D., Ph.D.( Stanford University School of Medicine)
Karen Bateman, B.S. (NINDS, National Institutes of Health)
*Toby Behar, Ph.D. (NINDS, National Institutes of Health)
Michael Bennett, D. Phil.( Albert Einstein College of Medicine)
Etty Benveniste, Ph.D. (University of Alabama at Birmingham)
Dwight Bergles, Ph.D. (Johns Hopkins University)
Mark Bevensee, Ph.D.( University of Alabama at Birmingham)
Angelique Bordey, Ph.D. (Yale University School of Medicine)
Tailoi Chan-Ling, Ph.D. (University of Sydney)
Jonathan Coles, Ph.D.( Centre Hospitalier Universitaire)
Frank Diaz (NINDS, National Institutes of Health)
Gerald Dienel, Ph.D. (University of Arkansas for Medical Sciences)
Laura Dugan, M.D. (Washington University)
David Eckstein, Ph.D. (NINDS, National Institutes of Health)
Gillian Einstein, Ph.D. (CSR, National Institutes of Health)
Mark Ellisman, Ph.D. (University of California at San Diego)
R. Douglas Fields, Ph.D. (NICHD, National Institutes of Health)
Marc Freeman, Ph.D. (University of Oregon)
Vittorio Gallo, Ph.D. (Children's National Medical Center)
Howard Gendelman, M.D. (University of Nebraska Medical Center)
Anuja Ghorpade, Ph.D. (University of Nebraska Medical Center)
James Goldman, M.D., Ph.D. (Columbia University)
Francisco Gonzalez-Scarano, M.D. (University of Pennsylvania)
Margaret Grabb, Ph.D. (National Institutes of Health)
Peter Guthrie, Ph.D.(CSR, National Institutes of Health)
Christine Haenggeli, M.D. (Johns Hopkins University School of Medicine)
Philip Haydon, Ph.D. (University of Pennsylvania)
Meena Hiremath, Ph.D. (ninds, National Institutes of Health)
Philip Horner, Ph.D. (University of Washington)
Jean Hou (ninds, National Institutes of Health)
Kim Hunter-Schaedle, Ph.D. (Juvenile Diabetes Research Foundation International)
Thomas Jacobs, Ph.D. (NINDS, National Institutes of Health)
Jim Kang, Ph.D. (New York Medical College)
Helmut Kettenmann, Ph.D. (Max-Delbruck-Center for Molecular Medicine)
Harold Kimelberg, Ph.D. (Albany Medical College)
Naomi Kleitman, Ph.D. (NINDS, National Institutes of Health)
Diane Lawrence, Ph.D. (NINDS, National Institutes of Health)
Gabrielle Leblanc, Ph.D. (NINDS, National Institutes of Health)
Soo-Siang Lim Ph.D. (National Science Foundation)
Jane Lin, Ph.D. (New York Medical College)
Quing-song Liu, Ph.D. (New York Medical College)
Eugene Major, Ph.D. (NINDS, National Institutes of Health)
Lawrence Mathes, Ph.D. (The Ohio State University)
Mark Mattson, Ph.D. (NIA, National Institutes of Health)
Ken McCarthy, Ph.D. (University of North Carolina- Chapel Hill)
Guy McKhann, M.D. (Columbia University)
Albee Messing, VM.D., Ph.D. (University of Wisconsin - Madison)
Mary Ellen Michel, Ph.D. (NINDS, National Institutes of Health)
*Maiken Nedergaard, Ph.D. (New York Medical College)
Maria Neff, M.D., Ph.D. (The Ohio State University)
Eric Newman, Ph.D. (University of Minnesota)
Soren Nielsen, M.D., Ph.D. (University of Aarhus)
John Park, M.D., Ph.D. (NINDS, National Institutes of Health)
Vladimir Parpura, M.D., Ph.D. (University of California)
Dominique Poulain, M.D. (INSERM U.378)
Diana Price, Ph.D. (University of California - San Diego)
*Bruce Ransom, M.D., Ph.D. (University of Washington School of Medicine)
Jeffrey Rothstein, M.D., Ph.D. (Johns Hopkins University)
Bruce Sabath (NINDS, National Institutes of Health)
Eliana Scemes, Ph.D. (Albert Einstein College of Medicine)
Lynnae Schwartz, M.D., Ph.D. (NINDS, National Institutes of Health)
Pankaj Seth, Ph.D. (NINDS, National Institutes of Health)
Paul Sheehy, Ph.D. (NINDS, National Institutes of Health)
Beth-Anne Sieber, Ph.D. (NIMH, National Institutes of Health)
Jerry Silver, Ph.D. (Case Western Reserve University)
Catherine Sigal, Ph.D. (Juvenile Diabetes Research Foundation International)
Karen Skinner, Ph.D. (NIDA, National Institutes of Health)
Robert Skoff, Ph.D. (Department of Anatomy and Cell Biology)
Harald Sontheimer, Ph.D. (The University of Alabama at Birmingham)
Giovanna Spinella, M.D. (NINDS, National Institutes of Health)
David Spray, Ph.D. (Albert Einstein College of Medicine)
Raymond Swanson, M.D. (University of California at San Francisco)
Takahiro Takano (New York Medical College)
Selva Baltan Tekkok, M.D., Ph.D. (University of Washington)
Robert Trujillo, M.D., Ph.D. (NINDS, National Institutes of Health)
Andrea Volterra, Ph.D. (University of Lausanne)
Xiaohai Wang (New York Medical College)
Linda Watkins, Ph.D. (University of Colorado at Boulder)
Zucheng Ye, Ph.D. (University of Washington)
Min Zhou, Ph.D. (Albany Medical College)
H. Ronald Zielke, Ph.D. (University of Maryland)
Suzanne Zukin, Ph.D. (Albert Einstein College of Medicine)

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