Astroglia: Important mediators of traumatic brain injury

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Abstract

Traumatic brain injury (TBI) research to date has focused almost exclusively on the pathophysiology of injured neurons with very little attention paid to non-neuronal cells. However in the past decade, exciting discoveries have challenged this century-old view of passive glial cells and have led to a reinterpretation of the role of glial cells in central nervous system (CNS) biology and pathology. In this chapter we review several lines of evidence, indicating that glial cells, particularly astrocytes, are active partners to neurons in the brain, and summarize recent findings that detail the significance of astrocyte pathology in traumatic brain injury.

Introduction

Traumatic brain injury (TBI) research to date has focused almost exclusively on the pathophysiology of injured neurons with very little attention paid to non-neuronal cells. This near-exclusive focus on neuroprotection likely reflects the predominant paradigm of the neuroscience community as a whole, which characterized glial cells as a specialized type of connective tissue that merely provided support for the neurons. However in the past decade, exciting discoveries have challenged this century-old view of passive glial cells and have led to a reinterpretation of the role of glial cells in central nervous system (CNS) biology and pathology. In this chapter we review several lines of evidence, indicating that glial cells, particularly astrocytes, are active partners to neurons in the brain, and summarize recent findings which detail the significance of astrocyte pathology in traumatic brain injury.

Section snippets

Astrocytes in normal brain function: recasting an old “star”

One line of evidence that astrocytes are more than supportive connective tissue comes from recent detailed analyses of the cellular morphology. A unique morphological feature of astrocytes is that nearly the entire cell surface is covered with processes that extend and become lamellae or filopodia as indicated by three-dimensional reconstruction of electron micrographs. Most lamellae and filopodia originate from processes, which, like the cell body, contain organelles and cytoskeletal elements;

Revisiting and revising the “Classical View” of astrocytes in CNS trauma

As discussed in the introduction, TBI research to date has focused mainly on neuroprotection and given little consideration to the role of glial cells in injury. This has significant implications for the understanding of brain pathology after TBI since the population of glial cells in brain is actually much larger than neurons. Furthermore, the importance of the complex communication and interaction between astrocytes and neurons described above are becoming more apparent in normal brain

Unraveling the mechanisms of acute astrocyte damage with in vitro mechanical injury

It is clear from the studies described above that in vivo experimental TBI or ischemia produces rapid and profound damage to astrocytes. Moreover, several in vitro models of ischemia also show acute astrocyte pathology. Additionally, several of the astrocytic intracellular events occurring acutely after TBI have been characterized in a series of in vitro studies using a mechanical injury model developed by Ellis et al. (1995). In this model, cells are grown on a membrane that is subjected to a

Conclusion

With some notable exceptions such as the study of gliosis and astrocytic swelling, most TBI research has generally focused on the pathophysiology of neurons. However, many recent developments in the field of glial biology demonstrate the active nature of neuronal-astrocyte signaling indicating the vital importance of astrocytes in normal brain function. Furthermore, recent studies in Neurotrauma demonstrate the vulnerability of astrocytes to CNS insults. Therefore, defining the time course of

Acknowledgments

Support provided by UCD Health Systems Research Award (CLF), NIH NS29995 (BGL), NIH NS45136 (BGL).

References (188)

  • P. Illes et al.

    Molecular physiology of P2 receptors in the central nervous system

    Eur. J. Pharmacol.

    (2004)
  • D.E. Jakubovicz et al.

    Lactic acid-induced swelling in C6 glial cells via Na+/H+ exchange

    Brain Res.

    (1989)
  • T. Kawamata et al.

    Lactate accumulation following concussive brain injury: the role of ion fluxes induced by excitatory amino acids

    Brain Res.

    (1995)
  • H. Kondou et al.

    Formation of inositol phosphates mediated by M3 muscarinic receptors in type-1 and type-2 astrocytes from neonatal rat cerebral cortex

    Neurosci. Lett.

    (1994)
  • D. Liu et al.

    Astrocytic demise precedes delayed neuronal death in focal ischemic rat brain

    Brain Res. Mol. Brain Res.

    (1999)
  • B.G. Lyeth et al.

    Effects of muscarinic receptor antagonism on the phosphatidylinositol bisphosphate signal transduction pathway after experimental brain injury

    Brain Res.

    (1996)
  • B.G. Lyeth et al.

    Group I metabotropic glutamate antagonist reduces acute neuronal degeneration and behavioral deficits after traumatic brain injury in rats

    Exp. Neurol.

    (2001)
  • B.G. Lyeth et al.

    Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat

    Brain Res.

    (1990)
  • S.S. Margulies et al.

    Physical model simulations of brain injury in the primate

    J. Biomech.

    (1990)
  • A.D. Martinez et al.

    Regulation of astrocyte gap junctions by hypoxia-reoxygenation

    Brain Res. Brain Res. Rev.

    (2000)
  • F. Aguado et al.

    Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ

    J. Neurosci.

    (2002)
  • S.M. Ahmed et al.

    Stretch-induced injury alters mitochondrial membrane potential and cellular ATP in cultured astrocytes and neurons

    J. Neurochem.

    (2000)
  • E. Anlauf et al.

    Astrocytic exocytosis vesicles and glutamate: a high-resolution immunofluorescence study

    Glia

    (2005)
  • A. Araque et al.

    Astrocyte-induced modulation of synaptic transmission

    Can. J. Physiol. Pharmacol.

    (1999)
  • L. Bambrick et al.

    Astrocyte mitochondrial mechanisms of ischemic brain injury and neuroprotection

    Neurochem. Res.

    (2004)
  • P. Bezzi et al.

    Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

    Nature

    (1998)
  • E.M. Blanc et al.

    Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca2+ homeostasis and cell death

    J. Neurochem.

    (1998)
  • D. Boehning et al.

    Novel neural modulators

    Annu. Rev. Neurosci.

    (2003)
  • J.P. Bolanos et al.

    Induction of nitric oxide synthase inhibits gap junction permeability in cultured rat astrocytes

    J. Neurochem.

    (1996)
  • A. Bondarenko et al.

    Calcium dependence of rapid astrocyte death induced by transient hypoxia, acidosis, and extracellular ion shifts

    Glia

    (2001)
  • A. Bondarenko et al.

    Rapid astrocyte death induced by transient hypoxia, acidosis, and extracellular ion shifts

    Glia

    (2001)
  • A. Bondarenko et al.

    Role of Na+-H+ and Na+-Ca2+ exchange in hypoxia-related acute astrocyte death

    Glia

    (2005)
  • R. Bullock et al.

    Glial swelling following human cerebral contusion: an ultrastructural study

    J. Neurol. Neurosurg. Psychiatry

    (1991)
  • R. Bullock et al.

    Factors affecting excitatory amino acid release following severe human head injury

    J. Neurosurg.

    (1998)
  • O.J. Castejon

    Morphological astrocytic changes in complicated human brain trauma: a light and electron microscopic study

    Brain Inj.

    (1998)
  • T.I. Chao et al.

    The synapse-astrocyte boundry: an anatomical basis for an inegrative role of glia in synaptic transmission

  • T. Chen et al.

    Group I metabotropic receptor antagonism blocks depletion of calcium stores and reduces potentiated capacitative calcium entry in strain-injured neurons and astrocytes

    J. Neurotrauma

    (2004)
  • D.W. Choi et al.

    The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death

    Annu. Rev. Neurosci.

    (1990)
  • N.E. Chorna et al.

    P2Y receptors activate neuroprotective mechanisms in astrocytic cells

    J. Neurochem.

    (2004)
  • J.E. Contreras et al.

    Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • A.H. Cornell-Bell et al.

    Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling

    Science

    (1990)
  • M.L. Cotrina et al.

    Astrocytic gap junctions remain open during ischemic conditions

    J. Neurosci.

    (1998)
  • M.L. Cotrina et al.

    Connexins regulate calcium signaling by controlling ATP release

    Proc. Natl. Acad. Sci. U.S.A.

    (1998)
  • M.L. Cotrina et al.

    ATP-mediated glia signaling

    J. Neurosci.

    (2000)
  • D. Crippa et al.

    Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis

    J. Physiol.

    (2006)
  • R. D’Ambrosio et al.

    Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia

    J. Neurosci.

    (1999)
  • M. D’Ascenzo et al.

    Electrophysiological and molecular evidence of L-(Cav1), N-(Cav2.2), and R-(Cav2.3) type Ca2+ channels in rat cortical astrocytes

    Glia

    (2004)
  • R. Dermietzel et al.

    Following tracks of hemichannels

    Cell Commun. Adhes.

    (2003)
  • W.D. Dietrich et al.

    Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat

    Acta Neuropathol.

    (1994)
  • Y. Du et al.

    Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons

    Proc. Natl. Acad. Sci. U.S.A.

    (1997)
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