Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury
Introduction
Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and young adults in industrialized countries (Waxweiler et al., 1995). In the United States, about 2 million cases are reported every year with approximately 500,000 people being hospitalized (Weight, 1998). In Canada, approximately 50,000 individuals sustain the injury each year (Statistics Canada, 1994).
TBI is a multifaceted disorder. Primarily, patients with brain injury suffer from surface contusion and laceration, focal or diffuse intracranial hemorrhages, and diffuse axonal injuries with retraction balls in the white matter tracts that are visible with the aid of various brain imaging techniques post-hospitalization. These primary injuries can lead to more serious secondary events such as ischemic insults, oxidative stress, massive edema, and alterations of endogenous neurochemical mechanisms that may be preventable if quickly hospitalized, but which can lead to complications if left untreated.
Glutamate is the most abundant excitatory neurotransmitter in the brain. Increased level of extracellular glutamate following head injury causes over-stimulation of glutamate receptors that may result in secondary events, leading to neuronal cell death. Such events can cause prolonged depolarization and subsequent ionic imbalance, ATP depletion and increases in intracellular free calcium levels that together culminate in cerebral edema, raised intracranial pressure (ICP), vascular compression and brain herniation, an often fatal complication of severe head injury. Thus, understanding of the fundamental mechanisms that lead to raised interstitial glutamate levels and its consequences is crucial.
Since the 1950s, a neurotoxic role for glutamate has been considered when Lucas and Newhouse (1957) demonstrated that the systemic injection of l-glutamate into immature mice destroys inner layers of retina, and to a minor extent, in adult rats. It was later shown by Olney (1969) that certain other brain regions were also affected in immature mice, leading to introduction of the term “excitotoxicity” and subsequently, in a wide range of mammals, including primates (Olney, 1990). In this review, we will explore the influence of glutamate transporters in TBI in relation to other mechanisms known to participate in excitotoxic injury.
Section snippets
Multiple sources of extracellular glutamate increase
Following TBI under both experimental and clinical settings, levels of extracellular glutamate increase acutely (Faden et al., 1989, Globus et al., 1995, Palmer et al., 1993, Bullock et al., 1998). The interstitial glutamate surge following the cerebral insult arises from several different sources as shown in Fig. 1. Glutamate may move into brain following disruption of the blood–brain barrier. Intraparenchymal hemorrhage is often seen following brain trauma, and autoradiography following
Glutamate transporters in the brain
To date, five subtypes of glutamate transporters have been cloned: GLAST (EAAT1), GLT-1 (EAAT2), EAAC-1 (EAAT3), EAAT4 and EAAT5 (see Danbolt, 2001). GLAST, and GLT-1 are predominantly localized in astrocytes (Danbolt et al., 1992, Rothstein et al., 1994, Lehre et al., 1995, Reye et al., 2002), while EAAC-1, EAAT4, and EAAT5 appears to be mostly neuronal (Berger and Hediger, 1998, Kugler and Schmitt, 1999, Dehnes et al., 1998, Arriza et al., 1997).
Of the glial transporters, GLT-1 accounts for
Ionotropic glutamate receptors and the role of calcium
Glutamate-mediated excitotoxicity as a consequence of compromised transporter activity and/or transporter levels occurs via an over-stimulation of glutamate receptors (Fig. 1). Ionotropic receptors are ligand-gated ion channels of heterotetrameric or pentameric structures each containing three transmembrane spanning domains and a cytoplasmic-facing re-entrant loop, with an extracellular n-terminal segment and intracellular c-terminal region (Dingledine et al., 1999). Upon activation, ionotropic
Post-traumatic ischemic insults and its consequences
Although alterations in glutamate transporters and glutamate receptor activation are key processes in developing excitotoxicity following TBI, a number of other complex events also occur, involving a multitude of pathological developments, many of which occur simultaneously. Among these, damaged blood vessels and extravasation of blood is a frequent consequence of trauma. Hemorrhages resulting from the injury may play a role in post-traumatic ischemic insults as this often leads to focal
Conclusions
Following TBI, increased levels of extracellular glutamate occur as a consequence of several pathological events that lead to an over-stimulation of glutamate receptors, and development of large cation fluxes. To prevent excitotoxicity and development of cerebral edema, two major complications of brain trauma, the excessive glutamate must be dealt with and ion gradients reestablished by the affected cells. Astrocytic glutamate transporters, by lowering interstitial glutamate concentration, play
Acknowledgment
Studies from the authors’ lab were supported by a grant from the Canadian Institutes of Health Research (MOP-53110), and by the Marie Robert Head Trauma Foundation (Quebec).
References (86)
- et al.
Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry
Neuron
(1995) Glutamate uptake
Prog. Neurobiol.
(2001)- et al.
An [Na+ + K+]coupled l-glutamate transporter purified from rat brain is located in glial cell processes
Neuroscience
(1992) - et al.
The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms
Neurochem. Int.
(2000) - et al.
Glutamate efflux via the reversal of the sodium-dependent glutamate transporter caused by glycolytic inhibition in rat cultured astrocytes
Neuroscience
(1994) - et al.
Brain glutamate transporter proteins form homomultimers
J. Biol. Chem.
(1996) - et al.
Action of complexin on SNARE complex
J Biol Chem
(2002) - et al.
Why did NMDA receptors antagonists fail clinical trials for stroke and traumatic brain injury?
Lancet Neurol.
(2002) - et al.
Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids.
Brain Res.
(1995) - et al.
Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat
Brain Res.
(1997)