Neuroscience 6e Web Topic 6.1 - Excitotoxicity Following Acute Brain Injury
Excitotoxicity refers to the ability of glutamate and related compounds to destroy neurons by prolonged excitatory synaptic transmission. Normally, the concentration of glutamate released into the synaptic cleft rises to high levels (approximately 1 mM) but remains at this concentration for only a few milliseconds. If abnormally high levels of glutamate accumulate in the cleft, the excessive activation of neuronal glutamate receptors can literally excite neurons to death.
The phenomenon of excitotoxicity was discovered in 1957 when D. R. Lucas and J. P. Newhouse serendipitously found that feeding sodium glutamate to infant mice destroys neurons in the retina. Roughly a decade later, John Olney at Washington University extended this discovery by showing that regions of glutamate-induced neuronal loss can occur throughout the brain. The damage was evidently restricted to the postsynaptic cells—the dendrites of the target neurons were grossly swollen—while the presynaptic terminals were spared. Olney also examined the relative potency of glutamate analogs and found that their neurotoxic actions paralleled their ability to activate postsynaptic glutamate receptors. Furthermore, glutamate receptor antagonists were effective in blocking the neurotoxic effects of glutamate. In light of this evidence, Olney postulated that glutamate destroys neurons by a mechanism similar to transmission at excitatory glutamatergic synapses, and coined the term excitotoxic to refer to this pathological effect.
Evidence that excitotoxicity is an important cause of neuronal damage after brain injury has come primarily from studying the consequences of reduced blood flow. The most common cause of reduced blood flow to the brain (ischemia) is the occlusion of a cerebral blood vessel (i.e., a stroke; see Clinical Applications in the Appendix). The idea that excessive synaptic activity contributes to ischemic injury emerged from the observation that concentrations of glutamate and aspartate in the extracellular space around neurons increase during ischemia. Moreover, injection of glutamate receptor antagonists into the brains of experimental animals protects neurons from ischemia-induced damage. Together, these findings imply that extracellular accumulation of glutamate during ischemia activates glutamate receptors excessively, and that this somehow triggers a chain of events that leads to neuronal death. The reduced supply of oxygen and glucose presumably elevates extracellular glutamate levels by slowing the energy-dependent removal of glutamate at synapses.
Excitotoxic mechanisms have been shown to be involved in other acute forms of neuronal insult, including hypoglycemia, trauma, and repeated intense seizures (called status epilepticus). Understanding excitotoxicity therefore has important implications for treating a variety of neurological disorders. For instance, a blockade of glutamate receptors could, in principle, protect neurons from injury due to stroke, trauma, or other causes. Unfortunately, clinical trials of glutamate receptor antagonists have not led to much improvement in the outcome of stroke. The ineffectiveness of this logical treatment is probably due to several factors, one of which is that substantial excitotoxic injury occurs quite soon after ischemia, prior to the typical initiation of treatment. It is also likely that excitotoxicity is only one of several mechanisms by which ischemia damages neurons; other candidates include damage secondary to inflammation. Pharmacological interventions that target all of these mechanisms nonetheless hold considerable promise for minimizing brain injury after stroke and other causes.
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