Excitotoxicity refers to the ability of glutamate and related compounds to destroy neurons through prolonged activation of the processes that underlie excitatory synaptic transmission. Normally, the concentration of glutamate released into the synaptic cleft rises to high levels (approx. 1 mM), but remains at this concentration for just a couple milliseconds. If abnormally high concentrations of glutamate accumulate in the extracellular space, the excessive activation of neuronal glutamate receptors can literally excite neurons to death.

This phenomenon was discovered in 1957, when it was found that feeding Sodium Glutamate to infant mice destroys neurons in the retina. Later, it was shown that regions of glutamate-induced neuronal loss occured throughout the brain. The damage inflicted by glutamate was restricted to the postsynaptic cells: the dendrites of the target neurons were grossly swollen, while the presynaptic terminals were spared. The relative potency of glutamate analogues were examined, and it was 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. It was therefore postulated that glutamate deestroyed neurons by a mechanism similar to that employed at excitatory glutamatergic synapses.

Evidence that excitotoxicity is an important cause of neuronal damage after injury has come from studying the consequences of oxygen deprivation. The most common cause of reduced blood flow to the brain (ischemia) is occlusion of a cerebral blood vessel (a stroke). The idea that synaptic activity might contribute to this sort of injury emerged from the observation that concentrations of glutamate and aspartate in the extracellular space increase during ischemia. Further, microinjection of glutamate receptor antagonists in experimental animals protects neurons from ischemia-induced damage. Together, these findings suggest that extracellular accumulation of glutamate during ischemia activates glutamate receptors and triggers a chain of events culminating in neuronal death. The reduced supply of exygen probably elevates extracellular glutamate levels by slowing down the energy-dependent uptake of glutamate at synapses. Excitotoxic mechanisms are probably also present in other acute forms of neuronal damage, including hypoglycemia, traumatic injury, and status epilepticus.

This excitotoxicity hypothesis has profound implications for treating many neurological disorders. For example, blockade of glutamate receptors after an injury could rescue neurons that would otherwise die.

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