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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Excessive Glutamate Receptor Activation and Neurological Disorders

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Glutamate and aspartate can be excitotoxins, especially when energy metabolism is compromised

Glutamate and other amino acids were first recognized as neurotoxins in the 1970s when these agents were given orally to immature animals. Acute neurodegeneration was observed in those areas not well protected by the blood—brain barrier, notably the arcuate nucleus of the hypothalamus. The mechanisms of neurodegeneration are divergent, and activation of all classes of ionotropic glutamate receptor has been implicated. Neurodegeneration, for example, following an ischemic insult, may involve mechanisms resembling a pathological exaggeration of LTP-like phenomena; that is, the neuronal insult results partially from AMPA receptor activation with concomitant NMDA receptor involvement and Ca2+ influx.

Metabolic inhibition that leads to impaired ATP production predisposes neurons to glutamate-mediated neurotoxicity [27]. Numerous mechanisms contribute, including impaired cytoplasmic Ca2+ homeostasis and release of oxygen free radicals, which exacerbate damage. Deficits in energy metabolism occur in ischemic tissue and are prominent in some chronic neurodegenerative disorders. Understanding the interplay between mitochondrial function and sensitivity to glutamate overloads may provide new molecular targets for neuroprotective therapy.

Intracerebroventricular injection of kainic acid results in a well-characterized pattern of neuronal cell damage. In the hippocampus, kainic acid causes an axon-sparing selective lesion of the CA3 pyramidal neurons, an area rich in KA1 and GluR6 mRNA expression (see above). The consequences of kainic acid lesioning are cell death and epileptiform discharges in cells normally innervated by the damaged pyramidal neurons. Other cell types in the hippocampus are relatively unharmed. This suggests that activation of KA receptors may contribute to this toxic effect of kainic acid.

Glutamate receptors are involved in ischemic cell damage and neuroprotection

Periods of anoxic insult to neuronal tissue that last more than a few seconds, such as during cardiac arrest or thrombotic stroke, often result in neurotoxicity (see Chap. 34). Oxygen deprivation precipitates a depletion of energy stores within neuronal and glial cell compartments with a concomitant acidosis and release of free radicals (Fig. 15-8). Depletion of energy stores affects cellular metabolism, energy-dependent ionic pumps and the ability of cells to maintain resting membrane potential. Consequently, depolarization of cells results in action potentials and the release of glutamate from presynaptic terminals, which activates postsynaptic AMPA and NMDA receptors. Entry of Ca2+ through glutamate receptors and voltage-sensitive Ca2+ channels increases the intracellular concentration of Ca2+. As described above, an elevation of intracellular Ca2+ will trigger a cascade of second-messenger systems, many of which remain activated long after the initial stimulus is removed. The inability of a population of cells to maintain a resting potential thus precipitates a positive feedback loop, leading to neuronal cell injury or death.

Figure 15-8. Potential paths leading to neuronal injury resulting from an episode of ischemic insult.

Figure 15-8

Potential paths leading to neuronal injury resulting from an episode of ischemic insult. An ischemic episode initiates a complex pathway involving the depletion of cellular energy stores and the release of free radicals. The energy depletion permits sustained (more...)

Animal models of ischemic cell injury have highlighted the potential benefits of suitable neuroprotectants targeted to the glutamate receptor family. In some stroke models, for example, administration of an NMDA receptor blocker even several hours after the initial insult results in substantial protection of the hippocampus and striatum, two of the regions most heavily damaged by interruption in blood supply. Ischemic tissue is acidotic due to release of lactate and other metabolites. The low pH should shut down certain splice variants of NMDA receptors, as described above, perhaps resulting in a natural neuroprotective action. Interestingly, some neuroprotective drugs, such as ifenprodil, appear to inhibit NMDA receptors by shifting the pK for the proton-accepting group in an alkaline direction, such that at physiological pH a larger fraction of the proton sites are occupied by protons, thus rendering a larger fraction of NMDA receptors unavailable for activation.

Epileptiform activity involves glutamate receptor activation

The involvement of excitatory amino acids in epilepsy has been well documented. A large number of animal models of epilepsy have clearly implicated a causal role for the glutamate-receptor family (see Chap. 37). Excessive stimulation of glutamatergic pathways, block of glutamate transporters or pharmacological manipulation resulting in glutamate-receptor activation can precipitate seizures. Epileptiform activity usually begins with excessive AMPA receptor activation; as seizure activity intensifies, an increased involvement of NMDA receptors is observed. Studies with a variety of animal models have shown that NMDA receptor antagonists can reduce the intensity and duration of seizure activity. Antagonism of AMPA-receptor activation usually prevents initiation of the seizure-like event. This suggests that epileptiform activity depends on the interplay between synaptic AMPA and NMDA receptors. Evidence from human tissue supports the role of amino acids in epilepsy. For example, in patients with refractory complex partial seizures with an associated structural focus, surgically removed hippocampal tissue shows an upregulation of AMPA and NMDA receptors.

Some neurodegenerative disorders may involve chronic glutamate receptor activation

Disorders of excitatory amino acid transmission have been implicated in amyotrophic lateral sclerosis (ALS) and the chronic neurodegenerative diseases olivopontocerebellar atrophy and Huntington's chorea. Neurolathyrism is a spastic disorder occurring in East Africa and India. It is associated with the dietary consumption of the legume Lathyrus sativus. The glutamate-like excitant β-N-oxalylamino-l-alanine has been identified as the toxin in this plant. Its action at AMPA receptors in the spinal cord may be responsible for the observed degeneration of lower and upper motor neurons.

The high incidence of ALS observed in residents of the Pacific island of Guam was determined to be due to the dietary ingestion of the cycad Cyas circinalis. This seed contains an amino acid, β-N-methylamino-l-alanine, which, in the presence of bicarbonate, becomes excitotoxic through a mechanism involving the activation of AMPA and NMDA receptors. Its action can be blocked by the NMDA receptor antagonist d-AP5. An important topic for future research will be to identify the roles, if any, that overactivation of glutamate receptors plays in such neurological disorders.

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28148


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