Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence?

Abstract

Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

Keywords: Alzheimer's disease; Huntington's disease; amyotrophic lateral sclerosis; excitotoxicity; glutamate receptors; glutamate transporters; neurodegeneration; system x−c.

Figure 1

Glutamate metabolism in the brain. Vesicular glutamate is synaptically released and binds to ionotropic glutamate receptors at the postsynapse. Glutamate is rapidly taken up by astrocytic glutamate transporters, especially EAAT2. Spillover from the synaptic cleft can activate perisynaptic mGluR5. Migroglia and astrocytes non-vesicularly release glutamate into the extrasynaptic extracellular space via system x${}_{\text{c}}^{-}$ (x${}_{\text{c}}^{-}$) where it can activate extrasynaptic NMDA receptors.

Figure 2

Kynurenine metabolism. By either indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), tryptophan is converted to N-formyl-L-kynurenine, which is metabolized to L-kynurenine by formaminidase. L-kynurenine may be metabolized to kynurenic acid by kynurenine aminotransferase (KAT), to 3-hydroxy-L-kynurenine by kynurenine-3-monooxygenase or to anthranilic acid by kynureninase. 3-Hydroxy-L-kynurenine and anthranilic acid can both be converted to 3-hydroxyanthranilic acid. 3-Hydroxyanthranilate oxidase (3-HAO) metabolizes 3-hydroxyanthranilic acid to 2-amino-3-carboxymuconate-semialdehyde which is non-enzymatically converted to quinolinic acid. Inhibition of KMO results in increased production of kynurenic acid while the generation of quinolinic acid is inhibited (modified from Vécsei et al., 2013).

Figure 3

Potential mechanisms that lead to excitotoxicity in ALS. EAAT2 downregulation and upregulation of system x${}_{\text{c}}^{-}$ cause increased activation of glutamate receptors. Moreover, signaling via NMDA receptors is potentiated by the upregulation of the co-activator D-serine.

Figure 4

Potential mechanisms that lead to excitotoxicity in AD. Altered calcium homeostasis and increased sensitization of NMDA receptors in AD renders neurons more sensitive to excitotoxicity. This is further amplified by the upregulation of extracellular glutamate via downregulation of EAAT2 and upregulation of system x${}_{\text{c}}^{-}$.

Figure 5

Potential mechanisms that lead to excitotoxicity in HD. Increased redistribution of NMDA receptors to the extrasynaptic compartment is thought to be the prevailing mechanism that fosters excitotoxicity in HD. Although EAAT2 and the glutamate-lowering kynurenine metabolite kynurenic acid (KYNA) are downregulated, these changes might be compensated for by a decrease in system x${}_{\text{c}}^{-}$ expression.