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.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Excessive extracellular glutamate can bind to the xC-transporters and lead to their toxic paralysis resulting in GSH depletion and cell death-a process referred to as 'oxidative glutamate toxicity'-in contrast to excitotoxic glutamate toxicity resulting from overstimulation of ionotropic receptors (Lewerenz et al, 2013). Thus, the combined effect of oxidative and excitotoxic glutamate toxicity has been associated with the neurotoxic effects and neurodegeneration under conditions of inflammation and possibly stress (Lewerenz and Maher, 2015). Probably owing to their spatial proximity, glutamate released by the xC-system has preferential access to extrasynaptic NMDA receptors in a paracrine manner leading to neuronal toxicity as described earlier (Camacho and Massieu, 2006;Hardingham and Bading, 2010).…”

“…Once thought to be exclusively astrocytic in location, now xC-transporters are known to be located on other glial cells including microglia (Lewerenz et al, 2013;Lewerenz and Maher, 2015). As described earlier, the xC-system exchanges cystine for glutamate in a 1 : 1 ratio where glutamate is extruded in exchange for intake of cystine, which is used for the synthesis of glutathione (GSH).…”

“…As described earlier, the xC-system exchanges cystine for glutamate in a 1 : 1 ratio where glutamate is extruded in exchange for intake of cystine, which is used for the synthesis of glutathione (GSH). GSH is the most abundant anti-oxidant molecule in the brain and its absence is usually fatal (Lewerenz et al, 2013;Lewerenz and Maher, 2015). Although in vitro functional ablation of the xC-system leads to fatal oxidative stress from depletion of GSH, in vivo genetic deletion of the system does not lead to oxidative stress or death, possibly due to GSH supplies from alternate cellular systems (Lewerenz et al, 2013;Lewerenz and Maher, 2015).…”

“…GSH is the most abundant anti-oxidant molecule in the brain and its absence is usually fatal (Lewerenz et al, 2013;Lewerenz and Maher, 2015). Although in vitro functional ablation of the xC-system leads to fatal oxidative stress from depletion of GSH, in vivo genetic deletion of the system does not lead to oxidative stress or death, possibly due to GSH supplies from alternate cellular systems (Lewerenz et al, 2013;Lewerenz and Maher, 2015). Although the source of oxidative stress has been assumed to be due to immune stimulation, states of intense neural activity such as stress can also increase demand for GSH-which is met through an NMDA-mediated hyperactivation of GSH biosynthesis within in the neurons (Baxter et al, 2015;Nathan and Cunningham-Bussel, 2013).…”

Astrocytic transporters in Alzheimer's disease

“…Disruption in glutamatergic signalling has been reported in both animal models of AD and people with dementia (62,64). Indeed a breakdown in glutamate homeostasis forms the basis of the 'glutamatergic' hypothesis in AD (65)(66)(67). It is also noteworthy that current symptomatic relief for AD is provided by memantine, a metabotropic glutamate receptor antagonist.…”