Abstract
Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.
Highlights
Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that leads to the loss of neuronal function and cell death
Regardless, it is known that the excessive activation of N-methyl-D-aspartic acid receptors (NMDAR) results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss
It starts with the induction, which begins with the overactivation of ionotropic glutamate receptors, such as N-methyl-D-aspartic acid receptors (NMDAR), αamino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPAR) and kainate receptors (KAR)
Summary
In central nervous system synapses, glutamate clearance is achieved by diffusion and transporter uptake, mainly into neighboring glial cells (van den Berg and Garfinkel, 1971; Benjamin and Quastel, 1972; Hertz et al, 1999), and is practically independent of enzymatic breakdown (Watkins and Evans, 1981). The exact time course of glutamate dynamics can be altered by the microanatomical synaptic properties (synaptic contact size, complexity of synaptic morphology, glial wrapping, etc.) and by the density of glutamate transporters (Jonas, 2000) Even taking all this into account, during a synaptic event, the peak concentration of glutamate in the synapse can be estimated to be 1.1 mM (1.0–1.5 mM), with a decay time constant of 1.2 ms (0.70–2.0 ms; Clements et al, 1992), while in extrasynaptic locations, the peak concentration can reach 190 μM (Dzubay and Jahr, 1999). Previous literature reported that GluN2A-containing receptors present faster kinetics, while GluN2B-containing receptors present slower opening, closing, and glutamate unbinding, indicating that NMDAR containing GluN2A open more reliably and with faster kinetics than
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
