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Review
. 2020 Apr 24:14:90.
doi: 10.3389/fncel.2020.00090. eCollection 2020.

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Adam Armada-Moreira  1   2   3 , Joana I Gomes  1   2 , Carolina Campos Pina  1   2 , Oksana K Savchak  1   2 , Joana Gonçalves-Ribeiro  1   2 , Nádia Rei  1   2 , Sara Pinto  1   2 , Tatiana P Morais  4 , Robertta Silva Martins  5 , Filipa F Ribeiro  1   2 , Ana M Sebastião  1   2 , Vincenzo Crunelli  4   6 , Sandra H Vaz  1   2
Affiliations
Review

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Adam Armada-Moreira et al. Front Cell Neurosci. .

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.

Keywords: NMDA receptors; astrocytes; calcium signaling; excitotoxicity; neurodegenerative diseases; oxidative stress.

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Figures

Figure 1
Figure 1
Schematic summary of different aspects of excitotoxicity, including the main cellular defenses against it, the main causes, the players involved in its mechanisms, and general cellular consequences. The shift from normal brain function to an excitotoxic state is brought about by the main causes, and this shift is avoided by the main cellular defenses. If the defenses fail, excitotoxicity is amplified by different mechanisms, causing cellular consequences.
Figure 2
Figure 2
Graphical depiction of the main calcium-dependent processes involved in excitotoxicity, leading to oxidative stress and cell death. Dotted lines with end arrows represent activation, dotted lines with T ends represent inhibition. Mcu, mitochondrial calcium uniporter.
Figure 3
Figure 3
Schematic representation of the alterations in excitatory neurotransmission in amyotrophic lateral sclerosis (ALS). Different pathophysiological mechanisms have been proposed to explain excitotoxicity in ALS. Interneuron alterations are observed in early disease stages, with a loss of cortical and spinal interneurons, leading to the disruption of inhibitory circuits. Consequently, there is an excitation–inhibition imbalance, increasing subsequent excitability and glutamate release to the synaptic cleft. Glutamate-mediated excitotoxicity may happen through an astrocyte-mediated downregulation of excitatory amino acid transporter 2 (EAAT2), which decreases the glutamate uptake from the synaptic cleft and potentiates the excitotoxic effects. Astrocytes in ALS also release neurotoxic factors that trigger changes to motor neuron glutamate receptors and render them susceptible to excitotoxicity, furthering neurodegeneration. Moreover, the excessive firing and the dysregulated calcium influx through atypical glutamate receptors results in an ionic dysfunction in motor neurons. The excessive entry of calcium into motor neurons results in mitochondrial overload and in the generation of reactive oxygen species (ROS), which ultimately causes oxidative stress. The presence of protein aggregates in mitochondria can also lead to alterations in normal cell metabolism, increasing the susceptibility to glutamatergic overstimulation as well as the activation of apoptotic pathways.
Figure 4
Figure 4
Underlying cellular mechanisms of Alzheimer’s disease (AD). The upstream key hallmarks of AD range from ionic dysfunction to the impairment of several cellular processes, including Ca2+-signaling dysregulation, abnormal Aβ production and aggregation and neuroinflammation. The crosstalk between the mentioned factors, leads to the pathological phenotype, involving mitochondrial dysfunction, excitotoxicity, and extrasynaptic NMDA receptor (eNMDAR) activation. As the symptomatic circle closes, the dysfunction of one leads to further activation of the others, altogether contributing to neurodegeneration and cognitive deficits, characteristics of the disease.
Figure 5
Figure 5
Aβ-induced astrocytic dysfunctions leading to excitotoxicity and AD pathogenesis. iNOS, inducible nitric oxide synthase; NO, nitric oxide; SR, serine racemase; GS, glutamine synthetase; CaN/NFAT—calcineurin/nuclear factor of activated T cells; GluT, glutamate transporters; GluR, glutamate receptors.
Figure 6
Figure 6
The connecting railway between Epilepsy and Excitotoxicity: Glutamatergic and GABAergic mechanisms in epilepsy-related excitotoxicity. Schematic representation of alterations in excitatory and inhibitory neurotransmission and their relationship with epilepsy-excitotoxicity dynamic. Both alterations in glutamate- and GABA-mediated neurotransmission have been reported to play a role in epileptogenesis. Increased glutamate levels are a key-feature of temporal lobe epilepsy, resulting from an impairment in GLT-1, which are compensated by increased GAD. The excessive and hypersynchronous neuronal firing promotes network hyperexcitability, culminating in glutamate-mediated excitotoxicity.
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