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Glutamate dyshomeostasis leads to Cell injury/death
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory||adjacent||High||Moderate||Marie-Gabrielle Zurich (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Glutamate is the major excitatory neurotransmitter in the mammalian CNS, where it plays key roles in development, learning, memory and response to injury. However, glutamate at high concentrations at the synaptic cleft acts as a toxin, inducing neuronal injury and death (Meldrum, 2000; Ozawa et al., 1998). Glutamate-mediated neurotoxicity has been dubbed as “excitotoxicity”, referring to the consequence of the overactivation of the N-methyl D-aspartate (NMDA)–type glutamate receptors (cf AOP 48), leading to increased Na+ and Ca2+ influx into neurons (Choi, 1992; Pivovarova and Andrews, 2010). Increased intracellular Ca2+ levels are associated with the generation of oxidative stress and neurotoxicity (Lafon-Cazal et al., 1993). Accordingly, the control of extracellular levels of glutamate dictates its physiological/pathological actions and this equilibrium is maintained primarily by the action of several glutamate transporters (such as GLAST, GLT1, and EAAC1) located on astrocytic cell membranes, which remove the excitatory neurotransmitter from the synaptic cleft, keeping its extracellular concentrations below toxic levels (Anderson and Swanson, 2000; Maragakis and Rothstein, 2001; Szydlowska and Tymianski, 2010).
In addition to synaptic transmission, physiological stimulation of glutamate receptors can mediate trophic effects and promote neuronal plasticity. During development, NMDA receptors initiate a cascade of signal transduction events and gene expression changes primarily involving Ca2+-mediated signaling, induced by activation of either Ca2+- permeable receptor channels or voltage-sensitive Ca2+ channels. The consecutive activation of major protein kinase signaling pathways, such as Ras-MAPK/ERK and PI3-K-Akt, contributes to regulation of gene expression through the activation of key transcription factors, such as CREB, SRF, MEF-2, NF-kappaB. Metabotropic glutamate receptors can also engage these signaling pathways, in part by transactivating receptor tyrosine kinases. Indirect effects of glutamate receptor stimulation are due to the release of neurotrophic factors, such as brain derived neurotrophic factor through glutamate-induced release of trophic factors from glia. The trophic effect of glutamate receptor activation is developmental stage-dependent and may play an important role in determining the selective survival of neurons that made proper connections. During this sensitive developmental period, interference with glutamate receptor function may lead to widespread neuronal loss (Balazs, 2006).
Evidence Collection Strategy
Evidence Supporting this KER
Glutamate dyshomeostasis and in particular excess of glutamate in the synaptic cleft will lead to overactivation of ionotropic glutamate receptors and cause cell injury/death, as described in AOP 48. The excess of glutamate can result from decreased uptake in astrocytes (Aschner et al., 2000; Brookes and Kristt, 1989), or neurons (Moretto et al., 2005; Porciuncula et al., 2003). But also from the increased release (Reynolds and Racz, 1987). This neurotoxic cascade involves calcium overload and ROS production leading to oxidative stress (Ceccatelli et al., 2010; Lafon-Cazal, 1993; Meldrum, 2000; Ozawa, 1998). Chemicals binding to sulfhydryl (SH)-/seleno-proteins cause a direct oxidative stress by perturbing mitochondrial respiratory chain proteins and by decreasing anti-oxidant defense mechanism (see KER : MIE to KEdown oxidative stress) and an indirect oxidative stress via perturbation of glutamate homeostasis/excitotoxicity. Thus, there may be some redundancy in the empirical support between this KER and the KER linking KEup oxidative stress and KEdown cell injury/death.
Glutamate has been shown to regulate BDNF production (Tao et al., 2002). Accordingly, glutamate may also indirectly contribute to cell injury/death by inducing modifications in the brain levels of trophic factors, since it is known that changes in trophic support can lead to cell injury/death, as well as to perturbation in the physiological establishment of neuronal network (Zhao et al., 2017).
Uncertainties and Inconsistencies
No uncertainty or inconsistency reported yet.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Support for the link between glutamate dyshomeostasis and cell injury /death can be found in rats, and mouse. However, as the neurotransmitter glutamate is already found in insects, it is plausible that this KER is valid throughout taxa (Harris et al., 2014).
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