This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Increased, glutamate leads to Overactivation, NMDARs
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Acetylcholinesterase Inhibition Leading to Neurodegeneration||adjacent||Moderate||High||Karen Watanabe (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Glutamate is the main excitatory neurotransmitter in the brain and spinal cord, where it activates both ionotropic and metabotropic receptors (Kandel et al., 2013). N-methyl-D-aspartate (NMDA) receptors are one class of ionotropic glutamate receptors found in the brain. They are unique in that they require multiple ligands, both glutamate and glycine, to first bind before they can open. Under normal conditions, the extracellular concentration of glycine is high enough to allow effective opening of NMDA receptors by glutamate (Kandel et al., 2013). NMDA receptors are also voltage-gated by a magnesium block and requires depolarization of the neuron to which the NMDA receptors are bound before ions can flow through the receptor channel (Kandel et al., 2013). A variety of pathological conditions involve the overactivation of glutamate receptors and result in some form of injury (Lipton and Rosenberg, 1994). For example, elevated extracellular glutamate levels have been shown to occur during periods of seizure activity (Lallement et al., 1991). Excess extracellular glutamate is known to be toxic to neurons and can result in cell death due to calcium dysregulation mediated through NMDA receptor activation (Michaels and Rothman, 1990).
Evidence Collection Strategy
Evidence was collected in multiple ways: literature searches of external databases, review of related KEs and KERS in the AOPWiki, and consultation with experts. Extensive literature searches were conducted in Scopus, Pubmed, and Google Scholar using keywords applicable to each KE, with an initial focus on zebrafish data to then focusing on rat data. Related KEs and KERs in the AOPWiki were also reviewed for relevant evidence and their sources. The “snowball method” was used to find additional articles, i.e., relevant citations within an article were obtained if they provided additional evidence. EndNote reference managing software was used to store results from the literature searches and when possible, a pdf of the manuscript was attached to each record. Papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP. An Excel spreadsheet was used to record reviewed papers and any information worth noting.
Evidence Supporting this KER
Glutamate release into the synaptic cleft is primarily caused by excitatory glutamatergic neurons, however there is evidence showing astrocytes releasing glutamate through a calcium-dependent process. A mechanism explaining how astrocytes release glutamate is not well defined, but it could be released through exocytosis (Nedergaard et al. 2002). Excessive extracellular glutamate overactivates NMDARs and propagates the excitotoxicity caused by some nerve agents (McDonough and Shih, 1997).
Uncertainties and Inconsistencies
There are no known uncertainties or inconsistencies with this relationship.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This relationship has been demonstrated in rats, and human toxicity through this pathway has also been indicated (King and Aaron, 2015).
Clements, J. D. & Westbrook, G. L. 1991. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron, 7, 605-13. DOI: 10.1016/0896-6273(91)90373-8.
Erreger, K., Geballe, M. T., Dravid, S. M., Snyder, J. P., Wyllie, D. J. & Traynelis, S. F. 2005. Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog. J Neurosci, 25, 7858-66. DOI: 10.1523/jneurosci.1613-05.2005.
Hu, E., Mergenthal, A., Bingham, C. S., Song, D., Bouteiller, J. M. & Berger, T. W. 2018. A Glutamatergic Spine Model to Enable Multi-Scale Modeling of Nonlinear Calcium Dynamics. Front Comput Neurosci, 12, 58. DOI: 10.3389/fncom.2018.00058.
Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. 2013. Synaptic Integration in the Central Nervous System. Principles of Neural Science, Fifth Edition. Blacklick, United States: McGraw-Hill Publishing.
King, A. M. & Aaron, C. K. 2015. Organophosphate and Carbamate Poisoning. Emergency Medicine Clinics of North America, 33, 133-151. DOI: 10.1016/j.emc.2014.09.010.
Lallement, G., Carpentier, P., Collet, A., Pernot-Marino, I., Baubichon, D. & Blanchet, G. 1991. Effects of soman-induced seizures on different extracellular amino acid levels and on glutamate uptake in rat hippocampus. Brain Research, 563, 234-240. DOI: 10.1016/0006-8993(91)91539-D.
Lester, R. A. & Jahr, C. E. 1992. NMDA channel behavior depends on agonist affinity. J Neurosci, 12, 635-43. DOI: 10.1523/jneurosci.12-02-00635.1992.
Lester, R. A., Tong, G. & Jahr, C. E. 1993. Interactions between the glycine and glutamate binding sites of the NMDA receptor. J Neurosci, 13, 1088-96. DOI: 10.1523/jneurosci.13-03-01088.1993.
Lipton, S. A. & Rosenberg, P. A. 1994. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med, 330, 613-22. DOI: 10.1056/nejm199403033300907.
McDonough, J. H., Jr. & Shih, T. M. 1997. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev, 21, 559-79. DOI: 10.1016/s0149-7634(96)00050-4.
Michaels, R. L. & Rothman, S. M. 1990. Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci, 10, 283-92. DOI: 10.1523/jneurosci.10-01-00283.1990.
Smolders, I., Khan, G. M., Manil, J., Ebinger, G. & Michotte, Y. 1997. NMDA receptor-mediated pilocarpine-induced seizures: characterization in freely moving rats by microdialysis. Br J Pharmacol, 121, 1171-9. DOI: 10.1038/sj.bjp.0701231.