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Occurrence, Focal Seizure leads to Increased, glutamate
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||Low||Karen Watanabe (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
The initial focal seizure starts by increasing the firing rate of neurons in a specific area. This is characterized by changes in membrane potential (Turski et al., 1986). Cholinergic nerve agents cause an increase in spontaneous excitatory postsynaptic currents (sEPSC) leading to increased release of glutamate and activation of N-methyl-D-aspartate receptors (NMDARs) (Lallement et al., 1991, Miller, 2015). This response happens quickly after the initial focal seizure and is then sustained for a longer period of time (McDonough and Shih, 1997).
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
Seizure activity has been shown to cause glutamate release (Lallement et al., 1991). Glutamate is the main excitatory transmitter in the brain and spinal cord, where it activates both ionotropic and metabotropic receptors (Kandel et al., 2013).
Glutamate (Glu) 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 (Nedergaard et al., 2002). A mechanism explaining how astrocytes release glutamate is not well defined, but it could be released through exocytosis (Nedergaard et al., 2002). When focal seizures start, the firing of glutamatergic neurons releases glutamate (Lallement et al., 1991). While the change in spiking activity of individual neurons at seizure onset appears to be heterogenous, there is an apparent increase in neuronal firing rate in some populations of neurons (Truccolo et al., 2011).
Uncertainties and Inconsistencies
There is not yet an explanation for the mechanisms behind glutamate release in response to seizure activity. Animals that developed seizure activity in response to sarin (aka GB) versus VX intoxication showed increasing extracellular glutamate and no changes in extracellular glutamate, respectively (O’Donnell et al., 2011).
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).
Britton, J. W., Frey, L. C., Hopp, J. L., Korb, P., Koubeissi, M. Z., Lievens, W. E., Pestana-Knight, E. M. & St. Louis, E. K. 2016. In: ST. LOUIS, E. K. & FREY, L. C. (eds.) Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. Chicago: American Epilepsy Society Copyright ©2016 by American Epilepsy Society.
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.
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.
Medina-Ceja, L., Morales-Villagrán, A. & Tapia, R. 2000. Action of 4-aminopyridine on extracellular amino acids in hippocampus and entorhinal cortex: a dual microdialysis and electroencehalographic study in awake rats. Brain Res Bull, 53, 255-62. DOI: 10.1016/s0361-9230(00)00336-1.
Medina-Ceja, L., Pardo-Peña, K., Morales-Villagrán, A., Ortega-Ibarra, J. & López-Pérez, S. 2015. Increase in the extracellular glutamate level during seizures and electrical stimulation determined using a high temporal resolution technique. BMC Neurosci, 16, 11. DOI: 10.1186/s12868-015-0147-5.
Meurs, A., Clinckers, R., Ebinger, G., Michotte, Y. & Smolders, I. 2008. Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin. Epilepsy Res, 78, 50-9. DOI: 10.1016/j.eplepsyres.2007.10.007.
Miller, S. L. 2015. The Efficacy of LY293558 in Blocking Seizures and Associated Morphological, and Behavioral Alterations Induced by Soman in Immature Male Rats and the Role of the M1 Muscarinic Acetylcholine Receptor in Organophosphate Induced Seizures. Doctor of philosophy in the neuroscience graduate program Doctoral dissertation, Uniformed Services University.
Morales-Villagrán, A., Medina-Ceja, L. & López-Pérez, S. J. 2008. Simultaneous glutamate and EEG activity measurements during seizures in rat hippocampal region with the use of an electrochemical biosensor. J Neurosci Methods, 168, 48-53. DOI: 10.1016/j.jneumeth.2007.09.005.
Nedergaard, M., Takano, T. & Hansen, A. J. 2002. Beyond the role of glutamate as a neurotransmitter. Nature Reviews Neuroscience, 3, 748-755. DOI: 10.1038/nrn916.
O’Donnell, J. C., McDonough, J. H. & Shih, T.-M. 2011. In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate. Archives of Toxicology, 85, 1607-1616. DOI: 10.1007/s00204-011-0724-z.
Peña, F. & Tapia, R. 1999. Relationships among seizures, extracellular amino acid changes, and neurodegeneration induced by 4-aminopyridine in rat hippocampus: a microdialysis and electroencephalographic study. J Neurochem, 72, 2006-14. DOI: 10.1046/j.1471-4159.1999.0722006.x.
Truccolo, W., Donoghue, J. A., Hochberg, L. R., Eskandar, E. N., Madsen, J. R., Anderson, W. S., Brown, E. N., Halgren, E. & Cash, S. S. 2011. Single-neuron dynamics in human focal epilepsy. Nat Neurosci, 14, 635-41. DOI: 10.1038/nn.2782.
Turski, L., Cavalheiro, E. A., Sieklucka-Dziuba, M., Ikonomidou-Turski, C., Czuczwar, S. J. & Turski, W. A. 1986. Seizures produced by pilocarpine: neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. Brain Res, 398, 37-48. DOI: 10.1016/0006-8993(86)91247-3.