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Key Event Title
|Level of Biological Organization|
Key Event Components
|synaptic transmission, glutamatergic||L-glutamate(1-)||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Molecular events lead to epilepsy||KeyEvent||Allie Always (send email)||Open for adoption|
|presynaptic neuron 1 activation to epilepsy||KeyEvent||Brendan Ferreri-Hanberry (send email)||Open for adoption|
|AChE Inhibition Leading to Neurodegeneration||KeyEvent||Allie Always (send email)||Under development: Not open for comment. Do not cite|
|All life stages|
Key Event Description
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. A mechanism explaining how astrocytes release glutamate is not well defined, but it could be released through exocytosis(Nedergaard et al. 2002). Glutamate is the main excitatory transmitter in the brain and spinal cord, where it activates both ionotropic and metabotropic receptors. There are 3 main ionotropic receptor classifications, AMPA, Kainate, and NMDA receptors, which are always excitatory (Kandel et al. 2013: 213). Excessive extracellular glutamate release overactivates these signaling pathways, and propagates the excitotoxicity caused by some nerve agents (McDonough and Shih 1997).
How It Is Measured or Detected
- Glutamate uptake by astrocytes and synaptic cleft concentration can be measured using liquid scintillation spectrometry and radiolabeled glutamate (H3 glutamate) (Lallement et al. 1991). Liquid scintillation spectrometry counts the activity of a radioactive sample by mixing the glutamate with a liquid scintillator (a material that fluorescens) and count photon emissions.
- Another mechanism to measure the glutamate concentration in the synaptic cleft is by microdialysis sampling. This mechanism is inexpensive and easy to use. When microdialysis is paired with other analytical methods such as High-Pressure Liquid Chromatography (HPLC), there is a higher instrumental selectivity and sensitivity (Watson et al. 2006).
Domain of Applicability
Zebrafish neurotransmitter systems, including glutamate, are being used more for investigating chemical toxicity (Horzmann and Freeman 2016). Some cited sources above have data from rat experiments.
Glutamate is functional throughout all life stages. Liu et al. (1996) suggests that immature rat brains show less glutamate-induced neurotoxicity than adult brains.
Glutamate and glutamate receptors have been studied in both males and females, with similar functionality (Jafarian et al. 2019).
Horzmann, K. A. and J. L. Freeman (2016), "Zebrafish get connected: investigating neurotransmission targets and alterations in chemical toxicity.” Toxics 4(3).
Jafarian, M., S. M. Modarres Mousavi, F. Alipour, H. Aligholi, F. Noorbakhsh, M. Ghadipasha, J. Gharehdaghi, C. Kellinghaus, S. Kovac, M. Khaleghi Ghadiri, S. G. Meuth, E. J. Speckmann, W. Stummer and A. Gorji (2019), "Cell injury and receptor expression in the epileptic human amygdala.” Neurobiology of Disease 124. DOI: 10.1016/j.nbd.2018.12.017.
Kandel, E., J. Schwartz, T. Jessell, S. Siegelbaum and A. J. Hudspeth (2013), Principles of Neural Science, Fifth Edition. Blacklick, United States, McGraw-Hill Publishing.
Lallement, G., P. Carpentier, A. Collet, I. Pernot-Marino, D. Baubichon and G. Blanchet (1991), "Effects of soman-induced seizures on different extracellular amino acid levels and on glutamate uptake in rat hippocampus.” Brain Research 563(1-2). DOI: 10.1016/0006-8993(91)91539-D.
Liu, Z., C. E. Stafstrom, M. Sarkisian, P. Tandon, Y. Yang, A. Hori and G. L. Holmes (1996), "Age-dependent effects of glutamate toxicity in the hippocampus.” Brain Res Dev Brain Res 97(2).
McDonough, J. H., Jr. and T. M. Shih (1997), "Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology.” Neurosci Biobehav Rev 21(5).
Nedergaard, M., T. Takano and A. J. Hansen (2002), "Beyond the role of glutamate as a neurotransmitter.” Nature Reviews Neuroscience 3(9). DOI: 10.1038/nrn916.
Watson, C. J., B. J. Venton and R. T. Kennedy (2006), "In vivo measurements of neurotransmitters by microdialysis sampling.” Analytical Chemistry 78(5).