Editing Excitatory synapse (section)

====Pathophysiology====

:Since glutamate is the most common excitatory neurotransmitter involved in synaptic neuronal transmission, it follows that disruptions in the normal functioning of these pathways can have severe detrimental effects on the nervous system.  A major source of cellular stress is related to glutaminergic overstimulation of a postsynaptic neuron via excessive activation of glutamate receptors (i.e., [[NMDA Receptor|NMDA]] and [[AMPA Receptor|AMPA]] receptors), a process known as excitotoxicity, which was first discovered accidentally by D. R. Lucas and J. P. Newhouse in 1957 during experimentation on sodium-fed lab mice.<ref name="Neuroscience, 4th ed."/>

:Under normal conditions, extracellular glutamate levels are held under strict control by surrounding neuronal and [[glial cell]] [[Membrane transport protein|membrane transporters]], rising to a concentration of about 1 mM and quickly falling to resting levels.<ref name="Science Daily">{{cite web |url=https://www.sciencedaily.com/articles/e/excitotoxicity.htm |title=Excitotoxicity and Cell Damage |year=2010}}</ref>  These levels are maintained via the recycling of glutamate molecules in the neuronal-glial cell process known as the [[glutamate–glutamine cycle]], in which glutamate is [[Chemical synthesis|synthesized]] from its precursor [[glutamine]] in a controlled manner in order to maintain an adequate supply of the neurotransmitter.<ref name="Neuroscience, 4th ed."/> However, when glutamate molecules in the synaptic cleft cannot be degraded or reused, often due to dysfunction of the glutamate–glutamine cycle, the neuron becomes significantly overstimulated, leading to a neuronal cell death pathway known as [[apoptosis]].  Apoptosis occurs primarily via the increased intracellular concentrations of calcium ions, which flow into the cytosol through the activated glutamate receptors and lead to the activation of [[phospholipase]]s, [[endonuclease]]s, [[protease]]s, and thus the apoptotic cascade. Additional sources of neuronal cell death related to excitotoxicity involve energy rundown in the [[mitochondria]] and increased concentrations of reactive [[Reactive oxygen species|oxygen]] and [[reactive nitrogen species|nitrogen]] species within the cell.<ref name="Neuroscience, 4th ed."/>