Editing Excitatory synapse (section)

==Disease==

:Excitatory synapses have a fundamental role in information processing within the brain and throughout the peripheral nervous system.  Usually situated on dendritic spines, or neuronal membrane protrusions on which glutamate receptors and postsynaptic density components are concentrated, excitatory synapses aid in the electrical transmission of neuronal signals.<ref name="Annual Review of Biochemistry"/>   The physical morphology of synapses is crucial in understanding their function, and it is well documented that the inappropriate loss of synaptic stability leads to the disruption of neuronal circuits and the resulting neurological diseases.  Although there are innumerable different causes for different [[Neurodegeneration|neurodegenerative]] illnesses, such as genetic dispositions or [[mutations]], the normal aging process, [[Parasite|parasitic]] and [[Virus|viral]] causes, or drug use, many can be traced back to dysfunctional signaling between the neurons themselves, often at the synapse.<ref name="Neuroscience, 4th ed."/>

===Excitotoxicity===
{{main|Excitotoxicity}}

====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."/>

====Treatment====

:Excitotoxic mechanisms are often involved in other conditions leading to neuronal damage, including [[hypoglycemia]], [[trauma (medicine)|trauma]], [[stroke]], [[seizure]]s, and many neurodegenerative diseases, and thus have important implications in disease treatment.  Recent studies have been performed that incorporate glutamate [[receptor antagonist]]s and excitotoxic cascade disruptors in order to decrease stimulation of postsynaptic neurons, although these treatments are still undergoing active research.<ref name="Biochemical Pharmacology">{{cite journal |title=Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors |author1=M. Aarts |author2=M. Tymianski |date=2003-09-15 |doi=10.1016/S0006-2952(03)00297-1 |volume=66 |issue=6 |journal=Biochemical Pharmacology |pages=877–886 |pmid=12963474}}</ref>

===Related neurodegenerative diseases===

:[[Alzheimer's disease]] (AD) is the most common form of neurodegenerative [[dementia]], or loss of brain function, and was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1907. 9.	<ref name="Disease Management Project">{{cite web |url=http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/alzheimers-disease/ |title=Alzheimer's Disease |author1=J. Tavee |author2=P. Sweeney }}</ref>  Diagnosis of the disease often stems from clinical observation as well as analysis of family history and other risk factors, and often includes symptoms such as memory impairment and problems with language, decision-making, judgment, and personality.<ref name="Pub-Med Health: Diseases and Conditions">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001767/ |title=Alzheimer's Disease |date=2010-10-04}}</ref>  The primary neurological phenomena that lead to the above symptoms are often related to signaling at excitatory synapses, often due to excitotoxicity, and stem from the presence of [[amyloid plaque]]s and [[neurofibrillary tangle]]s, as well as neuronal cell death and synaptic pruning.  The principle drug treatments on the market deal with antagonizing glutamate (NMDA) receptors at neuronal synapses, and inhibiting the activity of [[acetylcholinesterase]].  This treatment aims to limit the apoptosis of cerebral neurons caused by various pathways related to excitotoxicity, free radicals, and energy rundown.  A number of labs are currently focusing on the prevention of amyloid plaques and other AD symptoms, often via the use of experimental [[vaccine]]s, although this area of research is yet in its infancy.<ref name="Disease Management Project"/>

[[File:Histological sample of Substantia nigra in Parkinson's disease.jpg|thumb|Histological brain sample of the Substantia Nigra in Parkinson's disease, showing the presence of Lewy bodies and other signs of neurodegeneration.]]

:[[Parkinson's disease]] (PD) is a neurodegenerative disease resulting from the apoptosis of [[dopamine|dopaminergic neurons]] in the central nervous system, especially the [[substantia nigra]], as well as heightened response to the excitatory neurotransmitter, glutamate (i.e., excitotoxicity).<ref name="Parkinsonism and Related Disorders">{{cite journal |title=Excitotoxicity and New Antiglutamatergic Strategies in Parkinson's disease and Alzheimer's disease |author1=E. Koutsilieri |author2=P. Riederera |year=2007 |doi=10.1016/S1353-8020(08)70025-7 |pmid=18267259 |volume=13 |journal=Parkinsonism & Related Disorders |pages=S329–S331}}</ref>  While the most obvious symptoms are related to motor skills, prolonged progression of the disease can lead to cognitive and behavioral problems as well as dementia.  Although the mechanism of apoptosis in the brain is not entirely clear, speculation associates cell death with abnormal accumulation of [[ubiquitin]]ated proteins in cell occlusions known as [[Lewy body|Lewy bodies]], as well as hyperstimulation of neuronal NMDA receptors with excessive glutamate neurotransmitter via the aforementioned pathway.<ref name="Parkinsonism and Related Disorders"/>  Like Alzheimer's, Parkinson's Disease lacks a cure.  Therefore, in addition to lifestyle changes and surgery, the goal of pharmaceutical drugs used in the treatment of PD patients is to control symptoms and limit, when possible, the progression of the disease.  [[Levodopa|Levodopa (L-DOPA)]], the most widely used treatment of PD, is converted to dopamine in the body and helps to relieve the effect of decreased dopaminergic neurons in the central nervous system.  Other dopamine [[agonist]]s have been administered to patients in an effort to mimic dopamine’s effect at excitatory synapses, binding its receptors and causing the desired postsynaptic response.<ref name="Pub-Med Health: Diseases and Conditions – PD">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001762/ |title=Parkinson's Disease |year=2011}}</ref>