An excitatory synapse is a synapse

Synapse

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

 in which an action potential

Action potential

In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

 in a presynaptic neuron

Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

 increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travel, each neuron often making numerous connections with other cells. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will “fire,” that is, it will generate a new action potential at its axon hillock

Axon hillock

The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. As a result, the axon hillock is the last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many years it was believed...

, thus transmitting the information to yet another cell.

This phenomenon is known as an excitatory postsynaptic potential (EPSP). It may occur via direct contact between cells (i.e., via gap junction

Gap junction

A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells....

s), as in an electrical synapse

Electrical synapse

An electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic neurons known as a gap junction. At gap junctions, such cells approach within about 3.5 nm of each other, a much shorter...

, but most commonly occurs via the vesicular release of neurotransmitter

Neurotransmitter

Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s from the presynaptic axon

Axon

An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

 terminal into the synaptic cleft, as in a chemical synapse

Chemical synapse

Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...

.

The excitatory neurotransmitters, the most common of which is glutamate, then migrate via diffusion

Diffusion

Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...

 to the dendritic spine

Dendritic spine

A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...

 of the postsynaptic neuron and bind a specific transmembrane receptor

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 protein that triggers the depolarization

Depolarization

In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...

 of that cell. Depolarization, a deviation from a neuron’s resting membrane potential

Membrane potential

Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...

 towards its threshold potential

Threshold potential

The threshold potential is the membrane potential to which a membrane must be depolarized to initiate an action potential.It often can be between −40 and -55 mV, but it can vary based upon several factors...

, increases the likelihood of an action potential and normally occurs with the influx of positively charged sodium

Sodium

Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 (Na⁺) ions into the postsynaptic cell through ion channels activated by neurotransmitter binding.

Chemical vs electrical synapses

There are two different kinds of synapses present within the human brain: chemical and electrical. Chemical synapses are by far the most prevalent and are the main player involved in excitatory synapses. Electrical synapses, the minority, allow direct, passive flow of electrical current through special intercellular connections called gap junctions. These gap junctions allow for virtually instantaneous transmission of electrical signals through direct passive flow of ions between neurons (transmission can be bidirectional). The main goal of electrical synapses is to synchronize electrical activity among populations of neurons. The first electrical synapse was discovered in a crayfish

Caridoid escape reaction

The Caridoid Escape Reaction, also known as lobstering or tail-flipping, refers to an innate escape mechanism in marine and freshwater crustaceans such as lobsters, krill, shrimp and crayfish....

 nervous system.

Chemical synaptic transmission is the transfer of neurotransmitters or neuropeptides from a presynaptic axon to a postsynaptic axon. Unlike an electrical synapse, the chemical synapses are separated by a space called the synaptic cleft, typically measured between 15 and 25 nm. Transmission of an excitatory signal involves several steps outlined below.

Synaptic transmission

1. In neurons that are involved in chemical synaptic transmission, neurotransmitters are synthesized either in the neuronal cell body, or within the presynaptic terminal, depending on the type of neurotransmitter being synthesized and the location of enzymes involved in its synthesis. These neurotransmitters are stored in synaptic vesicles
   Synaptic vesicle
   In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
   
    that remain bound near the membrane by calcium-influenced proteins
   Synapsin
   The synapsins are a family of proteins that have long been implicated in the regulation of neurotransmitter release at synapses. Specifically, they are thought to be involved in regulating the number of synaptic vesicles available for release via exocytosis at any one time.Current studies suggest...
   
   .
2. In order to trigger the process of chemical synaptic transmission, upstream activity causes an action potential to invade the presynaptic terminal.
3. This depolarizing current reaches the presynaptic terminal, and the membrane depolarization that it causes there initiates the opening of voltage-gated calcium channels present on the presynaptic membrane.
4. There is high concentration of calcium
   Calcium
   Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
   
    in the synaptic cleft between the two participating neurons (presynaptic and postsynaptic). This difference in calcium concentration between the synaptic cleft and the inside of the presynaptic terminal establishes a strong concentration gradient that drives the calcium into the presynaptic terminal upon opening of these voltage-gated calcium channels. This influx of calcium into the presynaptic terminal is necessary for neurotransmitter release.
5. After entering the presynaptic terminal, the calcium binds a protein called synaptotagmin
   Synaptotagmin
   Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
   
   , which is located on the membrane of the synaptic vesicles. This protein interacts with other proteins called SNAREs
   SNARE (protein)
   SNARE proteins are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells....
   
    in order to induce vesicle fusion with the presynaptic membrane. As a result of this vesicle fusion, the neurotransmitters that had been packaged into the synaptic vesicle are released into the synapse, where they diffuse across the synaptic cleft.
6. These neurotransmitters bind to a variety of receptors on the postsynaptic cell membrane. In response to neurotransmitter binding, these postsynaptic receptors can undergo conformational changes that may open a transmembrane channel subunit either directly, or indirectly via a G-Protein signaling pathway. The selective permeability of these channels allow certain ions to move along their electrochemical gradients, inducing a current across the postsynaptic membrane that determines an excitatory or inhibitory response.

Responses of the postsynaptic neuron

When neurotransmitters reach the postsynaptic neuron of an excitatory synapse, these molecules can bind to two possible types of receptors that are clustered in a protein-rich portion of the postsynaptic cytoskeleton

Cytoskeleton

The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

 called the Postsynaptic density

Postsynaptic density

The postsynaptic density is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron...

 (PSD). Ionotropic receptors, which are also referred to as ligand-gated ion channel

Ligand-gated ion channel

Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...

s, contain a transmembrane domain that acts as an ion channel and can directly open after binding of a neurotransmitter. Metabotropic receptor

Metabotropic receptor

Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...

s, which are also called G-protein-coupled receptors, act on an ion channel through the intracellular signaling of a molecule called a G protein

G protein

G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...

. Each of these channels has a specific reversal potential

Reversal potential

In a biological membrane, the reversal potential of an ion is the membrane potential at which there is no net flow of that particular ion from one side of the membrane to the other...

, E_rev, and each receptor is selectively permeable to particular ions that flow either into or out of the cell in order to bring the overall membrane potential to this reversal potential. If a neurotransmitter binds to a receptor with a reversal potential that is higher than the threshold potential for the postsynaptic neuron, the postsynaptic cell will be more likely to generate an action potential and an excitatory postsynaptic potential will occur (EPSP). On the other hand, if the reversal potential of the receptor to which the neurotransmitter binds is lower than the threshold potential, an inhibitory postsynaptic potential

Inhibitory postsynaptic potential

An inhibitory postsynaptic potential is a synaptic potential that decreases the chance that a future action potential will occur in a postsynaptic neuron or α-motoneuron...

 will occur (IPSP).

Although the receptors at an excitatory synapse strive to bring the membrane potential towards their own specific E_rev, the probability that the single stimulation of an excitatory synapse will raise the membrane potential past threshold and produce an action potential is not very high. Therefore, in order to achieve threshold and generate an action potential, the postsynaptic neuron has the capacity to add up all of the incoming EPSPs based on the mechanism of summation

Summation (neurophysiology)

Summation, also known as frequency summation is the method of signal transduction between neurons, which determines whether or not an action potential will be triggered by the summation of postsynaptic potentials. Neurotransmitters emitting from the terminals of a presynaptic neuron fall under one...

, which can occur in time and space. Temporal summation occurs when a particular synapse is stimulated at a high frequency, which causes the postsynaptic neuron to sum the incoming EPSPs and thus increases the chance of the neuron firing an action potential. In a similar way, the postsynaptic neuron can sum together EPSPs from multiple synapses with other neurons in a process called spatial summation.

Acetylcholine

Acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 (ACh) is an excitatory, small-molecule neurotransmitter involved in synaptic transmission at neuromuscular junction

Neuromuscular junction

A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...

s controlling the vagus nerve

Vagus nerve

The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...

 and cardiac muscle

Cardiac muscle

Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...

 fibers, as well as in the skeletal and visceral motor system

Motor system

The motor system is the part of the central nervous system that is involved with movement. It consists of the pyramidal and extrapyramidal system....

s and various sites within the central nervous system. This neurotransmitter crosses the synaptic cleft and binds to a variety of postsynaptic receptors depending on the species

Species

In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...

, but all of these receptors depolarize the postsynaptic membrane and thus classify ACh as an excitatory neurotransmitter.

Glutamate

Glutamate

Glutamic acid

Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

 is a small, amino acid neurotransmitter, and is the primary excitatory neurotransmitter at almost all synapses in the central nervous system. This molecule binds multiple postsynaptic receptors including the NMDA receptor

NMDA receptor

The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

, AMPA receptor

AMPA receptor

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...

, and kainate receptor

Kainate receptor

Kainate receptors, or KARs, are non-NMDA ionotropic receptors which respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from red algae Digenea simplex. KARs are less well...

s. These receptors are all cation channels

Ion channel

Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...

 that allow positively charged ions such as Na⁺, K⁺, and sometimes Ca²⁺ into the postsynaptic cell, causing a depolarization that excites the neuron.

Catecholamines

The catecholamine

Catecholamine

Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...

s, which include Epinephrine

Epinephrine

Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

, Norepinephrine

Norepinephrine

Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, and Dopamine

Dopamine

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

, are excitatory biogenic amine neuromodulators

Neuromodulation

In Neuromodulation several classes of neurotransmitters regulate diverse populations of central nervous system neurons...

 that are derived from the amino acid tyrosine

Tyrosine

Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 and serve as excitatory neurotransmitters are various locations in the central nervous system as well as the peripheral nervous system

Peripheral nervous system

The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...

. Epinephrine and norepinephrine, also called adrenaline and noradrenaline, respectively, bind a number of G-protein-coupled receptors that induce their depolarizing effects on the postsynaptic cell in various ways, including activating and inactivating certain K⁺ channels. Epinephrine is found in the lateral tegmental system

Tegmentum

The tegmentum is a general area within the brainstem. It is located between the ventricular system and distinctive basal or ventral structures at each level...

, medulla

Medulla oblongata

The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...

, hypothalamus

Hypothalamus

The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

, and thalamus

Thalamus

The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...

 of the central nervous system, but their function is not fully understood. Norepinephrine is found in the brain stem

Brain stem

In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...

 and is involved in sleep and wakefulness, feeding behavior, and attention. Dopamine binds to G-protein-coupled receptors in many areas of the brain, especially the corpus striatum where it mediates the synaptic transmission that underlies the coordination of body movements.

Serotonin

Serotonin

Serotonin

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 is an excitatory neurotransmitter that regulates sleep and wakefulness and is found in neurons of the raphe

Raphe nuclei

The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...

 region of the pons and upper brain stem, which extend into the forebrain. Serotonin binds a number of receptors, including the 5-HT₃ receptors, which are ligand-gated ion channels that allow the passage of cations in order to depolarize the membrane potential of the postsynaptic neuron that they reside on. Levels of serotonin activity that are lower than normal have been linked to a variety of symptoms, especially depression, which is why many antidepressant drugs

Antidepressant

An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

 act to increase serotonin activity.

Histamine

Histamine

Histamine

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

 acts as an excitatory neurotransmitter by binding G-protein coupled receptors in neurons of the hypothalamus. These neurons project into many regions of the brain and spinal cord, allowing histamine to mediate attention, arousal, and allergic responses

Allergy

An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

. Of the four types of histamine receptors (H₁ - H₄), H₃ is found in the central nervous system and is responsible for regulating histamine effects on neurotransmission.

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. 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 neurodegenerative

Neurodegeneration

Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...

 illnesses, such as genetic dispositions or mutations, the normal aging process, parasitic and viral

Virus

A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 causes, or drug use, many can be traced back to dysfunctional signaling between the neurons themselves, often at the synapse.

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

NMDA receptor

The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

 and AMPA

AMPA receptor

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog 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.

Under normal conditions, extracellular glutamate levels are held under strict control by surrounding neuronal and glial cell

Glial cell

Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...

 membrane transporters, rising to a concentration of about 1 mM and quickly falling to resting levels. These levels are maintained via the recycling of glutamate molecules in the neuronal-glial cell process known as the glutamate-glutamine cycle

Glutamate-glutamine cycle

In biochemistry, the glutamate-glutamine cycle is a sequence of events by which an adequate supply of the neurotransmitter glutamate is maintained in the central nervous system....

, in which glutamate is synthesized

Chemical synthesis

In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 from its precursor glutamine

Glutamine

Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...

 in a controlled manner in order to maintain an adequate supply of the neurotransmitter. 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

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. 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

Phospholipase

A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

s, endonuclease

Endonuclease

Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain, in contrast to exonucleases, which cleave phosphodiester bonds at the end of a polynucleotide chain. Typically, a restriction site will be a palindromic sequence four to six nucleotides long. Most...

s, protease

Protease

A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

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 oxygen

Reactive oxygen species

Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 and nitrogen

Reactive nitrogen species

Reactive nitrogen species are a family of antimicrobial molecules derived from nitric oxide and superoxide produced via the enzymatic activity of inducible nitric oxide synthase 2 and NADPH oxidase respectively...

 species within the cell.

Treatment

Excitotoxic mechanisms are often involved in other conditions leading to neuronal damage, including hypoglycemia

Hypoglycemia

Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

, trauma

Trauma (medicine)

Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...

, stroke

Stroke

A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

, seizure

Seizure

An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s, and many neurodegenerative diseases, and thus have important implications in disease treatment. Recent studies have been performed that incorporate glutamate receptor antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

s and excitotoxic cascade disruptors in order to decrease stimulation of postsynaptic neurons, although these treatments are still undergoing active research.

Related neurodegenerative diseases

Alzheimer’s Disease (AD) is the most common form of neurodegenerative dementia

Dementia

Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

, or loss of brain function, and was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1907. 9. 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. 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 plaques and neurofibrillary tangle

Neurofibrillary tangle

Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...

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

Acetylcholinesterase

"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...

. 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

Vaccine

A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

s, although this area of research is yet in its infancy.

Parkinson’s Disease (PD) is a neurodegenerative disease resulting from the apoptosis of dopaminergic neurons

Dopamine

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 in the central nervous system, especially the substantia nigra

Substantia nigra

The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...

, as well as heightened response to the excitatory neurotransmitter, glutamate (i.e., excitotoxicity). 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

Ubiquitin

Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...

ated proteins in cell occlusions known as Lewy bodies

Lewy body

Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....

, as well as hyperstimulation of neuronal NMDA receptors with excessive glutamate neurotransmitter via the aforementioned pathway. 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 (L-DOPA)

Levodopa

L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...

, 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

Agonist

An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

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.

See also

• Inhibitory synapse
• Neurotransmission
  Neurotransmission
  Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
  
  
• Neuroscience
  Neuroscience
  Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
  
  
• Synaptogenesis
  Synaptogenesis
  Synaptogenesis is the formation of synapses. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development...
  
  
• Electrophysiology
  Electrophysiology
  Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
  
  
• Neurotoxicity
  Neurotoxicity
  Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...