Glutamate – An Excitatory Neurotransmitter
Neurotransmitters are essential for transferring information between neurons and are released from a presynaptic terminal into a synaptic cleft. When the neurotransmitters bind to the postsynaptic receptors (specialized protein molecules that capture and react to molecules of the neurotransmitter), it induces an ionic flux which depolarizes the neuron. Neurotransmitter binding may also cause metabolic changes such as the activation of secondary messenger systems. Efficient neurotransmitters must satisfy two requirements: the level of neurotransmitter in the synaptic cleft must be kept low in order to maximize the signal-to-noise ratio upon binding of fresh transmitter to its receptor; and the second requirement is the rapid replacement of a transmitter that is released from a presynaptic terminal (Glutamate and Glutamine in the Brain, 2000). I am choosing glutamate as my neurotransmitter of choice, so in order for glutamate to be an efficient neurotransmitter, a low external signal-to-noise ratio must be preset in order to prevent excitotoxicity which can damage and even kill nearby neurons. Glutamate must also need to be removed from the synapse or it must have to be resynthesized within the
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presynaptic site. Glutamic acid is the most plentiful excitatory neurotransmitter in the central nervous system (CNS) and is special because it does not cross the blood brain barrier (Erecinska and Silver 1990). There are three types of ionotropic postsynaptic glutamate receptors that have been identified: the kainate, 2-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA), and N-methyl-D-aspartate (NMDA). There are also three types of metabotropic glutamine receptors (mGluR’s) which act more slowly because they act through secondary messengers. Glutamatergic neurons mediate many vital processes such as the formation and retrieval of memories, encoding of information, spacial recognition, and the maintenance of consciousness (McEntee and Crook 1993). As mentioned earlier, glutamine is associated with excitotoxicity, a phenomenon that normally leads to neural injury. An excess excitation of the glutamine receptors has been linked with hypoglycemia, stroke and epilepsy and other neurological disorders such as autism, ALS, Parkinson’s schizophrenia, migraines, restless leg syndrome, Tourette’s, fibromyalgia, and multiple sclerosis. Too much protein has also been linked to an increase in eosinophils (a certain type of white blood cell) which leads to inflammation, impairs blood vessels which can result in migraines and irregularities in blood pressure, and impair areas of the brain such as the hypothalamus, hippocampal neurons and purkinjie neurons which affect speech and language. There is a large correlation between the injury and the excessive excitation of the NMDA receptor, which allows very unhealthy and toxic levels of Ca2+ to enter the neurons (Kristian and Siesjo 1998). In contrast to glutamate, the amino acid transmitters gamma-aminobutyric acid (GABA) typically have the inhibitory effect. There are several types of GABA receptors (GABAA, GABAB and GABAC) although they are all usually referred to as GABA. GABAs primary roll is to calm down, slow down and relax the brain. Insufficient levels of GABA result in nervousness, anxiety and panic disorders, aggressive behavior, anti-social behavior, attention deficit, and much more. Low levels of GABA also play a role in alcoholism, drug addiction, and cravings for sugar and carbs, because these substances will temporarily and artificially increase GABA levels. However, these substances deplete neurotransmitters so this will only perpetuate the problem. GABA and glutamate must be in balance for the brain to function properly. The glutamate-glutamine cycle is extremely important in understanding the metabolism of glutamate in the brain (Hertz 1979, Norenberg and Martinez-Hernandez 1979, Shank and Aprison 1977). This cycle begins with the release of glutamine (Gln) by glial cells and is metabolized into glutamate (Glu) by the enzyme glutaminase in the presynaptic terminal. Glutamate is packed into synaptic vesicles in a process that requires both Mg2+ and ATP, and then is released into the synaptic cleft. Glutamate is then removed by receptors in the postsynaptic cells (called astrocytes) and transporters in glial cells. Glutamate is then converted, in the astrocyte, into glutamine by the protein glutamine synthetase through the glutamine synthesis pathway: Glutamate+NH_3+ATP→Glutamine+ADP+P_i This microsomal pathway is abundant in astrocytes (Martinez-Hernandez et al. 1977, Norenberg and Martinez-Hernandez 1979). The majority of the glutamine taken up into neurons undergoes hydrolysis to convert glutamine into glutamate and ammonia: Glutamine→Glutamate+NH_3 The figure provided above can help visualize this process but is clearly an oversimplification of what is actually taking place. In the excitotoxicity theory, glutamine exerts its effects by binding to specific receptors on nerve cells. To keep things simple, there will only be two types of glutamine receptors: NMDA (as introduced above) and non-NMDA receptors. Once glutamine binds to a receptor, it excited the cell causing the cell to increase its charge by having positive ions flow into the cell. This increase in charge causes changes in the neuron that ultimately result in the release of many neurotransmitters at the synaptic terminals at the end of the cell. People that have cells that are over activated by glutamate are said to have Huntingtin’s Disease (HD). Scientist believe that this over activation is due to the impairments in energy metabolism caused by the altered Huntingtin gene that people with HD obtain. The lack of energy in the cell leads to changes in the NMDA receptor. NMDA receptors are special in that they are able to let in large amounts of Ca2+ ions. Ca2+ ions are important mediators of glutamine’s toxic effects in HD patients. They are also different than many of the other receptors in that their opening is blocked by a Mg2+ ion. This Mg2+ ion is only removed when the charge inside a cell rises to a specific value. Non-NMDA receptors do not allow Ca2+ to enter into a cell and will open any time a glutamate molecule binds to them. NMDA receptors however, need a glutamate molecule to bind along with an increase in charge inside the cell before it opens. Normally, as glutamate is released by the nerve cell, it binds to both NMDA and non-NMDA receptors of the receiving nerve cell. Since non-NMDA receptors do not need an increase in change to open the channel, positively charge ions will move into the cell. Ion pumps inside the cell remove some of the ions so that the charge inside of the cell does not rise too rapidly (Stephanie Liou 2011). These ion pumps will only work if there is enough energy inside the cell since they are working against the gradient. Due to the ion pumps, it will take longer for the charge inside the cell to rise enough to remove the Mg2+ ion from the NMDA receptor and allow Ca2+ ions to flow in. In HD nerve cells, there is not enough energy for the ion pumps to work properly and prevent the increase of voltage inside a cell. This, in turn, enables fewer glutamate molecules to bind to non-NMDA receptors to increase the charge in a cell needed to remove the Mg2+ ion (Stephanie Liou 2011). This premature unblocking of the NMDA receptor causes too many Ca2+ ions to enter the cell that activate a number of enzymes including phospholipases, endonucleases, and proteases such as calpain which eventually leads to cell death. To sum this all up, the defective huntingtin protein causes the cell to not produce enough energy. This lack of energy results in an increase in the sensitivity of NMDA receptors to glutamate molecules. As more and more NMDA molecules become activated, too much Ca2+ enters the cell. The excess amounts of Ca2+ results in the activation of various molecules that will eventually lead to cell death. In another disorder called Amyotrophic Lateral Sclerosis (ALS) glutamine is not swiftly cleared from the nerve cell junctions. Scientists found that compared to healthy people, patients with ALS have higher levels of glutamate in the serum and spinal fluid (National Institute of Neurological Disorders and Stroke 2006). Molecules called transporters help in keeping glutamine in proper concentrations around nerve cells. There is a lot of evidence that points to glutamine as the destructive factor in ALS and researchers are diligently working on finding ways this can be changed (ALS Association 2006). In Alzheimer’s disease, there is a sustained release of low glutamate concentrations, from both neurons and surrounding glia cells, which displaces the magnesium ion from the NMDA receptor channel (as described above).
When the brain is operating normally, there is a transient synaptic release of glutamate that causes calcium to flow into the cell. This helps with learning and memory. However, since there is a constant flow of calcium ions into the brain, the signal can no longer be detected which leads to the occurrence of dementia symptoms. Over the course of the disease, there is a constant release of glutamate which permanently increases the flow of calcium into the cell, which eventually leads to neurological
deterioration. Parkinson’s disease occurs in a part of the brain called the subthelamic nucleus. Here, NMDA receptors become persistently overexcited and allow high levels of calcium ions to enter the brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and eventually cell damage. All these diseases are the result from an excess amount of glutamate in the brain, and all eventually lead to cell death. Fortunately, there are drugs that are capable of reducing the effects of glutamate in cells. These compounds either block glutamate receptors or reduce the amount of glutamate being released by other cells.
In the book, Crispin: The Cross of Lead, the protagonist Crispin faces many conflicts throughout the book in which he must conquer in order to find who he really is. These conflicts change Crispin as a character over the course of the book, as he overcomes them to find out his true self. One conflict for Crispin is person vs society where he becomes known as a wolf’s head and does not have any friends, or family. This is until he meets Bear who helps Crispin overcome this conflict. For example, John Aycliffe tries to find Crispin, but helps him get away. As the story develops Crispin saves Bear from John Aycliffe, showing their friendship.
When a chemical signal is transmitted, the presynaptic neuron releases a neurotransmitter into the synapse. The signal is then sent to the postsynaptic neuron. Once the postsynaptic neuron has received the signal, additional neurotransmitter left in the synapse will be reabsorbed by the presynaptic
Creutzfeldt-Jakob is a fatal, progrossive and incurable neurologic disorder which affects the brain in a destructive way. Globally, it attacks one person in every one million people. Specifically, at United State there are more than 300 cases per year. However, it is extremely complicated to diagnose, so the number of cases might get higher in the future. CJD (Creutzfeldt-Jakob disease) symptoms usually occur in later life for women and men whose ages are between 60 and 70. This essay displays a definition of Creutzfeldt-Jakob disease based on its identity, causes, symptoms, risk factors and treatment.
Dementia is a long-term condition that normally affects people aged 65 and over, younger people can be affected. Having dementia can cause loss of key functions to the brain, such as; loss of memory; confusion; speech and language problems; loss of ability to make judgements; loss of concentration; difficulty in processing information; changes in behaviour and personality. These all lead to a person not been able to function properly. The person’s ability to function deteriorates over a period of time and is usually at least 6 months before positive diagnosis of dementia can be made. Dementia is caused when the brain is damaged by diseases such as Alzheimer’s which is the most common of dementia, vascular which is a series of mini strokes,
Amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. Jean-Marie Charcot was the first to recognize ALS as a distinct neurological disease with its own unique pathology. In ALS, nerve cells degenerate and deteriorate, and are unable to transmit messages to muscles. In around 90% of the cases of ALS, the cause remains unknown. Studies have concentrated on the responsibility of glutamate in motor neuron degeneration. Glutamate is one of several neurotransmitters in the brain. While there is no known cure for ALS, strides in medicine have allowed for the development of a wide variety of medications to treat the various symptoms of ALS, as well as dietary, physical therapy, and breathing techniques, all of which can lessen symptoms and increase life expectancy.
Dementia can occur in relation to many different illnesses. Some of the most common of which are Huntington’s Disease,
Neurotransmitters are chemicals made by neurons and used by them to transmit signals to the other neurons or non-neuronal cells (e.g., skeletal muscle; myocardium, pineal glandular cells) that they innervate. The neurotransmitters produce their effects by being released into synapses when their neuron of origin fires (i.e., becomes depolarized) and then attaching to receptors in the membrane of the post-synaptic cells. This causes changes in the fluxes of particular ions across that membrane, making cells more likely to become depolarized, if the neurotransmitter happens to be excitatory, or less likely if it is inhibitory.
This disease causes memory loss, difficulty in thinking processes, mood swings, depression, hallucinations, personality changes, and the inability to create new memories. Alzheimer’s disease is most common in people who are at the age of sixty years or older, but it can start as early as the age of nineteen. It can be categorized as a type of dementia. “Scientists believe Alzheimer’s disease prevents parts of a cell’s factory from running well” (Alzheimer’s Disease: The basics). Scientist believe that one cause of Alzheimer’s could be caused by plaques and tangles. Plaques are the build up of a protein called beta-amyloid in the nerve cells. Tangles are twisted fibers of the tau protein that build up inside of a cell. The exact cause of Alzheimer’s has not yet been determined, but scientists have reason to believe that it is because these plaques and tangles are blocking the communication of cells in the nervous system. Another probable cause is a mutation on the chromosomal genes 21, 14, and 1. This is why it is believed to be a genetically inherited
Alzheimer’s disease is a progressive disease that destroys memory and other important mental functions. Alzheimer’s disease affects central nervous, neuromuscular, and digestive system. In the digestive system, swallowing difficulties are common for people who suffer from Alzheimer’s disease. In the neuromuscular system, the ability to walk and maintain their posture in a chair is common for people with Alzheimer’s. In Alzheimer’s disease, the connections between brain cells and the brain cells themselves deteriorate and die, which causes a steady decline in memory and mental function. It is the most common cause for dementia, which is a brain disorder that results in the loss of intellectual and social skills. (Staff, 2013) It is severe enough to interfere with every day activities. It is important to seek support through counseling and maintain medical assistance through medication or any other form of aid. Alzheimer’s disease is a condition that should be considered a priority in order to be able to maintain a decent lifestyle.
Ulta has a unique and revamped program that not only attracts consumers back, but offers birthday markdowns and other discounts. This reward system is called Ultamate Reward. Loyalty programs are made to build (an connection?) with customers, so they can feel comfortable coming back. The loyalty programs also allow consumers to earn points for every dollar they spend and earn double the points during consumers’ birthday month. These points can be redeemed with discount price for future transactions. Unlike Ulta, Sephora only allows consumers to redeem their points with product samples instead of discount prices. Ulta’s goal in this program is to “provide a level of transparency not found in many retail loyalty programs” (Jafari). Ulta sends
Dementia is an organic brain syndrome which results in global cognitive impairments. Dementia can occur as a result of a variety of neurological diseases. Some of the more well known dementing diseases include Alzheimer's disease (AD), multi-infarct dementia (MID), and Huntington's disease (HD). Throughout this essay the emphasis will be placed on AD (also known as dementia of the Alzheimer's type, and primary degenerative dementia), because statistically it is the most significant dementing disease occurring in over 50% of demented patients (see epidemiology).
Immunodeficiency diseases are any diseases that cause an absence or inadequate immune response. They usually effect the immune cells, T-cells, B-cells, complement cells, or phagocytes. Immunodeficiency disease can cause many complications in the body. The compromise of the immune system can eventually lead to death if it is not treated promptly and correctly. A rare immunodeficiency disease that can lead to death is Wiskott-Aldrich Syndrome.
It is the most common cause of premature senility. When a person has Alzheimer’s it slowly destroys the person's memory, along with different skills such as thinking skills. When you have Alzheimer’s your brain tissue will start to shrink and keep shrinking while creating holes in your brain. Out of everything your brain is mostly affected which makes it harder for the brain to communicate with the rest of your body. This makes the healthy neurons in the brain lose connections with other healthy neurons and die. As more of these neurons die, it affects more of the brain which causes the brain to shrink. While this is happening abnormal deposits of proteins from the amyloid plaques and tau tangles are being deposited in the brain.
Rationale: As explained in the background, CGRP activates adenylate cyclase increasing the cytosolic cAMP. My preliminary data show that cAMP potentiates increased Ca2+ influx into the SGNs synonymous with the synaptopathy. The preliminary experiments that showed CGRP might potentiate synptopathy was done by Qiong Wang, a former postdoc in our lab. Due to the lack of appropriate antibodies she had to count the axonal fibers instead of synapses. This method is obsolete now, as SGNs are found usually in bundles before they make synapses, which makes this method unreliable. I intend to redo the treatment with CGRP and cAMP in the organotypic culture
Synaptic transmission is the process of the communication of neurons. Communication between neurons and communication between neuron and muscle occurs at specialized junction called synapses. The most common type of synapse is the chemical synapse. Synaptic transmission begins when the nerve impulse or action potential reaches the presynaptic axon terminal. The action potential causes depolarization of the presynaptic membrane and it will initiates the sequence of events leading to release the neurotransmitter and then, the neurotransmitter attach to the receptor at the postsynaptic membrane and it will lead to the activate of the postsynaptic membrane and continue to send the impulse to other neuron or sending the signal to the muscle for contraction (Breedlove, Watson, & Rosenzweig, 2012; Barnes, 2013). Synaptic vesicles exist in different type, either tethered to the cytoskeleton in a reserve pool, or free in the cytoplasm (Purves, et al., 2001). Some of the free vesicles make their way to the plasma membrane and dock, as a series of priming reactions prepares the vesicular ...