Related Research Articles
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.
In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.
CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.
Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.
Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.
Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.
Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.
Long-term potentiation (LTP), thought to be the cellular basis for learning and memory, involves a specific signal transmission process that underlies synaptic plasticity. Among the many mechanisms responsible for the maintenance of synaptic plasticity is the cadherin–catenin complex. By forming complexes with intracellular catenin proteins, neural cadherins (N-cadherins) serve as a link between synaptic activity and synaptic plasticity, and play important roles in the processes of learning and memory.
Memory allocation is a process that determines which specific synapses and neurons in a neural network will store a given memory. Although multiple neurons can receive a stimulus, only a subset of the neurons will induce the necessary plasticity for memory encoding. The selection of this subset of neurons is termed neuronal allocation. Similarly, multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on to encode the memory, and this process is referred to as synaptic allocation. Memory allocation was first discovered in the lateral amygdala by Sheena Josselyn and colleagues in Alcino J. Silva's laboratory.
Nitromemantine is a derivative of memantine developed in 2006 for the treatment of Alzheimer's disease. It has been shown to reduce excitotoxicity mediated by over-activation of the glutamatergic system, by blocking NMDA receptors.
Hilmar Bading is a German physician and neuroscientist. He is a member of the German National Academy of Science Leopoldina.
The concentration of calcium in the cell nucleus can increase in response to signals from the environment. Nuclear calcium is an evolutionary conserved potent regulator of gene expression that allows cells to undergo long-lasting adaptive responses. The 'Nuclear Calcium Hypothesis’ by Hilmar Bading describes nuclear calcium in neurons as an important signaling end-point in synapse-to-nucleus communication that activates gene expression programs needed for persistent adaptations. In the nervous system, nuclear calcium is required for long-term memory formation, acquired neuroprotection, and the development of chronic inflammatory pain. In the heart, nuclear calcium is important for the development of cardiac hypertrophy. In the immune system, nuclear calcium is required for human T cell activation. Plants use nuclear calcium to control symbiosis signaling.
Extrasynaptic NMDA receptors are glutamate-gated neurotransmitter receptors that are localized to non-synaptic sites on the neuronal cell surface. In contrast to synaptic NMDA receptors that promote acquired neuroprotection and synaptic plasticity, extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways. Extrasynaptic NMDA receptors are responsible for initiating excitotoxicity and have been implicated in the etiology of neurodegenerative diseases, including stroke, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
R. Suzanne Zukin is an American neuroscientist and a professor of neuroscience who directs a research lab as a F. M. Kirby Chair in Neural Repair and Protection and director of the Neuropsychopharmacology Center at Albert Einstein College of Medicine. Zukin's areas of research include neurodegenerative disorders, Ischemia, Epigenetics and Autism and uses molecular biology approaches to research these disorders. Zukin has made seminal contributions to the understanding of NMDA and AMPA receptor function and activity.
References
- 1 2 Zhang, Sheng-Jia; Zou, Ming; Lu, Li; Lau, David; Ditzel, Désirée A. W.; Delucinge-Vivier, Celine; Aso, Yoshinori; Descombes, Patrick; Bading, Hilmar (2009-08-01). "Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity". PLOS Genetics. 5 (8): e1000604. doi: 10.1371/journal.pgen.1000604 . ISSN 1553-7404. PMC 2718706 . PMID 19680447.
- ↑ Zhang, Sheng-Jia; Buchthal, Bettina; Lau, David; Hayer, Stefanie; Dick, Oliver; Schwaninger, Markus; Veltkamp, Roland; Zou, Ming; Weiss, Ursula (2011-03-30). "A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage". The Journal of Neuroscience. 31 (13): 4978–4990. doi: 10.1523/JNEUROSCI.2672-10.2011 . ISSN 1529-2401. PMC 6622995 . PMID 21451036.
- ↑ Lau, David; Bengtson, C. Peter; Buchthal, Bettina; Bading, Hilmar (2015-08-25). "BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A". Cell Reports. 12 (8): 1353–1366. doi: 10.1016/j.celrep.2015.07.038 . ISSN 2211-1247. PMID 26279570.
- ↑ Hardingham, G. E.; Fukunaga, Y.; Bading, H. (2002-05-01). "Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways". Nature Neuroscience. 5 (5): 405–414. doi:10.1038/nn835. ISSN 1097-6256. PMID 11953750. S2CID 659716.
- ↑ Hardingham, Giles E.; Bading, Hilmar (2010-10-01). "Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders". Nature Reviews. Neuroscience. 11 (10): 682–696. doi:10.1038/nrn2911. ISSN 1471-0048. PMC 2948541 . PMID 20842175.