Dissertations / Theses on the topic 'D-aspartate'
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1
Carlson, Stephen Lee. "Characterization of D-Aspartate Receptor Currents in Aplysia californica." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/478.
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D-Aspartate (D-Asp) is an endogenous compound found in the central nervous system (CNS) of a variety of organisms. Despite its prevalence, however, relatively little understood of its physiological role. The prevailing theory is that D-Asp is an alternate agonist of N-methyl-D-aspartate receptor (NMDAR) channels. The goal of this work was to characterize the currents activated by D-Asp in neurons Aplysia californica, focusing on cells of the buccal S cluster (BSC). First, a general electrophysiological characterization was carried out, examining ion permeability, agonist dose-response, and the kinetics of activation, inactivation, and desensitization. D-Asp activated non-specific cation currents characterized by permeability to Na+ and K+. D-Asp-induced currents shared similar current-voltage relationships and time courses of activation and inactivation with L-glutamate (L-Glu)-induced currents. D-Asp currents, however, were subject to prolonged desensitization. Additionally, D-Asp activated currents independently of L-Glu, the known agonist of NMDAR channels, suggesting a non-NMDAR-dependent role of D-Asp. Next, select antagonists were used in an effort to pharmacologically characterize D-Asp receptor channels. These experiments suggested that D-Asp whole cell currents may be characterized by activation of multiple receptor sites, including NMDARS, excitatory amino acid transporters (EAATs), and a putative non-L-Glu D-Asp receptor. Furthermore, bath-applied D-Asp attenuated L-Glu-activated currents. Finally, D-Asp currents were compared to those evoked by acetylcholine (ACh) and serotonin (5-HT) in BSC cells. Results suggested that D-Asp activated receptor channels independently of ACh and 5-HT. Ten minute bath application of 5-HT was found to potentiate D-Asp current responses, likely through activation of a protein kinase C (PKC)-dependent mechanism, suggesting that D-Asp induced currents may be subject to synaptic plasticity associated with learning. While the identity of the putative D-Asp receptor remains elusive, the current work has advanced our understanding of the role D-Asp may play in the nervous system. These results should provide the groundwork for future studies aimed at identifying this unknown receptor channel, as well as investigation of the potential relationship of D-Asp receptor modulation to learning and memory in Aplysia, which may have relevance in higher organisms.
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Sim, Neil. "Molecular imaging probes for N-methyl-D-aspartate receptors." Thesis, Durham University, 2014. http://etheses.dur.ac.uk/10816/.
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The non-invasive detection of neuronal transmission is of prime importance in order to understand brain function better. This will aid cognitive neuroscience, as well as medical science, in the early detection of diseased states. Herein, approaches to molecular imaging of the NMDA receptor, a receptor subtype of the excitatory neurotransmitter glutamate, through the use of targeted contrast agents, is described. Initially, a series of NMDA receptor-targeted MRI contrast agents was developed based upon a known competitive NMDA receptor antagonist, appended to an N-linked ‘Gd-DOTA’ core that possesses a fast-exchanging water molecule. Their use as responsive MR imaging probes was evaluated in vitro using a neuronal cell line model, and three contrast agents showed large enhancements in cellular relaxation rates. In order to confirm NMDA receptor localisation, derivatives of the lead compounds were also prepared. The derivatives contained a biotin moiety, which allowed direct visualisation of the cell-surface receptors, after addition of an AvidinAlexaFluor®-488 conjugate. Using these derivatives, the specificity and reversibility (in the presence of glutamate) of binding at the NMDA receptor was demonstrated in living cells using laser scanning confocal microscopy. In an attempt to generate a single-component NMDA receptor-targeted optical imaging agent, a very bright europium complex conjugated to an NMDA receptor-binding moiety was synthesised. Unfortunately, upon incubation with a neuronal cell line model, complex localisation appeared to be dictated by the ligand structure and not by the receptor-binding moiety. One emerging imaging technique with potential applications in neuronal imaging is photoacoustic imaging. Two NMDA receptor-targeted photoacoustic imaging agents were synthesised and their ability to label NMDA receptors assessed in vitro. Finally, preliminary in vivo evaluation of the most promising photoacoustic imaging agent is described.
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Bera, Katarzyna D. "Autoantibodies to N-methyl D-aspartate receptors in autoimmune encephalitis." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:6bbda982-ab5c-4982-b23a-0478c689869c.
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N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a recently described autoimmune encephalopathy defined by the presence of serum antibodies that bind NMDARs (NMDAR-Abs). NMDAR-Ab encephalitis is a severe, but treatmentresponsive encephalitis with subacute onset. It can be associated with tumours and affects mainly young adults. Patients present with cognitive dysfunction, seizures, psychiatric and sleep disorders and most develop dyskinesias, autonomic instability and reduced consciousness. To explore further the NMDAR-Abs and their potential pathogenicity, a series of in vitro investigations were performed and preliminary attempts at passive transfer of disease. Human embryonic kidney (HEK) cells transfected with the NR1 and NR2B subunits, and live cultured neurons, were used first to detect NMDAR-Ab binding. Immunocytochemistry and ow cytometry demonstrated that binding to transfected HEK cells could be improved when NMDAR were presented in clusters by cotransfection with the postsynaptic density protein PSD-95. The NR1 subunit was identified as the target of NMDAR-Abs, and a novel quantitative assay based on immunoprecipitation of NR1 tagged by fusion with green uorescent protein was developed. Measurement of NMDAR-Ab levels showed that antibody levels corresponded to the clinical disease score within individual patients. Although the purification of full length NR1 was not successful, a secreted N-terminal construct was created and expressed in HEK cells. The binding of NMDAR-Abs was confirmed and this construct will be used for active immunisation in future. To explore pathogenic mechanisms in vitro, the main antibody subclasses were shown to be IgG1 and IgG3. Moreover the patients' autoantibodies, but not healthy control antibodies, were able to activate the complement cascade in vitro in cell lines and primary cultures. Finally, the NMDAR-Abs were shown to bind to primary microglial cultures and to cause morphological changes corresponding to early activation processes after prolonged exposure. The research has developed new assays that could be used for diagnosis and serial studies and revealed new potential mechanisms in NMDAR-Ab encephalitis.
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Yassin, Maged M. I. "N-methyl-D-aspartate, anoxia and glutamate antagonists in mammalian brain." Thesis, Queen's University Belfast, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241524.
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Wu, Y. "Extrasynaptic signalling and plasticity mediated by N-Methyl-D-aspartate receptors." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1369568/.
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Synaptic N-Methyl-D-aspartate receptors (NMDARs) are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs located on the dendritic shaft. Here we find that in CA1 pyramidal neurons backpropagating action potentials (bAPs) recruit shaft NMDARs exposed to ambient glutamate of non-vesicular origin. In contrast, spine NMDARs are "protected" under baseline conditions from such glutamate by perisynaptic transporters: bAP-evoked Ca2+ entry through these receptors can be detected upon synaptic glutamate release or local glutamate uncaging. During theta-burst firing, NMDAR-dependent Ca2+ entry either upregulates or downregulates an h-channel conductance (Gh) of the cell depending on whether synaptic glutamate release is intact or blocked. Gh plasticity in turn regulates dendritic input probed by local glutamate uncaging. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of Gh-dependent plasticity. These results uncover a novel meta-plasticity mechanism potentially important for neural coding and memory formation.
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Lui, Pik Wa. "Modulation of N-methyl-D-aspartate receptor expression in neuronal cell culture." HKBU Institutional Repository, 2002. http://repository.hkbu.edu.hk/etd_ra/419.
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LeMaistre, Jillian. "Regulation of brain blood flow by astrocyte D-serine and N-methyl-D-aspartate receptors." Journal of Cerebral Blood Flow and Metabolism, 2012. http://hdl.handle.net/1993/8585.
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Functional hyperemia is an endogenous regulatory process coupling synaptic activity and elevated neuronal energy demand with increased local blood flow. This involves signalling between neurons, astrocytes and blood vessels, comprising the neurovascular unit. Astrocyte processes ensheath both synapses and blood vessels, permitting multi-modal responses to synaptic activity, where astrocyte cytoplasmic Ca2+ is elevated, triggering endfeet processes to release vasoactive molecules, such as arachidonic acid (AA) metabolites and gliotransmitters, such as D-serine. D-Serine is a co-agonist of the glycine regulatory site at N-methyl-D-aspartate (NMDA)-type glutamate receptors, and NMDA receptors play a role in functional hyperemia in vivo. Thus, our aim was to examine the role of astrocyte D-serine in NMDA receptor-mediated vasodilation. Using isolated pressurized mouse middle cerebral arteries (MCAs), we determined that co-application of glutamate and D-serine induced dose-dependent dilation which was mediated by NMDA receptors and endothelial nitric oxide synthase (eNOS) in an endothelial-dependent mechanism. This is the first evidence of direct vascular effects of D-serine and glutamate and suggests a possible role for endothelial NMDA receptor activation. Several studies indicate vascular endothelial cells express NMDA receptor subunits. However, expression in mouse endothelial cells has not been well characterized, so we identified NR1 and NR2C/2D subunit expression in primary brain endothelial cultures by PCR and immunocytochemistry, and further confirmed endothelial NR2C/2D expression in situ by immunohistochemistry. To further investigate astrocyte D-serine release and NMDA receptor-mediated functional hyperemia within the neurovascular unit, we used an acute cortical brain slice model where stimulation of astrocyte cytoplasmic Ca2+ induced vasodilation of nearby arterioles. Pharmacologically, D-serine release and NMDA receptor activation were implicated in this vasodilation. Endothelial-derived nitric oxide was also determined to induce dilation by inhibiting the production of an AA metabolite, 20-hydroxyeicostetranoic acid (20-HETE), a vasoconstrictor. This suggests an interaction between astrocyte vasoactive molecules, nitric oxide and D-serine, which warrants further investigation. Overall, our results provide evidence of modulation of NMDA receptor-mediated neurovascular coupling by astrocytic D-serine.
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Rutter, Anthony Richard. "Biochemical and pharmacological characterisation of the interaction between NMDA receptors and the scaffolding protein PSD-95." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248043.
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Kotecha, Suhas Ashok. "G-protein coupled receptor modulation of N-methyl-D-aspartate channel activity." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ63766.pdf.
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Tofighy, Azita. "N-methyl-d-aspartate receptor desensitisation and anoxia in rat olfactory cortex." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361309.
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Torres, Jacques-Henri. "Récepteur au n-méthyl-d-aspartate et souffrance neuronale du coma hypoglycémique." Montpellier 1, 1988. http://www.theses.fr/1988MON11381.
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Elhallaoui, Menana. "Modélisation moléculaire d'antagonistes non compétitifs du récepteur NMDA [N-Méthyl-D-aspartate]." Bordeaux 2, 1994. http://www.theses.fr/1994BOR2B003.
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Nixon, Kimberly. "N-methyl-D-aspartate receptor subunit expression following perinatal exposure to ethanol /." Digital version accessible at:, 2000. http://wwwlib.umi.com/cr/utexas/main.
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Paliouras, Grigorios Nikiforos. "Effect of ethanol on the Jak-Stat pathway : is this an NMDA mediated event?" Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79062.
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Alcohol affects many neurochemical processes, causing long-lasting changes in both the adult and developing brain. The Jak-Stat transcriptional activation pathway plays a role in the control of neuronal proliferation, survival and differentiation, but the effects of ethanol on the system have not been fully elucidated. The goal of this project was to define the effects of acute and subchronic ethanol exposure on the expression of proteins in the Jak-Stat pathway, using cultured NG108-15 cells, and in addition, to test the hypothesis that these effects are mediated through the NMDA receptor. I found that ethanol dose-dependently decreased Jak2 and Stat3 following subchronic exposure of NG108-15 in culture. Acute ethanol exposure caused a dose-dependent decrease in Stat3 protein levels. Incubation with MK-801 or ketamine, two noncompetitive NMDA receptor antagonists, or the receptor agonist NMDA, produced dose-dependent decreases in Stat3 protein as well.
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Wenzel, Andreas. "Heterogeneity and developmental regulation of N-methyl-D-aspartate receptors in the brain /." Zürich, 1997. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=12006.
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Wilson, John A. "The role of N-methyl D-aspartate (NMDA) receptor antagonists in neuropathic pain." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/25324.
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The aim of this thesis is to investigate the use of NMDAR antagonists in preventing naturopathic sensitisation. The chronic constriction injury (CCI) model of neuropathic pain is used to study the role of NMDARs in the development of neuropathic pain and subsequent modulation. Behavioural effects are assessed in association with changes in NMDAR subtypes. Memantine and ketamine (NMDAR antagonists) are shown to attenuate typical behavioural responses (thermal hyperalgesia and cold allodynia) to nerve injury. In addition, NMDAR antagonist pre-treatment is shown to effect the subsequent NMDAR subunit expression, with improved susceptibility to subsequent NMDAR antagonist treatment. The clinical use of epidural ketamine as a preventative drug prior to lower limb amputation is investigated in a double blind randomised placebo controlled study. No significant effects on the incidence of post-amputation pain were found, although the overall incidence of pain was lower than in comparable studies. Ketamine is shown to improve peri-operative analgesia and have long lasting effects (up to one week) on sensory processing in the remaining stump. In summary, NMDAR antagonists seem to be effective in attenuating neuropathic pain in animal models. The promise shown in these studies has not translated into a reduction in post-amputation pain in a clinical study. Ketamine remains a clinically useful drug in peri-operative pain management but the role of ketamine and other clinically available NMDAR antagonists in the prevention of neutropathic sensitisation is still not clearly defined.
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Fan, Mannie Man Yee. "Mechanisms of modulation of N-methyl-D-aspartate (NMDA) receptors by mutant huntingtin." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30863.
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Evidence supports a role for neuronal damage arising from excessive activation of
glutamate receptors (especially the NMDA subtype) in the pathogenesis of Huntington's
disease (HD), although clinical trials involving NMDA receptor inhibition have mostly
failed. Further understanding of the underlying molecular mechanisms is therefore
needed to refine therapeutic approaches. My work has focused on the elucidation of
molecular pathways linking huntingtin (htt) to NMDA receptors (NMDARs).
I found that NMDAR subunits NR1/NR2B are shifted from internal pools to the
plasma membrane, with faster NMDAR insertion to the surface in striatal neurons from
YAC72 HD mice. YAC72 striatum shows a relative enrichment of NR1 C2' isoforms in the
vesicle/microsome-enriched fraction and preferential association of these isoforms with
NR2B subunits, suggesting alternative splicing of NR1 may favour faster forward
trafficking of receptors to potentiate NMDAR current and toxicity in this HD mouse model.
I demonstrated co-localization and interaction of the htt-interacting protein HIP-1
and actin-crosslinking α-actinin proteins, together in a complex with NMDARs in mouse
striatal neurons and forebrain tissue. In fact, HIP-1 can directly interact with α-actinin,
thus providing a physical link between htt and NMDARs.
To broaden the search for candidate proteins mediating the effects of mutant htt
(mhtt) on NMDAR function, I collaborated with Kinexus Bioinformatics Corp. to examine
expression patterns of a variety of protein kinases, phosphatases, and heat shock/stress
proteins, in HEK cells over-expressing NR1/NR2B-type NMDARs and wild-type or mutant
htt. Multiple proteins involved in the heat shock response pathway, including Hsp-70 and
CK2, show altered subcellular distribution with co-expression of mhtt and NR1/NR2B, an effect potentiated by NMDAR stimulation. CK2 expression is also elevated in striatal
tissue from YAC HD mice, and its activity plays a protective role against NMDAR toxicity.
Altered expression of stress response proteins in the presence of mhtt and NR1/NR2B
may reflect anattempt to mitigate mhtt-induced sensitivity to excitotoxicity.
Findings from this thesis provide additional insight into the molecular mechanisms
underlying increased NMDAR-mediated excitotoxicity in the YAC mouse model of HD.
Target molecules and pathways identified in this work may contribute to the optimization
of strategies for the treatment of HD.Medicine, Faculty of
Graduate
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Raouf, Ramin K. "Functional regulation of N-methyl-D-aspartate receptors by serine/threonine protein kinases." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0009/MQ29348.pdf.
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Lomas, Lisa Madonia Picker Mitchell Jon. "Sex differences in opioid antinociception modulation by the N-methyl-D-aspartate system /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1441.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Psychology Behavioral Neuroscience." Discipline: Psychology; Department/School: Psychology.
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Morgan, Elaine M. "The role of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243084.
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Jocoy, Emily Laura. "NR2 subunits and their role in striatal N-methyl-D-aspartate receptor function." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1872142721&sid=9&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Jezequel, Julie. "Impact of psychotomimetic molecules on glutamatergic N-Methyl-D-Aspartate receptors surface trafficking." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0232/document.
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Les récepteurs glutamatergiques de type N-Méthyl-D-Aspartate (RNMDA) jouent un rôle majeur dans de nombreux processus physiologiques, et leur implication dans la physiopathologie de certains troubles neuropsychiatriques tels que la schizophrénie est suggérée par un robuste faisceau de données cliniques et précliniques. Cependant, les mécanismes cellulaires et moléculaires conduisant à une telle dérégulation des RNMDA restent inexpliqués. La diffusion membranaire, mécanisme de contrôle spatial et temporel de la distribution des RNMDA à la surface des neurones, constitue un puissant régulateur de la transmission synaptique. Mon projet de thèse repose ainsi sur l’hypothèse originale qu’une altération de la diffusion de surface des RNMDA jouerait un rôle central dans l’émergence de troubles psychotiques. Afin d‘explorer cette piste, j’ai étudié l’impact de molécules aux propriétés psychomimétiques (i.e induisant un état psychotique) sur la diffusion de surface des RNMDA. Les résultats obtenus au cours de ma thèse démontrent que des molécules psychomimétiques, aux modes d’action distincts (antagonistes du RNMDA et autoanticorps anti-RNMDA), perturbent la diffusion membranaire ainsi que la localisation synaptique des RNMDA, conduisant à terme à des défauts de transmission glutamatergique. Mon travail de thèse propose donc qu’un défaut de diffusion membranaire des RNMDA conduirait à des altérations fonctionnelles pouvant contribuer à l’émergence de troubles psychotiques. L’ensemble de mon travail apporte ainsi un regard nouveau sur la mécanistique des troubles psychotiques et ouvre la voie à de nouvelles pistes thérapeutiquesGlutamatergic N-Methyl-D-Aspartate receptors (NMDAR) play a key role in many physiological processes, and their implication in the pathophysiology of several neuropsychiatric disorders is now well established. Multiple lines of evidence converge towards a dysregulation of the NMDAR in psychotic disorders such as schizophrenia (SCZ). However, the molecular and cellular deficits underlying NMDAR dysfunction remain misunderstood. By tightly controlling NMDAR synaptic localization, surface trafficking represents a powerful regulator of synaptic transmission. Could an alteration of NMDAR surface trafficking underlie NMDAR dysfunction and contribute to the emergence of psychotic disorders? To tackle this question, my PhD project aimed at investigating the impact of different psychotomimetic molecules on NMDAR surface trafficking. In the first part of my project, I explored the impact of NMDAR autoantibodies (NMDAR-Ab) from SCZ and healthy subjects. My results revealed that NMDAR-Ab from SCZ patients rapidly disturb NMDAR synaptic trafficking and distribution, through a loss of NMDAR-EphrinB2 receptor interaction, eventually preventing the induction of synaptic plasticity. In the second part of my PhD project, I showed that psychotomimetic NMDAR antagonists also alter NMDAR synaptic mobility and localization. Downregulation of PSD proteins expression prevented NMDAR antagonists-induced deficits, suggesting that such alterations ensue from modifications of NMDAR intracellular interactions. Taken together, these results demonstrate that psychotomimetic molecules profoundly impact NMDAR surface trafficking, supporting a pathogenic role of this unsuspected process in the emergence of psychotic symptoms
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Steinmetz, Ralf Dirk. "Functional expression of recombinant N-methyl-D-aspartate (NMDA) receptors in eukaryotic cell lines." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961238070.
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King, Rachel Marie. "NR2Aand NR2B containing N-methyl-D-aspartate receptors in synaptic plasticity during cortical development." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520637.
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Riedemann, Maria-Therese. "Corticosterone-induced changes in N-methyl-D-aspartate receptor-mediated transmission in the hippocampus." Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550309.
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Due to its great importance in learning and memory, the hippocampus has received a lot of attention from studies investigating synaptic plasticity, the molecular correlates of learning and memory. Corticosterone (CaRT) is the endogenous glucocorticoid in rodents and is of high physiological significance to the organism. In response to stress the glucocorticoid concentration rises rapidly, releasing the hormone into the blood and allowing it to exert its actions on the level of the pituitary, the hypothalamus and the hippocampus. Interestingly, learning and memory are also subject to glucocorticoid actions in the hippocampus and the duration of increased glucocorticoid exposure has opposite effects on these measures: while long- term CORT exposure or chronic stress often leads to impairments of learning or memory, short-term CORT exposure has been shown to enhance or facilitate learning and memory. All of these studies have ascribed an important role to the N-methyl-D-aspartate receptor (NMDAR) in modulating CORT-induced changes in synaptic plasticity. Against this background this project aimed at the understanding of rapid CORT-induced effects on synaptic NMDAR-mediated transmission in the rat hippocampus. Using patch-clamp technique it could be shown that CORT rapidly caused an increase in NMDAR-mediated transmission in the hippocampus and that this effect was independent of protein synthesis but dependent on calcium and CaMKII activation. Accordingly, increased levels of phosphorylated CaMKII at its autophosphorylation site Thr286 following CaRT exposure were monitored. Furthermore, increased CaMKII-dependent surface expression of NMDARs following CORT exposure was observed, indicating that CORT induces trafficking of NMDARs. Accordingly, it could be shown that CORT exposure led to an increased association of GluN2B-containing receptors with the motor protein KIF-17. This finding was further corroborated by increased CORT-induced binding of NMDARs to the postsynaptic anchor protein PSD-95. Furthermore, increases in basal NMDAR-mediated transmission were accompanied by changes in the synaptic cluster size of PSD-95 in response to CORT treatment.
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Foster, Brett Lucas. "Modulation of resting human electroencephalographic dynamics by N-methyl-D-aspartate Antagonist Nitrous Oxide." Swinburne Research Bank, 2009. http://hdl.handle.net/1959.3/69924.
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Thesis (PhD) - Swinburne University of Technology, Brain Sciences Institute, 2009.A thesis submitted for the degree of Doctorate of Philosophy, Brain Sciences Institute, Swinburne University of Technology - 2009. Typescript. Bibliography: p. 153-183.
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Bright, Nieka L. "Glutamate Receptor, Ionotropic N-methyl-D-aspartate 2B Polymorphisms and Concussive Recovery in Athletes." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/216565.
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KinesiologyPh.D.
Athletes vary in their ability to recover from concussions. Following a concussion, a pathophysiological cascade of events transpires, rendering symptoms. One such event, the indiscriminate release of the excitatory neurotransmitter glutamate, may result in hyperactivation of glutamate receptors (e.g., N-methyl-D-aspartate receptors [NMDARs]) and self-propagate a state of neurotoxicity that may be enhanced via the concomitant release of Ca2+, particularly through NMDARs containing the NR2B subunit. Genetic variation in regulatory regions of the glutamate receptor, ionotropic N-methyl-D-aspartate 2B (GRIN2B) gene, which codes for the NR2B subunit, may play a role in varied recovery among concussed athletes. Indeed, the rs1019385 promoter single nucleotide polymorphism (SNP) has been shown to alter transcription in dominant versus recessive allele carriers such that expression of the T allele results in increased upregulation of the GRIN2B gene. Therefore, the primary purpose of this study was to determine the association of this GRIN2B SNP and concussive recovery; a second GRIN2B SNP (rs890), in the 3'untranslated region, was also explored. A secondary purpose was to examine SNP associations with initial evaluation concussion severity scores. A triple-blind, between-subjects, genetic association design was utilized. The independent variable was genotype for both GRIN2B SNPs (rs1019385, rs890). The primary dependent variable, concussive recovery, was defined as the number of days from the time of injury until full return-to-play (RTP) clearance was granted by a university concussion center's physician; recovery was categorized as either normal (≤ 20 days) or prolonged (> 20 days). The secondary dependent variables were initial evaluation concussion severity scores and consisted of: (a) vestibulo-ocular reflex (VOR) result, (b) Balance Error Scoring System (BESS) sum, and (c) Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) composite scores. Fifty-three, mostly White (69.7%), male (75.0%) concussed athletes (18.96 ± 6.31 years of age) participated in the study; two participants were excluded due to inconclusive genetic results. Participants were evaluated at a university concussion center per standardized concussion assessment battery, using the aforementioned severity indicators, and provided saliva samples for genotyping experiments. Follow-up visits were performed, as needed, until participants were asymptomatic and cleared for full RTP. No significant associations were demonstrated for the codominant (p = .35, p = .70), dominant (p = .39, p = 1.00) or recessive (p = .72, p = .51) genetic models for the rs1019385 and rs890 SNPs (respectively). Similarly, there were no significant differences in any initial evaluation severity scores between genotype for any genetic model. This exploratory study investigated the association between two GRIN2B SNPs and varied concussive recovery among athletes. Although no statistical and minimal clinical significance was demonstrated, future investigations should incorporate a larger sample and next-generation sequencing to investigate the 21,000 to 25,000 genes and their variations across the human genome as complex disorders (e.g., concussions) likely involve a multitude of genetic variations (and their interactions), many with small effects. Further elucidation of genetic factors involved in concussive recovery could equip clinicians with superior counseling methods and treatment options for athletes at-risk for prolonged recovery.
Temple University--Theses
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Vasuta, Oana Cristina. "Functional regulation of N-methyl-D-aspartate receptor subtypes and their involvement in hippocampal plasticity." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/17410.
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Regulation of NMDAR activity by desensitization is important in physiological and pathological states. We previously reported that desensitization decreases during hippocampal neuronal development, correlating with NMDAR composition, synaptic localization and association with PSD-95. To determine if PSD-95-induced changes in NMDAR desensitization occur because of direct binding to NR2 subunits or due to recruitment of regulatory proteins, we tested the effects of various PSD-95 constructs on NMDAR currents in HEK293 cells and neurons. In HEK cells, wt PSD-95 significantly reduced wt NMDAR desensitization without altering currents of NMDARs containing NR2A-S1462A, a mutation that abolishes PSD-95 binding. Moreover, PDZ1-2 domain was sufficient for this effect in neurons with low endogenous PSD-95 levels. Moreover, other PSD-95 family members with highly homologous PDZ1-2 domains significantly reduced NMDAR desensitization. In mature neurons, disruption of PSD-95/NMDAR interaction through PKC activation, or through interference peptides, increased desensitization to levels found in immature neurons. We conclude that direct binding of PSD-95 increases stability of NMDAR responses to agonist exposure.
Desensitization is a property that shapes synaptic responses, and modulates the calcium signal mediated by the two predominant NMDARs subtypes in hippocampus, with possible consequences for their functioning. Further, we examined the involvement of NR2 subtypes in synaptic plasticity in hippocampal dentate gyrus of juvenile mice. Exercise was used as a means to alter expression of the NR2 subunits in this region. We compared two groups of animals: Controls, which were housed in conditions of minimal enrichment, and
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Runners, which had access to an exercise wheel. NMDAR-dependent LTP expression was significantly greater in Runners than in Controls; in the presence of NR2B subunit antagonists, it was significantly reduced in both groups. NR2A subunit antagonist blocked LTP in slices from Runners and produced a slight depression in Control animals. LTD could not be prevented by either of the NR2B specific antagonists. Strikingly, eliminating NR2A subunit-containing receptor activity prevented LTD in Runners, but not in Control animals. Overall, these results indicate that interplay between subtype, subcellular localization and size of NMDAR subpopulations accounts for their diverse role in synaptic plasticity induction, and that exercise increases the contribution of NR2A to plasticity.
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She, Kevin. "N-methyl-D-aspartate receptors of the central nervous system : network connectivity, trafficking, and plasticity." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43286.
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Activity through NMDA type glutamate receptors sculpts connectivity in the developing nervous system and is typically studied in the visual system in vivo where individual synapses are difficult to visualize. Here, we developed a model of NMDA-receptor dependent synaptic competition in dissociated cultured hippocampal neurons. GluN1 -/- (KO) mouse hippocampal neurons were cultured alone or in defined ratios with wild type (WT) neurons. Synapse development was assessed by immunofluorescence for PSD-95 apposed to VGlut1. Synapse density was specifically enhanced only onto minority WT neurons co-cultured with majority KO neighbour neurons and this increased synapse density was dependent on activity through NMDA receptors. This enhanced synaptic density onto NMDA receptor-competent neurons in minority co-culture represents a cell culture paradigm for studying synaptic competition.
Trafficking of NMDA receptors to the cell surface is critical for proper brain function. Recent evidence suggest that surface trafficking of other ionotropic glutamate receptors requires ligand binding for exit from the endoplasmic reticulum. We show that glutamate binding is required for trafficking of NMDA receptors to the cell surface by expressing a panel of GluN2B ligand binding mutants in heterologous cells and primary rodent neurons and found that glutamate efficacy correlates with surface expression. Such a correlation was found even with inhibition of endocytosis indicating differences in forward trafficking. These results indicate that ligand binding is critical for receptor trafficking to the cell surface.
NMDA receptors mediate many forms of synaptic plasticity. GluN2B is proposed to bind and recruit CaMKII to synapses to mediate multiple forms of synaptic plasticity. We find that accumulation of CFP-CaMKIIα at synapses is induced in wild-type but not in KO neurons by bath stimulation of NMDA receptors or by a chemical long-term potentiation protocol. Stimulated synaptic accumulation of CFP-CaMKIIα was rescued in KO neurons by YFP-GluN2B or chimeric GluN2A/2B tail but not by GluN2A, chimeric GluN2B/2A tail, or GluN2B with point mutations in the CaMKII binding site. Thus, activity-regulated synaptic aggregation of CaMKII is dependent on the cytoplasmic CaMKII binding site of GluN2B and not on differential permeation properties between GluN2B and GluN2A.
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Reynolds, Anna R. "Examination of Hippocampal N-Methyl-D-Aspartate Receptors Following Chronic Intermittent Ethanol Exposure In Vitro." UKnowledge, 2013. http://uknowledge.uky.edu/psychology_etds/14.
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Chronic intermittent ethanol exposure (CIE) is associated with degeneration of hippocampal neurons. The present study used hippocampal cultures to examine the loss of NeuN immunoreactivity, a relaible marker or neuronal density, after 1, 2, or 3 cycles of 5 days EtOH exposure (50 mM), followed by a 24-hour period of EWD or continuous EtOH exposure. NeuN immunoreactivity was decreased by 13%, 19%, and 16% in the CA1, CA3, and dentate gyrus after 3 cycles of CIE respectively; thionine staining confirmed significant cellular losses within each hippocampal subregion. Two cycles of CIE in aged tissue cultures resulted in significant decreases in NeuN immunoreactivity in all hippocampal subregions; however continuous ethanol exposure or exposure to one cycle of CIE did not. Further, exposure to the N-Methyl-D-aspartate receptor (NMDAR) antagonist 2-amino-7-phosphonvaleric acid (APV) (30 uM) during periods of EWD attenuated the loss of NeuN in all hippocampal subregions, while exposure to APV (40 uM) prevented the loss of NeuN in the CA1 and dentate gyrus. These results suggest that the loss of mature neurons after CIE is associated with the overactivation on the NMDAR.
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Semos, Madeline Louise. "The role of N-methyl-D-aspartate receptors and nitric oxide in spinal nociceptive processing." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294627.
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Hobbs, Catherine M. "The functional expression of N-methyl-D-aspartate glutamate-type receptors by megakaryocytes and platelets." Thesis, University of Bath, 2010. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527791.
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This study investigated the role of NMDARs in the differentiation of MEG-01 cells and in the activation of human platelets. This investigation demonstrated that the NR1, NR2D and NR3 subunit proteins are expressed in human platelets, with the NR1 subunit also expressed in MEG-01 cells. The NR2A subunit protein was not detectable in either MEG-01 cells or human platelets. PMA-induced differentiation of MEG-01 cells did not appear to stimulate changes in expression of any of the subunit proteins tested. Using assays to measure the changes in [Ca2+]i and ATP secretion, it was determined that donors could be separated into those who responded to the agonists applied and those who did not; responses also decreased over time in both assays. Human platelets from responding donors demonstrate an increase in [Ca2+]i in response to extracellular glutamate, and that increases in ATP secretion are detected at a 10-fold lower concentration. The same is also true with extracellular glycine. Increases in [Ca2+]i were elicited on the addition of extracellular NMDA; extracellular D-serine had no effect. NMDAR inhibitors, MK-801 and D-AP5, inhibited ATP secretion evoked by either glutamate alone or in combination with glycine. D-serine inhibited responses elicited by extracellular glycine. NMDARs play a role in MK differentiation, with the adhesion of MEG-01 cells cultured on a fibrinogen-surface and differentiated with PMA reduced by both inhibitors. PMA-treated MEG-01 cells increased both in size and irregularity, with the addition of NMDAR-specific inhibitors having no effect. S-nitrosylation also inhibits activation of NMDAR, and a new molecule has been developed which can detect S-nitrosylated proteins through a single step process in live cells. Overall, this study has shown that both human platelets and MEG-01 cells express NMDAR subunits, which have been demonstrated to form functional receptors in human platelets.
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Thouin, Anaïs Chiara. "Investigating the effects of N-methyl-D-aspartate receptor autoantibodies on cortical oscillations in vitro." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3730.
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N-methyl-D-Aspartate receptors (NMDARs) play a key role in memory formation and learning, and modulate gamma-frequency oscillations (-: 30-80Hz). Gamma-oscillations are important in perception, cognition and memory formation. They are disrupted in patients with schizophrenia, in whom NMDAR hypofunction has been posited, and in animal models of schizophrenia. Furthermore, NMDAR antagonists reduce -oscillation power and frequency in vitro. NMDA receptor antibody (NMDAR-Ab) encephalitis recapitulates some of the features seen with blockade or ablation of NMDARs, including anterograde memory loss and psychiatric symptoms. We hypothesised that patients’ autoantibodies against NMDARs could disrupt neuronal network activity and that this may be responsible for the neuropsychiatric symptoms experienced by patients. We examined the effect of acute and subacute NMDAR-Ab exposure on -frequency oscillations in the medial entorhinal cortex (mEC), using an in vitro rat brain slice preparation. We also performed the first comparison of four different diagnostic assays used for the detection of NMDAR-Abs. We found that: 1. Cell-based assay using live cells was 100% sensitive but poorly specific in the detection of NMDAR-Abs. Immunohistochemistry was 100% specific and also sensitive (85%). Two cell-based assays using fixed cells produced significant non-specific staining and had intermediate sensitivity and specificity values. 2. Acute exposure to purified IgG from patients with NMDAR-Ab encephalitis reduced the power of -frequency oscillations in the mEC but not in the hippocampus. 3. Immunoglobulin deposition was not found in the slices acutely exposed to patient or control IgG. ii 4. Subacute exposure to IgG by single intracerebral injection of either patient or control IgG did not alter mEC -oscillations ex vivo. No change in NMDAR-mediated responses was detected. 5. IgG uptake into presumed neurons was detected in slices from these animals, but it was not possible to co-localise the IgG to either excitatory neurones or inhibitory interneurones with certainty.
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Wendt, Stefan [Verfasser]. "Microglia sense cortical spreading depression via N-methyl-D-aspartate receptor dependent potassium currents / Stefan Wendt." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1133074367/34.
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Ward, Amie S. (Amie Sue). "Characterization of Tolerance and Cross-tolerance between Noncompetitive N-methyl-D-aspartate (NMDA) Antagonists in Rats Trained to Self-administer Ketamine." Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc278135/.
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Ketamine and phencyclidine (PCP) are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) type of ligand-gated glutamate receptors. Both agents have high abuse liability, and may produce dependence. Tolerance to the reinforcing effects of drugs of abuse is widely regarded as a key component of the dependence process. Therefore, the present study was conducted to examine whether tolerance develops to the reinforcing effects of ketamine, and whether PCP and dizocilpine, a noncompetitive NMDA antagonist with negligible abuse liability, produce cross-tolerance to the reinforcing effects of ketamine. Further, identification of the neural mechanisms that underlie tolerance to the reinforcing effects of drugs may yield information regarding drug dependence.
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Meddows, Elisabeth. "Identification of the molecular determinants important in the assembly of N-methyl-D-aspartate (NMDA) receptors." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365682.
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Ring, Joshua Roderick. "SYNTHETIC AROMATIC AGMATINE ANALOGS AS ALLOSTERIC MODULATORS OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR CHANNEL." UKnowledge, 2006. http://uknowledge.uky.edu/gradschool_diss/413.
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The N-methyl-D-aspartate (NMDA) receptors are highly regulated ligand-gated ion channels, which are affected by many substrates. Overactivation of the NMDA receptor can lead to hyperexcitability and a number of neurotoxic effects and neurological diseases. Agmatine has been demonstrated to act allosterically as an inhibitory modulator at the polyamine recognition sites of the NMDA receptor complex. The present study synthesized and evaluated a library of agmatine analogs for their ability to displace tritiated MK-801 from NMDARs in P2 membrane preparations from rat brains at ligand concentrations of 1 mM and 50 uM. A full dose-response curve was generated for the most active compounds, in the presence and absence of a pathological level of spermidine (100 uM). A forty-five member subset of arylidenamino-guanidino compounds was synthesized and all were demonstrated to be NMDA receptor inhibitory modulators in the above assay. Three of these compounds generated biphasic curves, indicating activity at two binding sites: the postulated high-affinity agmatine binding site, and a low-affinity site (perhaps the channel itself). (4-Chlorobenzylidenamino)-guanidine hydrochloride demonstrated an IC50 of 3.6 uM at the former site and 124.5 uM at the latter. Several computer models were generated to direct further synthesis. Based on the structure-activity relationship of the arylidenamino-guanidino compounds, a pharmacophore model of the agmatine binding site of the NMDAR was proposed.
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Berry, Jennifer Nicole. "TIME-DEPENDENCE OF DISTAL-TO-PROXIMAL HIPPOCAMPAL NEURODEGENERATION PRODUCED BY N-METHYL-D-ASPARTATE RECEPTOR ACTIVATION." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_theses/72.
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Excitotoxicity is the overexcitation of neurons due to the excessive activation of excitatory amino acid receptors and is thought to be involved in many neurodegenerative states. The manner in which the neuron breaks down during excitotoxicity is still unclear. The current study used the organotypic hippocampal slice culture model to examine the time-dependent loss of the synaptic vesicular protein synaptophysin and the loss of N-methyl-D-aspartate (NMDA) receptor NR1 subunit availability following an excitotoxic insult (20 μM NMDA) to provide a better understanding of the topographical nature of neuronal death following NMDA receptor activation. Significant NMDA-induced cytotoxicity in the CA1 region of the hippocampus (as measured by propidium iodide uptake) was evident early (15 minutes after exposure) while significant loss of the NR1 subunit and synaptophysin was found at later timepoints (72 and 24 hours, respectively), suggesting delayed downregulation or degradation in axons and dendrites as compared to the soma. The addition of the competitive NMDA receptor antagonist 2-amino-7-phosphonovaleric acid (APV) significantly attenuated all NMDA-induced effects. These results suggest that NR1 and synaptophysin levels as measured by immunoreactivity are not reliable indicators of early cell death.
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Davidson, Avril. "A biochemical investigation of the N-methyl-D-aspartate receptor in the rat central nervous system." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/19668.
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Activation of the N-methyl-D-aspartate(NMDA) receptor is important in both physiological and pathological phenomena, including synaptogenesis, long-term potentiation, neuroexcitotoxicity and epilepsy. Although implicated in postnatal formation of synaptic connections, over-activation of the NMDA receptor in the neonate, as a result of say a hypoxic-ischaemic insult, can lead to neuronal damage. Antagonists for specific sites on the NMDA receptor complex may therefore prove to be novel therapeutic agents for preventing excitotoxic neuronal damage. I have therefore investigated the ontogeny of the NMDA receptor complex as well as modulation of the receptor in both adult and neonatal rat brain tissue. Radioligand binding studies were performed using high-affinity NMDA receptor antagonists. [3H]3-((±)-2-carboxypiperazin-4-yl)propyl-1-phosphonoate ([^3H]CPP) and [^3H]D-2-amino-5-phosphonopentanoate([^3H]D-AP5), both competitive antagonists which bind to the NMDA neurotransmitter recognition site, and [^3H]dizocilpine a non-competitive antagonist which binds to a site within the lumen of the NMDA-associated ion channel, were used. Optimal experimental conditions were established for the binding of each ligand to membranes prepared from rat brain tissue. This allowed reliable and reproducible measurements to be made under different modulatory conditions. Using mature tissue the binding of [^3H]CPP was compared with that of [^3H]AP5 in the presence of compounds active at the glycine modulatory site including glycine, 7-chlorokynurenate and 3-amino-1-hydroxypyrrolid-2-one(HA-966). Differential effects were seen on the binding of each ligand. The findings provide further evidence for the hypothesis that the NMDA receptor exists in more than one conformational state, these being regulated by glycine. [^3H]CPP and [^3H]dizocilpine were used to investigate the ontogeny of their respective binding sites. Each ligand bound to membranes prepared at various postnatal ages between birth and adulthood. The binding of both ligands was detectable at the earliest ages examined, increasing with postnatal age.
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Martin, Elodie. "Etude de l'impact des antagonistes du récepteur N-méthyl-D-aspartate (NMDA) dans la douleur neuropathique." Thesis, Université Clermont Auvergne (2017-2020), 2017. http://www.theses.fr/2017CLFAS012.
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Les antagonistes du récepteur N-méthyl-D-aspartate (NMDA) comme la kétamine, le dextrométhorphane et la mémantine sont utilisés pour la prise en charge de la douleur neuropathique. La kétamine est très efficace contre les douleurs neuropathiques réfractaires aux traitements conventionnels. Cependant, son utilisation est limitée du fait de nombreux effets indésirables. Un relais antalgique est alors proposé. Ce travail de thèse s’insère dans un programme de recherche dédié aux antagonistes du récepteur NMDA dans la prise en charge de la douleur neuropathique. Le premier objectif était d’évaluer dans une étude clinique randomisée, en simple insu, en groupes parallèles, contrôlée versus placebo, les effets antalgiques du dextrométhorphane et de la mémantine, administrés en relais de la kétamine chez 60 patients souffrant de douleurs neuropathiques d’origine périphérique. L’impact de ces traitements sur le statut cognitivo-émotionnel des patients et leur qualité de vie a également été examiné, ainsi que la modulation des effets de ces médicaments par le polymorphisme génétique impliqué dans le métabolisme (CYP2D6, CYP3A4,5), la biodisponibilité et l’élimination (NR1I2) de ces deux molécules. En parallèle une étude mécanistique centrée sur le dextrométhorphane a été réalisée chez vingt volontaires sains (étude randomisée, en double aveugle, en groupes croisés). L’objectif était d’étudier dans un modèle d’hyperalgie induite par le froid « Freeze injury » les caractéristiques pharmacologiques et mécanistiques déterminant les effets anti-nociceptifs, centraux et cognitifs du dextrométhorphane ainsi que le polymorphisme génétique impliqué dans leur modulation. Chez les patients, les effets antalgiques immédiats de la kétamine ont été confirmés et s’accompagnaient de l’amélioration des scores d’anxiété et de dépression, des aspects cognitifs et affectifs et du sommeil. Toutefois, par rapport au placebo, la mémantine et le dextrométhorphane n’ont pas permis de renforcer significativement l’antalgie induite par la kétamine. Chez les volontaires sains, le dextrométhorphane a révélé des effets anti-hyperalgiques suite à une sensibilisation périphérique et centrale. Cependant, aucun effet analgésique sur la douleur thermique aiguë n’a été observé. Ces deux approches clinique et mécanistique concernant l’effet curatif des antagonistes du récepteur NMDA ont permis d’une part de montrer : 1 - chez le patient, l’effet curatif prolongé de la kétamine et l’intérêt du dextrométhorphane et de la mémantine dans la prise en charge du retentissement négatif de la douleur neuropathique sur le statut cognitivo-émotionnel et la qualité de vie des patients; 2 - chez le volontaire sain, l’efficacité anti-hyperalgique du dextrométhorphane sur les phénomènes de sensibilisation périphérique et centrale ainsi que ses répercussions sédatives et cognitives. En complément de ces deux études et dans le but de confirmer en clinique les effets curatifs du dextrométhorphane sur le triptyque douleur-cognition-émotion, une étude clinique randomisée, en double aveugle, en groupes parallèles, contrôlée versus placebo est en cours de réalisation chez 40 patientes souffrant de douleur neuropathique chimio-induite subséquente au traitement du cancer du sein. En conclusion de ce travail de thèse, l’étude des effets du dextrométhorphane dans deux populations différentes souligne l’intérêt de la recherche translationnelle. Chez le sujet volontaire sain, le dextrométhorphane exerce un effet anti-hyperalgique marqué et provoque des effets centraux délétères. Chez le patient présentant une douleur neuropathique d’origine périphérique et étant répondeur à la kétamine, seule une tendance est observée en faveur de l’effet anti-nociceptif du dextrométhorphane donné en relais de la kétamine. En revanche l’administration de dextrométhorphane s’accompagne d’un certain bénéfice au niveau cognitif et sur la qualité de vie des patientsN-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine, dextromethorphan and memantine have gained an increasing interest in the management of neuropathic pain. In Pain Clinics, ketamine is widely used in the relief of neuropathic pain. However, its use in clinical practice is limited due to its numerous side effects. It is therefore necessary to propose to patients a drug relay with other NMDA receptor antagonists. This work is part of an academic program research dedicated to NMDA receptor antagonists in the management of neuropathic pain. Its first objective was to evaluate the antalgic effects of dextromethorphan and memantine. This randomized, single-blind, parallel-group, placebo-controlled study in 60 ketamine responder patients aimed also to assess the cognitive-emotional status of patients and their quality life. In parallel, a mechanistic study focusing on dextromethorphan was performed in 20 healthy volunteers in a randomized, double-blind, cross-over, placebo-controlled study. The objective was to investigate in a freeze-injury model the pharmacokinetic and mechanistic characteristics of the anti-nociceptive, central and cognitive effects of dextromethorphan as well as the genetic polymorphism involved in its response variability.In patients, the immediate analgesic effects of ketamine were confirmed with improved anxiety and depression scores, cognitive and affective aspects of pain, and different sleep parameters. However, memantine and dextromethorphan, compared to placebo, did not significantly increase the ketamine-induced analgesia. The analysis of the genetic polymorphism did not reveal any variability in the analgesic efficacy of these treatments. In healthy volunteers, dextromethorphan revealed anti-hyperalgesic effects following peripheral and central sensitization but no analgesic effect on acute heat pain. Moreover, the variability of the anti-nociceptive activity of dextromethorphan described in the literature seems to be more related to the genetic polymorphism of the CYP2D6 gene than to that of the CYP3A4,5 and ABCB1 genes. Finally, dextrorphan, the main active metabolite of dextromethorphan, appears to be responsible for the deleterious sedative and cognitive effects of the drug. These two clinical and mechanistic approaches concerning the curative effect of the NMDA receptor antagonists showed : 1 - in patients, the prolonged curative effect of ketamine and the interest of dextromethorphan and memantine in the management of the neuropathic pain-related cognitive-emotional and quality of life impairment; 2 - in healthy volunteers, the anti-hyperalgesic efficacy of dextromethorphan on peripheral and central sensitization and its sedative and cognitive side effects. In addition to these two studies, a randomized, double-blind, parallel-group, placebo-controlled clinical study is ongoing in 40 patients with chemotherapy-induced peripheral neuropathic pain subsequently to the treatment of breast cancer. In conclusion the assessment of the effects of dextromethorphan in two different populations led to discordant results. In the healthy volunteer, dextromethorphan exerts a marked anti-hyperalgesic effect and causes deleterious central effects. In the patient with peripheral neuropathic pain, only a trend is observed in favor of the anti-nociceptive effect of dextromethorphan given in ketamine responder patients. More studies with larger population are needed to determine the importance of the CYP2D6, CYP3A4,5 and ABCB1 genetic polymorphisms on the anti-nociceptive activity of dextromethorphan. The translational approach of this thesis does not allow a firm conclusion on the clinical use of dextromethorphan in the curative treatment of chronic peripheral neuropathic pain. The use of dextromethorphan as a preventive agent via other administration routes (i.e. local) or in combination with other drugs, all require further exploration in order to improve the benefit/risk ratio of this molecule
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Yongtao, Zhang, and Zhang Yongtao. "Synthesis and structural characterization of silver (I)-(D-, L- and DL-) aspartate and silver (I)-(D- and L-) glutamate coordination polymers." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/626799.
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Chiral assemblies of metal atoms linked by organic ligands are attracting considerable attention for their unique structural aesthetics and interesting properties. In order to explore the novel helical supramolecular of silver with amino acid complexes and develop the potential applications of them, the silver nitrate and two types of amino acid (L-, D- and DL-) aspartic acid and (L- and D-) glutamic acid are used to generate chiral silver(I) coordination polymers. In this work, five coordination polymers, {[Ag3(D-Asp)2(NO3)]}n. nH2O (1), {[Ag3(L-Asp)2(NO3)]}n. nH2O (2), {[Ag4(DL-Asp)2(NO3)2]}n.2nH2O (3), {[Ag4(D-Glu)2(NO3)2]}n· 2nH2O (4) and {[Ag4(L-Glu)2(NO3)2]}n· 2nH2O (5) are synthesized under hydrothermal conditions. The X-Ray Diffraction and related software were used for measuring and analyzing the crystal structures. X-ray single crystal structure analysis shows that the complexes (1) and (2) are a pair of six-helix bundle with a helical pitch of 70.6 Å. The adjacent helices are connected by argentophilic Ag-Ag interactions to form sextuple. The D-Asp and L-Asp in complex (3) generate achiral layers. Moreover, the L-Glu ligands in complexes (4) and D-Glu ligands in (5) combine with Ag(I) ions, and both the two structures have no charity. However, complex (4) and (5) are a pair of 3D structural enantiomer.
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Dumontet, Charles. "Acide d-aspartique beta-hydroxamate : essai clinique de phase i/ii chez les patients atteints de sida." Lyon 1, 1991. http://www.theses.fr/1991LYO1M069.
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Greyling, Yolande. "N-methyl-D-aspartate (NMDA) and sigma receptor antagonism as neuroprotective strategy for polycyclic amines / Yolande Greyling." Thesis, North-West University, 2008. http://hdl.handle.net/10394/4202.
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Polycyclic cage compounds and their effects on different receptors and receptor channels have been studied extensively. It is evident that these compounds may prove to be of great value in future treatment of neurodegenerative diseases. Although many of the mechanisms involved in the process of neurodegeneration are still not fully elucidated, researchers are getting closer to identifying more and new possible targets for drug treatment.
In this study the focus was mainly on the effect of polycyclic cage compounds on calcium homeostasis, a key process in neurodegeneration. The role of sigma receptors in calcium homeostasis was also evaluated. As can be seen in the literature, these receptors are an exciting new prospect for drug targeting and treatment of not only neurodegenerative diseases but tumor related illnesses as well.
A series of pentacycloundecane derivatives containing sigma bias substituents were selected and synthesised using reductive amination. Their effect on intracellular calcium in synaptoneursomes, were evaluated using fluorescent techniques and their affinity for sigma receptors was determined through a radio ligand binding study on Sprague-Dawley rat liver membranes. The difference between the oxa-and aza derivatives as well as the effect of chain length between the cage and the piperidine moiety on calcium influx and binding affinity were evaluated.Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2009.
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Morgan, Celia Janet Ann. "An investigation of the acute and chronic effects of the N-methyl-D-aspartate receptor antagonist ketamine." Thesis, University College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429564.
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Dorville, Agnès. "Optimisation des propriétés des antagonistes des récepteurs N-méthyl-D-aspartate et cholecystokinine-B par modélisation moléculaire." Paris 5, 1993. http://www.theses.fr/1993PA05P608.
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Morel, Véronique. "Approche translationnelle de l'impact des antagonistes du récepteur NMDA (N-méthyl-D-aspartate) dans la douleur neuropathique." Thesis, Clermont-Ferrand 1, 2014. http://www.theses.fr/2014CLF1MM07.
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Les antagonistes du récepteur NMDA sont des molécules intéressantes dans la prise en charge des douleurs neuropathiques. Certaines d’entre elles, comme la kétamine, génèrent de nombreux effets indésirables, limitant leur utilisation en clinique. D’autres comme la mémantine ou le dextrométhorphane, ont fait l’objet de nombreuses études précliniques et cliniques aux résultats controversés. L’objectif de ce travail était de déterminer l’impact de ces deux molécules sur la douleur neuropathique en évaluant leurs effets antinociceptifs, cognitifs, et les événements cellulaires associés au récepteur NMDA via la phosphorylation de différents résidus de la sous-unité NR2B comme les tyrosines 1336 et 1472 (pTyr 1336 NR2B et pTyr 1472 NR2B) et la serine 1303 (pSer 1303 NR2B), dans un modèle de douleur neuropathique induite par la ligature du nerf spinal L5 chez le rat. Après des résultats précliniques encourageants, une étude clinique, randomisée, en simple insu, contrôlée vs placebo a été réalisée chez 40 patientes atteintes d’un cancer du sein et subissant une mastectomie. L’objectif était d’évaluer si la mémantine administrée en amont de la mastectomie pourrait prévenir le développement de douleurs neuropathiques et l’altération de la cognition, de la qualité de vie et du sommeil, qui accompagnent la prise en charge du cancer du sein. Chez l’animal, il a été montré que la mémantine, administrée en amont du geste chirurgical, prévient le développement des symptômes de douleur neuropathique et la dégradation des processus cognitifs. L’analyse densitométrique des western-blots montre une diminution d’expression spinale et supraspinale au niveau de l’insula et de l’hippocampe de pTyr 1472 NR2B chez ces mêmes animaux. Par contre, administrée en post-chirurgical, la mémantine n’a pas d’effet sur ces différents paramètres. Concernant le dextrométhorphane, les résultats précliniques ont montré que l’administration curative de cette molécule chez les animaux douloureux réverse les symptômes de douleur neuropathique, restaure la mémoire spatiale et entraîne une diminution d’expression spinale de pTyr 1336 NR2B. En clinique, les résultats ont révélé à 3 mois post-chirurgie, 1- une diminution significative de l’intensité douloureuse chez les patientes traitées par la mémantine comparée au groupe placebo, 2- une amélioration des symptômes de douleur neuropathique liés à une chimiothérapie néoadjuvante et 3- une amélioration de la composante affective du questionnaire des douleurs de Saint-Antoine. Cependant, aucune différence significative n’a été observée sur la cognition, la qualité de vie et la qualité du sommeil. L’étude de ces 2 antagonistes, la mémantine et le dextrométhorphane, a permis de déterminer deux approches différentes dans la prise en charge des douleurs neuropathiques via des cibles moléculaires distinctes. En effet, chez l’animal, la mémantine a un effet préventif sur le développement de la douleur neuropathique et sur la dégradation de processus cognitifs via la diminution d’expression spinale et supraspinale de pTyr 1472 NR2B, tandis que le dextrométhorphane a un effet curatif sur ces mêmes paramètres via la diminution d’expression spinale de pTyr 1336 NR2B.L’approche translationnelle concernant l’effet prophylactique de la mémantine en clinique a permis de confirmer l’action préventive de cette molécule sur la douleur globale induite par la mastectomie, ainsi qu’une diminution des symptômes de douleurs neuropathiques liés à une chimiothérapie. Il serait ainsi possible d’envisager l’extension de cette prophylaxie à un plus grand nombre de patientes devant subir une mastectomie ainsi qu’à des chimiothérapies connues pour engendrer des douleurs neuropathiques associées à d’importantes altérations de la cognition et de la qualité de vie. L’effet curatif du dextrométhorphane doit être à présent confirmé en clinique, notamment dans les douleurs neuropathiques post-mastectomieNMDA receptor antagonists are potentially interesting molecules in the management of neuropathic pain. Some of them, such as ketamine, generate numerous adverse effects, limiting their use in the clinic. Other molecules, such as memantine or dextromethorphan, have been the subject of numerous preclinical and clinical studies, the results of which, however, remain controversial. The objective of this thesis work was to determine the impact of these two molecules on neuropathic pain by evaluating their antinociceptive effects, and cellular events associated with the NMDA receptor via the phosphorylation of different residues of the NR2B subunit such as tyrosines 1336 and 1472 (pTyr 1336 NR2B and pTyr 1472 NR2B) and serine 1303 (pSer 1303 NR2B), in a model of neuropathic pain induced by spinal nerve ligation L5 in rats. Following encouraging preclinical results, a randomized, single-blind, placebo-controlled clinical study was conducted in 40 breast cancer patients undergoing mastectomy. The objective was to evaluate whether memantine administered prior to mastectomy could prevent the development of neuropathic pain and the impairment of cognition, quality of life and sleep that accompany the management of breast cancer. In animals, it has been shown that memantine, administered prior to surgery, prevents the development of neuropathic pain symptoms and impairment of cognitive processes. Densitometric analysis of western blots showed a decrease in spinal and supraspinal expression of pTyr 1472 NR2B in the insula and hippocampus of these same animals. On the other hand, when administered post-surgically, memantine has no effect on these different parameters. Concerning dextromethorphan, preclinical results showed that curative administration of this molecule in painful animals reverses the symptoms of neuropathic pain, restores spatial memory and leads to a decrease in the spinal expression of pTyr 1336 NR2B. In the clinic, results showed at 3 months post-surgery, 1- a significant decrease in pain intensity in patients treated with memantine compared to the placebo group, 2- an improvement in neuropathic pain symptoms associated with neoadjuvant chemotherapy, and 3- an improvement in the affective component of the St. Antoine's Pain Questionnaire. However, no significant differences were observed in cognition, quality of life and quality of sleep. The study of these 2 antagonists, memantine and dextromethorphan, allowed to determine two different approaches in the management of neuropathic pain via distinct molecular targets. In animals, memantine has a preventive effect on the development of neuropathic pain and on the degradation of cognitive processes via the decrease in spinal and supraspinal expression of pTyr 1472 NR2B, while dextromethorphan has a curative effect on these same parameters via the decrease in spinal expression of pTyr 1336 NR2B. Translated with www.DeepL.com/Translator (free version)
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Abu, Izuddin Fahmy. "Exploring block and permeation of N-methyl-D-Aspartate (NMDA) receptor channels for treatment of neurodegenerative disorders." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/38591/.
Full textAbstract:
N-methyl-D-aspartate receptors (NMDAR) are ionotropic glutamate receptors which can be blocked by Mg2+ in a voltage-dependent manner and are highly permeable to Ca2+, hence they represent a medically relevant target for neurodegenerative disorders caused by excitotoxicity. The two main objectives of this study were, (i) to determine the impact of Q/R/N, +1 and -8 sites modification in the M2 pore region of GluN2A NMDAR subunit on Mg2+ block and other open channel blockers; and (ii) to evaluate novel multi-target-directed ligands (MTDL) for Alzheimer’s disease therapy. The Xenopus laevis oocyte expression system was employed where NMDAR subunit cRNAs were injected into the oocytes and responses to NMDA/glycine and channel blockers were recorded using two-electrode voltage clamp (TEVC) electrophysiology. Pore region mutations to investigate the impact of Q/R/N and adjacent sites were characterized using Mg2+, memantine, MK-801, philanthotoxin analogues and an MTDL compound, CR18. NN at the Q/R/N and +1 sites in GluN2A subunits were mutated to GR and RR, while W at the -8 position (in relation to the Q/R/N site), was mutated to N. Wild type and mutated GluN2A were co-expressed with GluN1-1a in Xenopus oocytes and antagonistic responses by channel blockers were recorded with TEVC. At -75 mV, the RR mutation significantly increased IC50s of Mg2+, memantine and MK-801 by 27-, 42- and 325-fold respectively, compared to wild-type. As for the GR mutation, IC50s were also significantly increased for memantine and MK-801 by 5- and 132-fold respectively, compared to wild type. W to N mutation at the -8 position did not significantly affect blocking potencies for all channel blockers. Blocking potency for PhTX-343 was not significantly altered by any mutations. This study provided evidence that the presence of G and R at the Q/R/N and +1 sites are likely responsible for the changes in blocking sensitivity and play important roles in ion permeability. The fact that PhTX-343 remained potent despite the mutations suggest that this compound might have a different mode of action or different binding site other than the M2 region and should be further characterized. In the MTDL study, twenty one novel compounds were tested on GluN1-1a/GluN2A NMDAR subunits. Thirteen were memantine-derivatives (MAB) incorporated with antioxidant moieties, three were spermine-derived polyamines also incorporated with antioxidants, and five were combinatorial forms of donepezil and carvedilol. The antagonistic properties of the compounds were tested electrophysiologically at -60 mV and compared with Mg2+ and memantine. The MAB series were found to be weak NMDAR channel blockers suggesting the loss of memantine functionality due to attachment of the antioxidant structure to its amine group. Subsequently, modification of the linker point to memantine moieties to free its amine group eventually resulted in weaker NMDAR channel blockers with IC50s of more than 100 µM. The spermine-derived polyamines (CR compounds) were potent NMDAR blockers with IC50s (0.69 to 2.35 µM) comparable to memantine (2.28 µM) and significantly lower than Mg2+ (10.1 µM) and also exhibited voltage-dependence block. Our mutation study revealed that CR18, the most potent MTDL compound was less sensitive in NMDAR containing GR or RR mutation in GluN2A subunits. This is a favourable property of an NMDAR blocker for potential Alzheimer’s disease treatment since GluN3 subunits containing GR or RR at the Q/R/N and +1 sites are less permeable to Ca2+ influx and has been shown to exert neuroprotective effects.
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Lau, Wai Kit Jaeger. "Developmental expression of N-methyl-D-aspartate and gamma-aminobutyric acid receptors in the rat basal ganglia." HKBU Institutional Repository, 2004. http://repository.hkbu.edu.hk/etd_ra/535.
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Braganza, Elena Marie [Verfasser]. "Influence of the N-Methyl-D-Aspartate Receptor coagonist, D-Cycloserine, on Memory Consolidation and subsequent Learning under Sleep Deprivation / Elena Marie Braganza." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1224232801/34.
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Martel, Marc-Andre´. "Role of the NR2 subunit composition and intracellular C-terminal domain in N-methy-D-aspartate receptor signalling." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4228.
Full textAbstract:
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ionotropic receptors. When activated, NMDARs let extracellular sodium and calcium ions enter neurons. This calcium influx, depending on its duration, intensity and the presence of nearby signalling proteins can signal to synaptic plasticity. Additionally, physiological NMDAR activity promotes pro-survival cascades and gene transcription, whereas both lack of activation and overactivation of these receptors trigger pro-death signals. Several neurodegenerative pathologies such as stroke/ischemia and Alzheimer’s disease are thought to involve NMDAR overactivation, so-called “excitotoxicity”, but since NMDARs are important for normal neuronal physiology, potential therapeutical approaches needs to go beyond simple antagonism. Here, we studied the receptor subunit composition and the molecular cascades downstream of the receptor activation to try and isolate the pro-death pathways in NMDAR-mediated excitotoxicity. We found that the NR2 subunit composition did not dictate the type of NMDAR-mediated signals, as receptors comprised of NR2B subunits were able to signal to death, survival and plasticity. However, we also found that the intracellular tail of the NR2B subunit was more efficient at triggering neuronal death compared to the NR2A C-terminus, which suggests that different pro-death signalling complexes are associated to each subunit. Two pro-death signals, the p38 and c-Jun N-terminal kinase (JNK) cascades, are key mediators of neuronal excitotoxicity. In a non-neuronal cell line, NMDAR-mediated cell death could be reconstituted but was found to rely solely on JNK and not p38. This was due to the lack of pro-death signals from the NR2B-PDZ domain, a cytoplasmic interacting domain which forms a signalling cassette with the neuronal proteins PSD-95 and neuronal nitric oxide synthase. This PDZ-ligand recruits the p38 cascade in neurons, but was absent in non-neuronal cells. The pro-death p38 pathway could be inhibited in neurons by disrupting the PDZ domain interactions, which protects against excitotoxicity. This disruption was not affecting normal synaptic transmission, potentiation or survival signalling, suggesting that this could be a therapeutically viable avenue. Thus, this work has expanded the understanding of how NMDAR subunits and their cytoplasmic domains mediate signalling leading to a variety of cellular outcomes; a crucial point for the development of a strategy specifically targeting NMDAR- mediated pro-death signalling.