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1
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.
2
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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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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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.
5
Brothwell, Shona Lindsay Crawford. "Properties of NMDA receptors in Substantia nigra pars compacta dopaminergic neurones." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612352.
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Lin, Raozhou, and 林饒洲. "Kif5b interaction with NMDA receptors regulates neuronal function." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/208429.
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Intracellular transportation is an essential cellular event controlling neuronal development, morphology, function and survival. Kinesin-1 is the molecular motor conveying cargo along microtubule by utilizing the chemical energy from ATP hydrolysis. This motor consists of two heavy chains and two light chains. Both heavy and light chains are responsible for cargo bindings. There are three kinesin-1 heavy chains in eukaryotic cells. Kif5a and Kif5c are neuronal specific, while Kif5b is ubiquitously expressed. Kif5b carries various cargos essential for neuronal functions, and the early embryonic death of Kif5b null mice suggests the importance of Kif5b in vivo.
N-methyl-d-aspartate receptors (NMDARs) are glutamate elicited channel, which is permeable to calcium and crucial for synaptic plasticity in the central nervous system. NMDARs are heteromeric assemblies consisting of NR1, NR2 and NR3 subunits. These transmembrane subunits contain three parts. Other than the transmembrane domain, the extracellular domain serves as the ligand binding site while the intracellular domain interacts with various partners regulating downstream signaling and receptor trafficking. Synaptic NMDAR activation regulates synaptic plasticity, while extrasynaptic NMDAR activation leads to excitotoxicity.
In this project, I find that kinesin-1 directly interacts with NMDAR subunit, NR1, NR2A and NR2B in vivo. NMDAR colocalizes with kinesin-1 in the cell body and neurites. By GST-pull-down assays with different Kif5b fragments, the cytoplasmic domains of NR1, NR2A and NR2B are found to directly bind with Kif5b via a Kif5b C-terminal region independent of kinesin light chains.
To examine the role of Kif5b in NMDAR trafficking, dominant negative Kif5b fragments are expressed in cell lines together with NR1-1a and GFP-NR2B. Overexpression of dominant negative Kif5b significantly disrupts GFP-NR2B forward trafficking and prevents it from entering into Golgi apparatus. Furthermore, the surface NR1 and NR2B levels are significantly reduced whilst the NR2A levels are not affected in Kif5b+/- mice in which the Kif5b protein level is reduced by 50% compared with the wild-type littermates. Consistent with this observation, the NR1 and NR2B levels are decreased in fractions containing synaptosomal membrane but not the one containing only postsynaptic densities, suggesting that the extrasynaptic NMDAR levels are affected in Kif5b+/- mice.
NMDARs are highly permeable to calcium while activated, thereby activating neuronal nitric oxide synthases (nNOS) to produce nitric oxide (NO). It is found that NMDA triggered calcium influx is perturbed in Kif5b+/- neurons, while the synaptic NMDA receptor mediated calcium influx is normal. In Kif5b+/- slices, the production of NO reduces significantly. Calcium ionophore, A23187, rescue this NO defect, indicating insufficient supply of calcium as the main contribution to this defect. Therefore, Kif5b-dependent extrasynaptic localization of NMDA receptors mediates calcium influx upon NMDA stimulation and controls NO production.
In the summary, above results suggest kinesin-1 as a novel motor involving in NMDA receptor trafficking. This interaction may contribute to the extrasynaptic distribution of NMDARs. By regulating NO production through interaction with NMDARs, Kif5b may mediate neuronal survival in cerebral ischemia and certain aggressive behaviors. This provides a novel target for therapy development against stroke and schizophrenia.published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
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Yu, Chi Wang. "NMDA receptor mediated toxicity in primary neuronal cultures from rodent cerebral cortex /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202004%20YU.
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Ryan, Tomás John. "Functional investigation of NMDA receptor molecular evolution." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608544.
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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.
10
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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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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Molina, Leonardo A. "Alteration of neural dynamics in the rat medial prefrontal cortex by an NMDA antagonist." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Neuroscience, c2012, 2012. http://hdl.handle.net/10133/3264.
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NMDA receptor antagonists such as Ketamine and PCP are potent psychoactive drugs used recreationally. This class of drug induces a number of phenomena in humans similar to those associated with schizophrenia including reduced selective attention, altered working memory, thought disorders and hallucinations. These psychotomimetic drugs have thus been used as a longstanding model to study this disease in animals. Importantly, such animal models allow for recording of brain activity using invasive techniques that are inappropriate in humans. Previous electrophysiological studies have shown that MK-801, a potent non-competitive NMDA receptor antagonist, increases gamma-frequency oscillations and produces a state of disinhibition in the prefrontal cortex of rats wherein the activity of putative excitatory pyramidal neurons increases while the activity of putative inhibitory interneurons decreases. These features are relevant to schizophrenia because molecular evidence suggests dysfunction of inhibitory cortical interneurons, while electroencephalographic recordings show altered gamma-frequency oscillations in this disease. It has been hypothesized that the disinhibited cortical state produces “noisy” information processing, but this has not been directly observed in the interaction of neuronal firing in either humans or animal models. We therefore tested this hypothesis by examining the synchronization of neural activity in the NMDA receptor antagonist model of schizophrenia. We used high-density electrophysiological recordings in the medial prefrontal cortex of freely moving rats before and after systemic injection of MK-801. Analysis of these recordings revealed that drug administration: (i) increases gamma power in field potentials in a manner dissociated from increased locomotion; (ii) does not change the gamma power in multi-unit activity; (iii) decreases spike synchronization among putative pyramidal neurons in the gamma range (30ms), and despite of this it (iv) does not change the synchronization between gamma-range field potentials or between sum-of-spikes and field potentials. These effects in synchronization may be revealing of potent cognitive effects associated with NMDA receptor antagonism, and may reflect impaired communication processing hypothesized to occur in schizophrenia.xi, 42 leaves : ill. ; 29 cm
13
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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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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Luo, Jialie. "Molecular mechanisms underlying the neuroprotection of novel anti-alzheimer dimers targeting pathologically activated NMDA receptors /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BICH%202008%20LUO.
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Norris, Jacob N. "Role of the NMDA receptor in consummatory successive negative contrast." [Fort Worth, Tex.] : Texas Christian University, 2009. http://etd.tcu.edu/etdfiles/available/etd-10152009-100239/unrestricted/Norris.pdf.
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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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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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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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MacQueen, David A. "Non-competitive NMDA receptor antagonist impairs olfactory memory span in rats." View electronic thesis (PDF), 2009. http://dl.uncw.edu/etd/2009-1/macqueend/davidmacqueen.pdf.
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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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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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Roberts, Michael J. 1973. "NMDA receptor activity is necessary for long-term memory in the non-spatial, hippocampal-dependent, social transmission of food preference task." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31532.
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Memory of some forms requires the hippocampus, a brain structure in the medial temporal lobe that reveals remarkable synaptic plasticity. Most synapses in the hippocampus require NMDA-receptors for the induction of this plasticity. Memories that require the hippocampus may also require NMDA-receptor mediated plasticity. This thesis tested the involvement of NMDA receptor activity in memory for a non-spatial, social learning task that requires the hippocampus: the social transmission of food preference, NMDA receptor antagonist (CPP) injected systemically 55 minutes prior to training impaired performance 72 hours later, but not 48 hours, 24 hours, or 15 minutes later. NMDA receptor antagonist (AP-5) injected into the dorsal hippocampus 30 minutes prior to training also impaired performance at the 72-hour delay. Injections of CPP at 10 minutes or 24 hours post-training had no effect on performance. These results suggest that hippocampal NMDA receptor activity is necessary for stable learning of the non-spatial social transmission of food preference.
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White, Lynn H. "NMDA receptor blockade and spatial learning : a reinvestigation." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=69672.
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N-methyl-D-aspartate (NMDA) receptor activation is believed necessary for certain types of learning. The present experiments investigated the effects of the NMDA antagonist, MK-801, on spatial learning and memory in rats. Experiment 1 tested the effects of MK-801 on the acquisition and retention of a water maze task. MK-801 produced a performance, but not a spatial learning deficit. Experiment 2 tested the effects of MK-801 on the acquisition and retention of a radial arm maze task (RAM). MK-801 had no effect on initial acquisition and retention, but impaired subsequent reversal learning when the pattern of rewarded and unrewarded arms was reversed. Experiment 3 investigated the effects of MK-801 on RAM reversal learning in rats previously trained on the initial task in the absence of drugs. MK-801 produced a dose dependent impairment on reversal learning. These results are consistent with one interpretation that MK-801 impairs the ability to suppress interference from previously learned information.
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Tirado, Santiago Giovanni. "An investigation of the role of hippocampal NMDA receptors in spatial learning /." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102737.
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Declarative learning entails the internalization of facts and events. This type of learning depends on the integrity of the hippocampal system. In rodents, spatial learning is studied as a model of declarative learning. In this thesis, electrophysiological and behavioral experiments assessed the role of NMDA receptors in synaptic plasticity and rats' spatial learning and memory. Primed burst potentiation (PBP), a form of synaptic strengthening, was studied in freely-behaving rats treated with NMDA receptor antagonists. The impairments caused by the antagonists correlated with those observed in behavioral studies. The results support the idea that NMDA receptors in the hippocampal system mediate the internalization of the contents and organization of new environmental information, and show that the receptors are not relevant for spatial working memory or performance once a representation of the environment is stable. The results also suggest that stable spatial representations resemble multiple relations of events and do not correspond to topographical maps of an environment. As learning proceeds, representations are activated by smaller subsets of environmental cues, which eventually become sufficient for effective navigation. The representations thus are encoded as relationships of stimuli that share similarities or that are unique to a particular event. The organization of novel information is given through NMDA receptor-mediated synaptic plasticity. This plasticity mechanism could resemble a process similar to the synaptic changes observed during PBP.
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Finn, Richard James. "Localization of N-methyl-D-aspartate receptor subunit 2 mRNAs within the central nervous system of the weakly electric fish Apteronotus leptorhynchus." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=30376.
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Partial cDNAs for each of the four known N-methyl-D-aspartate (NMDA) receptor 2 (NMDAR2A-D) subunits have been cloned from the brain of A. leptorhynchus and are found to display a high degree of sequence homology (83--78% amino acid identity) to their mammalian homologues. In situ hybridization experiments reveal that each transcript has a distinct expression pattern in the apteronotid central nervous system (CNS) and is present in a "mosaic" distribution within important cell types of the electrosensory lateral line lobe (ELL). Apt. NMDAR2A transcript is expressed in forebrain regions as well as throughout the pyramidal cell layer (PCL) and granule cell layer (GCL) of the ELL. Apt. NMDAR2B mRNA is enriched in mid- and forebrain structures as well as the PCL and GCL of the ELL. Apt. NMDAR2C transcript is largely restricted to cerebellar regions but is also found in the PCL and GCL of the ELL's medial, centromedial, and centrolateral segments. Apt. NMDAR2D mRNA is expressed in sites of cell proliferation and in a segmental gradient within granule cells of the ELL.
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Huggins, David John. "Multiscale docking using evolutionary optimisation." Thesis, University of Oxford, 2005. http://ora.ox.ac.uk/objects/uuid:f166d5ec-5085-48b9-838a-626f754f73fb.
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Molecular docking algorithms are computational methods that predict the binding site and docking pose of specified ligands with a protein target. They have proliferated in recent years, due to the explosion of structural data in biology. Oxdock is an algorithm that uses various techniques to simplify this complex task, the most significant being the use of a multiscale approach to analyse the problem using a simple representation in the early stages. Oxdock is shown to be a very useful tool in computational biology, as exemplified by two cases. The first case is the analysis of the NMDA subclass of neuronal glutamate receptors and the subsequent elucidation of their function. The second is the investigation of the newly discovered plant glutamate receptors and the clarification of their natural ligands. The results in both instances open new areas of research into exciting areas of biology. Despite its effectiveness in solving many problems, Oxdock does fail in a number of circumstances. It is thus important to devise a new and improved method for molecular docking. This is achieved by combining the speed of the multiscale approach with the optimising ability of Evolutionary Programming. This yields an algorithm that is shown to be precise, accurate and specific. The new algorithm, Eve, is then modified to illustrate its potential in both lead optimisation and de novo drug design. These capacities, combined with its ability to predict the location of binding sites and the docking pose of a ligand, highlight the promise of computational methods in solving problems in many areas of biological chemistry.
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Bullard, Laura A. "The effects of the NMDA antagonist dizocilpine on an olfactory delayed match-to-sample task in rats." View electronic thesis (PDF), 2009. http://dl.uncw.edu/etd/2009-1/bullardl/laurabullard.pdf.
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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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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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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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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.