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https://www.readbyqxmd.com/read/28611597/functional-properties-of-human-nmda-receptors-associated-with-epilepsy-related-mutations-of-glun2a-subunit
#1
Dmitry A Sibarov, Nadine Bruneau, Sergei M Antonov, Pierre Szepetowski, Nail Burnashev, Rashid Giniatullin
Genetic variants of the glutamate activated N-methyl-D-aspartate (NMDA) receptor (NMDAR) subunit GluN2A are associated with the hyperexcitable states manifested by epileptic seizures and interictal discharges in patients with disorders of the epilepsy-aphasia spectrum (EAS). The variants found in sporadic cases and families are of different types and include microdeletions encompassing the corresponding GRIN2A gene as well as nonsense, splice-site and missense GRIN2A defects. They are located at different functional domains of GluN2A and no clear genotype-phenotype correlation has emerged yet...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28598327/co-agonists-differentially-tune-glun2b-nmda-receptor-trafficking-at-hippocampal-synapses
#2
Joana S Ferreira, Thomas Papouin, Laurent Ladépêche, Andrea Yao, Valentin C Langlais, Delphine Bouchet, Jérôme Dulong, Jean-Pierre Mothet, Silvia Sacchi, Loredano Pollegioni, Pierre Paoletti, Stéphane Henri Richard Oliet, Laurent Groc
The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes...
June 9, 2017: ELife
https://www.readbyqxmd.com/read/28594440/calcium-signalling-in-medial-intercalated-cell-dendrites-and-spines
#3
Cornelia Strobel, Robert K P Sullivan, Peter Stratton, Pankaj Sah
The amygdala plays a central role in fear conditioning and extinction. The medial intercalated (mITC) neurons are GABAergic cell clusters interspaced between the basolateral (BLA) and central amygdala (CeA). These neurons are thought to play a key role in fear and extinction, controlling the output of the CeA by feed-forward inhibition. BLA to mITC cell inputs are though to undergo synaptic plasticity, a mechanism underlying learning, which is mediated by NMDA-receptor dependent mechanisms that require changes in cytosolic calcium...
June 8, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28585567/role-of-src-family-kinases-in-bdnf-mediated-suppression-of-cocaine-seeking-and-prevention-of-cocaine-induced-erk-glun2a-and-glun2b-dephosphorylation-in-the-prelimbic-cortex
#4
Sarah M Barry, Jacqueline F McGinty
Models of relapse have demonstrated that neuroadaptations in reward circuits following cocaine self-administration underlie reinstatement of drug seeking. Dysregulation of the pathway from the prelimbic cortex to the nucleus accumbens is implicated in reinstatement. A single BDNF infusion into the prelimbic cortex following a final cocaine self-administration session results in attenuation of reinstatement of cocaine-seeking. Inhibiting BDNF's receptor, TrkB, ERK/MAP kinase activation, or NMDA receptors blocks this attenuating effect, indicating that the interaction between glutamate-mediated synaptic activity and TrkB signaling is imperative to BDNF's suppressive effect on drug-seeking...
June 6, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28582391/all-atom-nmda-receptor-transmembrane-domain-model-development-and-simulations-in-lipid-bilayers-and-water
#5
Samaneh Mesbahi-Vasey, Lea Veras, Michael Yonkunas, Jon W Johnson, Maria G Kurnikova
N-methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family that mediate excitatory synaptic transmission in the central nervous system. The channels of NMDARs are permeable to Ca2+ but blocked by Mg2+, distinctive properties that underlie essential brain processes such as induction of synaptic plasticity. However, due to limited structural information about the NMDAR transmembrane ion channel forming domain, the mechanism of divalent cation permeation and block is understood poorly...
2017: PloS One
https://www.readbyqxmd.com/read/28554889/development-of-glutamatergic-proteins-in-human-visual-cortex-across-the-lifespan
#6
Caitlin R Siu, Simon P Beshara, David G Jones, Kathryn M Murphy
Traditionally, human primary visual cortex (V1) has been thought to mature within the first few years of life, based on anatomical studies of synapse formation, and establishment of intra- and inter-cortical connections. Human vision, however, develops well beyond the first few years. Previously, we found prolonged development of some GABAergic proteins in human V1 (Pinto et al., 2010). Yet as over 80% of synapses in V1 are excitatory, it remains unanswered if the majority of synapses regulating experience-dependent plasticity and receptive field properties develop late like their inhibitory counterparts...
May 29, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28525360/role-of-sigma-1-receptor-in-high-fat-diet-induced-peripheral-neuropathy
#7
Tieying Song, Jianhui Zhao, Xiaojing Ma, Zaiwang Zhang, Bo Jiang, Yunliang Yang
The neurobiological mechanisms of obesity-induced peripheral neuropathy are poorly understood. We evaluated the role of Sigma-1 receptor (Sig-1R) and NMDA receptor (NMDARs) in the spinal cord in peripheral neuropathy using an animal model of high fat diet-induced diabetes. We examined the expression of Sig-1R and NMDAR subunits GluN2A and GluN2B along with postsynaptic density protein 95 (PSD-95) in the spinal cord after 24-week HFD treatment in both wild-type and Sig-1R-/- mice. Finally, we examined the effects of repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice on peripheral neuropathy...
June 14, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28512860/intrinsic-cellular-and-molecular-properties-of-in-vivo-hippocampal-synaptic-plasticity-are-altered-in-the-absence-of-key-synaptic-matrix-molecules
#8
Stephan Jansen, Christine Gottschling, Andreas Faissner, Denise Manahan-Vaughan
Hippocampal synaptic plasticity comprises a key cellular mechanism for information storage. In the hippocampus, both long-term potentiation (LTP) and long-term depression (LTD) are triggered by synaptic Ca(2+) -elevations that are typically mediated by the opening of voltage-gated cation channels, such as N-methyl-D-aspartate receptors (NMDAR), in the postsynaptic density. The integrity of the post-synaptic density is ensured by the extracellular matrix (ECM). Here, we explored whether synaptic plasticity is affected in adult behaving mice that lack the ECM proteins brevican, neurocan, tenascin-C and tenascin-R (TG)...
May 17, 2017: Hippocampus
https://www.readbyqxmd.com/read/28511693/antagonistic-action-on-nmda-glun2b-mediated-currents-of-two-peptides-that-were-conantokin-g-structure-based-designed
#9
Edwin A Reyes-Guzman, Nohora Vega-Castro, Edgar A Reyes-Montaño, Esperanza Recio-Pinto
BACKGROUND: The GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAr) modulates many physiological processes including learning, memory, and pain. Excessive increase in NMDAr/GluN2B activity has been associated with various disorders such neuropathic pain and neuronal death following hypoxia. Thus there is an interest in identifying NMDAr antagonists that interact specifically with the GluN2B subunit. Recently based on structural analysis between the GluN2B subunit and conantokin-G, a toxin that interacts selectively with the GluN2B subunit, we designed various peptides that are predicted to act as NMDAr antagonists by interacting with the GluN2B subunit...
May 16, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/28511005/characterization-of-l-theanine-excitatory-actions-on-hippocampal-neurons-toward-the-generation-of-novel-n-methyl-d-aspartate-receptor-modulators-based-on-its-backbone
#10
Fatiha Sebih, Matthieu Rousset, Salima Bellahouel, Marc Rolland, Marie Celeste de Jesus Ferreira, Janique Guiramand, Catherine Cohen-Solal, Gérard Barbanel, Thierry Cens, Mohammed Abouazza, Adrien Tassou, Maud Gratuze, Céline Meusnier, Pierre Charnet, Michel Vignes, Valérie Rolland
l-Theanine (or l-γ-N-ethyl-glutamine) is the major amino acid found in Camellia sinensis. It has received much attention because of its pleiotropic physiological and pharmacological activities leading to health benefits in humans, especially. We describe here a new, easy, efficient, and environmentally friendly chemical synthesis of l-theanine and l-γ-N-propyl-Gln and their corresponding d-isomers. l-Theanine, and its derivatives obtained so far, exhibited partial coagonistic action at N-methyl-d-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons...
May 30, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28507080/divergent-roles-of-a-peripheral-transmembrane-segment-in-ampa-and-nmda-receptors
#11
Johansen B Amin, Catherine L Salussolia, Kelvin Chan, Michael C Regan, Jian Dai, Huan-Xiang Zhou, Hiro Furukawa, Mark E Bowen, Lonnie P Wollmuth
Ionotropic glutamate receptors (iGluRs), including AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subtypes, are ligand-gated ion channels that mediate signaling at the majority of excitatory synapses in the nervous system. The iGluR pore domain is structurally and evolutionarily related to an inverted two-transmembrane K(+) channel. Peripheral to the pore domain in eukaryotic iGluRs is an additional transmembrane helix, the M4 segment, which interacts with the pore domain of a neighboring subunit. In AMPARs, the integrity of the alignment of a specific face of M4 with the adjacent pore domain is essential for receptor oligomerization...
June 5, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28468946/novel-mode-of-antagonist-binding-in-nmda-receptors-revealed-by-the-crystal-structure-of-the-glun1-glun2a-ligand-binding-domain-complexed-to-nvp-aam077
#12
Annabel Romero-Hernandez, Hiro Furukawa
Competitive antagonists against N-methyl-D-aspartate (NMDA) receptors have played critical roles throughout the history of neuropharmacology and basic neuroscience. There are currently numerous NMDA receptor antagonists containing a variety of chemical groups. Among those compounds, a GluN2-specific antagonist, (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid (NVP-AAM077), contains a unique combination of a dioxoquinoxalinyl ring, a bromophenyl group, and a phosphono group...
July 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28459106/functional-assessment-of-the-nmda-receptor-variant-glun2a-r586k
#13
Katie F M Marwick, Peter Parker, Paul Skehel, Giles Hardingham, David J A Wyllie
Background: The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor that has important roles in synaptogenesis, synaptic transmission, and synaptic plasticity. Recently, a large number of rare genetic variants have been found in NMDAR subunits in people with neurodevelopmental disorders, and also in healthy individuals. One such is the GluN2A(R586K) variant, found in a person with intellectual disability. Identifying the functional consequences, if any, of such variants allows their potential contribution to pathogenesis to be assessed...
March 17, 2017: Wellcome Open Research
https://www.readbyqxmd.com/read/28400283/the-role-of-glun2b-containing-nmda-receptors-in-short-and-long-term-fear-recall
#14
Eva Mikics, Mate Toth, Laszlo Biro, Biborka Bruzsik, Boglarka Nagy, Jozsef Haller
N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall...
April 8, 2017: Physiology & Behavior
https://www.readbyqxmd.com/read/28389335/maternal-hypomagnesemia-alters-hippocampal-nmdar-subunit-expression-and-programs-anxiety-like-behaviour-in-adult-offspring
#15
R N Schlegel, J G Spiers, K M Moritz, C L Cullen, S T Björkman, T M Paravicini
It is well established that maternal undernutrition and micronutrient deficiencies can lead to altered development and behaviour in offspring. However, few studies have explored the implications of maternal Mg deficiency and programmed behavioural and neurological outcomes in offspring. We used a model of Mg deficiency (prior to and during pregnancy and lactation) in CD1 mice to investigate if maternal Mg deficiency programmed changes in behaviour and NMDAR subunit expression in offspring. Hippocampal tissue was collected at postnatal day 2 (PN2), PN8, PN21 and 6 months, and protein expression of NMDAR subunits GluN1, GluN2A and GluN2B was determined...
April 4, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28384476/allosteric-interactions-between-nmda-receptor-subunits-shape-the-developmental-shift-in-channel-properties
#16
Weinan Sun, Kasper B Hansen, Craig E Jahr
During development of the central nervous system, there is a shift in the subunit composition of NMDA receptors (NMDARs) resulting in a dramatic acceleration of NMDAR-mediated synaptic currents. This shift coincides with upregulation of the GluN2A subunit and triheteromeric GluN1/2A/2B receptors with fast deactivation kinetics, whereas expression of diheteromeric GluN1/2B receptors with slower deactivation kinetics is decreased. Here, we show that allosteric interactions occur between the glutamate-binding GluN2 subunits in triheteromeric GluN1/2A/2B NMDARs...
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28320269/status-epilepticus-impairs-synaptic-plasticity-in-rat-hippocampus-and-is-followed-by-changes-in-expression-of-nmda-receptors
#17
T Y Postnikova, O E Zubareva, A A Kovalenko, K K Kim, L G Magazanik, A V Zaitsev
Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus...
March 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28283559/a-rare-variant-identified-within-the-glun2b-c-terminus-in-a-patient-with-autism-affects-nmda-receptor-surface-expression-and-spine-density
#18
Shuxi Liu, Liang Zhou, Hongjie Yuan, Marta Vieira, Antonio Sanz-Clemente, John D Badger, Wei Lu, Stephen F Traynelis, Katherine W Roche
NMDA receptors (NMDARs) are ionotropic glutamate receptors that are crucial for neuronal development and higher cognitive processes. NMDAR dysfunction is involved in a variety of neurological and psychiatric diseases; however, the mechanistic link between the human pathology and NMDAR dysfunction is poorly understood. Rare missense variants within NMDAR subunits have been identified in numerous patients with mental or neurological disorders. We specifically focused on the GluN2B NMDAR subunit, which is highly expressed in the hippocampus and cortex throughout development...
April 12, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28270746/effects-of-repeated-ethanol-exposures-on-nmda-receptor-expression-and-locomotor-sensitization-in-mice-expressing-ethanol-resistant-nmda-receptors
#19
Carolina R den Hartog, Meghin Gilstrap, Bethany Eaton, Daniel H Lench, Patrick J Mulholland, Gregg E Homanics, John J Woodward
Evidence from a large number of preclinical studies suggests that chronic exposure to drugs of abuse, such as psychostimulants or ethanol induces changes in glutamatergic transmission in key brain areas associated with reward and control of behavior. These changes include alterations in the expression of ionotropic glutamate receptors including N-methyl-D-aspartate receptors (NMDAR) that are important for regulating neuronal activity and synaptic plasticity. NMDA receptors are inhibited by ethanol and reductions in NMDA-mediated signaling are thought to trigger homestatic responses that limit ethanol's effects on glutamatergic transmission...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28269783/modulating-the-balance-of-synaptic-and-extrasynaptic-nmda-receptors-shows-positive-effects-against-amyloid-%C3%AE-induced-neurotoxicity
#20
Yan Huang, Wei Shen, Jie Su, Bin Cheng, Dong Li, Gang Liu, Wen-Xia Zhou, Yong-Xiang Zhang
Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect...
March 2, 2017: Journal of Alzheimer's Disease: JAD
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