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https://www.readbyqxmd.com/read/28526038/phosphorylation-of-tau-at-y18-but-not-tau-fyn-binding-is-required-for-tau-to-modulate-nmda-receptor-dependent-excitotoxicity-in-primary-neuronal-culture
#1
Takashi Miyamoto, Liana Stein, Reuben Thomas, Biljana Djukic, Praveen Taneja, Joseph Knox, Keith Vossel, Lennart Mucke
BACKGROUND: Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear...
May 19, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28522210/novel-trigeminal-slice-preparation-method-for-studying-mechanisms-of-nociception-transmission
#2
Mikiko Hirahara, Naoshi Fujiwara, Kenji Seo
BACKGROUND: The trigeminal subnucleus caudalis (Vc) plays a critical role in transmission and modulation of nociceptive afferent inputs, and exhibits a similar layer construction to the spinal dorsal horn. However, afferent inputs enter the brainstem and project to a separately located nucleus. It has previously been difficult to record responses of the Vc to afferent fiber activation in a brainstem slice preparation. The aim of the present study was to establish a novel brainstem slice preparation method to study trigeminal nociceptive transmission mechanisms...
May 15, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28512009/combining-d-cycloserine-with-appetitive-extinction-learning-modulates-amygdala-activity-during-recall
#3
Claudia Ebrahimi, Stefan P Koch, Eva Friedel, Ilsoray Crespo, Thomas Fydrich, Andreas Ströhle, Andreas Heinz, Florian Schlagenhauf
Appetitive Pavlovian conditioning plays a crucial role in the pathogenesis of drug addiction and conditioned reward cues can trigger craving and relapse even after long phases of abstinence. Promising preclinical work showed that the NMDA-receptor partial agonist D-cycloserine (DCS) facilitates Pavlovian extinction learning of fear and drug cues. Furthermore, DCS-augmented exposure therapy seems to be beneficial in various anxiety disorders, while the supposed working mechanism of DCS during human appetitive or aversive extinction learning is still not confirmed...
May 13, 2017: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/28511693/antagonistic-action-on-nmda-glun2b-mediated-currents-of-two-peptides-that-were-conantokin-g-structure-based-designed
#4
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-towards-the-generation-of-novel-n-methyl-d-aspartate-receptor-modulators-based-on-its-backbone
#5
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 Meunier, 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 co-agonistic action at N-methyl-D-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons...
May 16, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28510125/molecular-design-of-proneurogenic-and-neuroprotective-compounds-allosteric-nmda-receptor-modulators
#6
D S Karlov, E V Radchenko, V A Palyulin, N S Zefirov
N-Methyl-D-aspartic acid (NMDA) receptor is a promising target for treatment of neurodegenerative diseases and other brain disorders as well as for designing proneurogenic compounds able to stimulate neurogenesis in adult brain. We analyzed the structure of the binding site of negative allosteric modulators in the amino-terminal domain of the NMDA receptor and identified possible modes of their binding as well as performed molecular design of new modulators that significantly differ from the known ones in structure and binding mode...
March 2017: Doklady. Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28507080/divergent-roles-of-a-peripheral-transmembrane-segment-in-ampa-and-nmda-receptors
#7
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...
May 15, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28507031/memory-consolidation-within-the-central-amygdala-is-not-necessary-for-modulation-of-cerebellar-learning
#8
Adam B Steinmetz, Ka H Ng, John H Freeman
Amygdala lesions impair, but do not prevent, acquisition of cerebellum-dependent eyeblink conditioning suggesting that the amygdala modulates cerebellar learning. Two-factor theories of eyeblink conditioning posit that a fast-developing memory within the amygdala facilitates slower-developing memory within the cerebellum. The current study tested this hypothesis by impairing memory consolidation within the amygdala with inhibition of protein synthesis, transcription, and NMDA receptors in rats. Rats given infusions of anisomycin or DRB into the central amygdala (CeA) immediately after each eyeblink conditioning session were severely impaired in contextual and cued fear conditioning, but were completely unimpaired in eyeblink conditioning...
June 2017: Learning & Memory
https://www.readbyqxmd.com/read/28506554/selective-dopamine-receptor-4-activation-mediates-the-hippocampal-neuronal-calcium-response-via-ip3-and-ryanodine-receptors
#9
Ya-Li Wang, Jian-Gang Wang, Fang-Li Guo, Xia-Huan Gao, Dan-Dan Zhao, Lin Zhang, Jian-Zhi Wang, Cheng-Biao Lu
Intracellular calcium is a key factor in most cellular processes, including cell growth, differentiation, proliferation and neurotransmitter release. Dopamine (DA) mediates synaptic transmission by regulating the intracellular calcium content. It is not clear, however, which specific subunit of the DA receptor contributes to DA modulation of intracellular calcium content changes. Through the traditional technique of Fura-2 calcium imaging, this study demonstrated that the DA can induce transient calcium in cultured hippocampal neurons and that this response can be mimicked by a selective dopamine receptor 4 (DR4) agonist PD168077 (PD)...
May 12, 2017: Brain Research
https://www.readbyqxmd.com/read/28491480/new-treatment-strategies-of-depression-based-on-mechanisms-related-to-neuroplasticity
#10
REVIEW
Yu-Jhen Huang, Hsien-Yuan Lane, Chieh-Hsin Lin
Major depressive disorder is a severe and complex mental disorder. Impaired neurotransmission and disrupted signalling pathways may influence neuroplasticity, which is involved in the brain dysfunction in depression. Traditional neurobiological theories of depression, such as monoamine hypothesis, cannot fully explain the whole picture of depressive disorders. In this review, we discussed new treatment directions of depression, including modulation of glutamatergic system and noninvasive brain stimulation. Dysfunction of glutamatergic neurotransmission plays an important role in the pathophysiology of depression...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28484273/role-of-akt-independent-mtorc1-and-gsk3%C3%AE-signaling-in-sublethal-nmda-induced-injury-and-the-recovery-of-neuronal-electrophysiology-and-survival
#11
Przemyslaw Swiatkowski, Ina Nikolaeva, Gaurav Kumar, Avery Zucco, Barbara F Akum, Mihir V Patel, Gabriella D'Arcangelo, Bonnie L Firestein
Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury...
May 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28483976/targeting-a-potassium-channel-syntaxin-interaction-ameliorates-cell-death-in-ischemic-stroke
#12
Chung-Yang Yeh, Ashlyn M Bulas, Aubin Moutal, Jami L Saloman, Karen A Hartnett, Charles T Anderson, Thanos Tzounopoulos, Dandan Sun, Rajesh Khanna, Elias Aizenman
The voltage-gated K(+) channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K(+) efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn(2+)-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE protein syntaxin 1A...
May 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28483393/activation-of-5-ht7-receptors-reverses-nmda-r-dependent-ltd-by-activating-pka-in-medial-vestibular-neurons
#13
Yan-Hai Li, Lei Han, Kenneth Lap-Kei Wu, Ying-Shing Chan
The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus...
May 5, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28482635/the-anti-amyloid-%C3%AE-and-neuroprotective-properties-of-a-novel-tricyclic-pyrone-molecule
#14
Izumi Maezawa, Bende Zou, Jacopo Di Lucente, William S Cao, Conrado Pascual, Sahani Weerasekara, Man Zhang, Xinmin Simon Xie, Duy H Hua, Lee-Way Jin
There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28475556/high-concentrations-of-tranexamic-acid-inhibit-ionotropic-glutamate-receptors
#15
Irene Lecker, Dian-Shi Wang, Kirusanthy Kaneshwaran, C David Mazer, Beverley A Orser
BACKGROUND: The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors...
May 5, 2017: Anesthesiology
https://www.readbyqxmd.com/read/28474543/neuroprotective-effects-of-citrus-fruit-derived-flavonoids-nobiletin-and-tangeretin-in-alzheimer-s-and-parkinson-s-disease
#16
Nady Braidy, Sahar Behzad, Solomon Habtemariam, Touqeer Ahmed, Maria Daglia, Seyed Mohammad Nabavi, Eduardo Sobarzo-Sanchez, Seyed Fazel Nabavi
Neurodegenerative diseases, namely Alzheimer`s disease and Parkinson's disease represent a deleterious impact worldwide. Despite extensive preclinical and clinical research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacological intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L...
March 27, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28473645/dopamine-receptors-differentially-control-binge-alcohol-drinking-mediated-synaptic-plasticity-of-the-core-nucleus-accumbens-direct-and-indirect-pathways
#17
Xincai Ji, Sucharita Saha, Jenya Kolpakova, Melissa Guildford, Andrew R Tapper, Gilles E Martin
Binge alcohol drinking, a behavior characterized by rapid repeated alcohol intakes, is most prevalent in young adults and a risk factor for excessive alcohol consumption and alcohol dependence. Although alteration of synaptic plasticity is thought to contribute to this behavior, there is currently little evidence that this is the case. We used drinking-in-the-dark (DID) as a model of binge alcohol drinking to assess its effects on spike-timing-dependent plasticity (STDP) in medium spiny neurons (MSNs) of the core nucleus accumbens (NAc) by combining patch clamp recordings with calcium imaging and optogenetics...
May 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28472639/post-injury-administration-of-a-combination-of-memantine-and-17%C3%AE-estradiol-is-protective-in-a-rat-model-of-traumatic-brain-injury
#18
Nicole L Day, Matthew S Carle, Candace L Floyd
Traumatic brain injury (TBI) often leads to substantial adverse cognitive and health outcomes, including permanent disability and death. Preventing these outcomes requires attenuation of the secondary biochemical damage that follows the initial biomechanical insult, but a clinically proven pharmacotherapeutic capable of such has not been identified. In fact, the heterogeneous nature of TBI and the complexity of secondary injury cascades suggest a polytherapeutic approach that targets multiple pathways might be necessary...
May 1, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28468999/ketamine-induced-converged-synchronous-gamma-oscillations-in-the-cortico-basal-ganglia-network-of-non-human-primates
#19
Maya Slovik, Boris Rosin, Shay Moshel, Rea Mitelman, Eitan Schechtman, Renana Eitan, Aeyal Raz, Hagai Bergman
NMDA (N-methyl-D-aspartate) antagonists are widely used in anesthesia, pain management, schizophrenia animal model studies and recently as potential antidepressants. However the mechanisms underlying their anesthetic, psychotic, cognitive and emotional effects are still elusive. The basal-ganglia (BG) integrate input from different cortical domains through its dopamine modulated connections, to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodents cortical and BG networks...
May 3, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28457974/a-novel-nmda-receptor-positive-allosteric-modulator-that-acts-via-the-transmembrane-domain
#20
Tzu-Ming Wang, Brandon M Brown, Lunbin Deng, Benjamin D Sellers, Patrick J Lupardus, Heidi J A Wallweber, Amy Gustafson, Evera Wong, Matthew Volgraf, Jacob B Schwarz, David H Hackos, Jesse E Hanson
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs...
April 27, 2017: Neuropharmacology
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