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Kenneth J O'Riordan, Neng-Wei Hu, Michael J Rowan
Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor...
March 13, 2018: Scientific Reports
P Zanos, T D Gould
Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine's widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine's antidepressant actions but lack its undesirable effects...
March 13, 2018: Molecular Psychiatry
Allie J Widman, Lori L McMahon
Low-dose ketamine, an open-channel N -methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Bernhard Wünsch, Marina Szermerski, Frederik Börgel, Dirk Schepmann, Thomas Betzel, Simon Ametamey, Ahmed Haider
In order to analyze the NMDA receptor distribution in the central nervous system, fluorinated ligands selectively addressing the ifenprodil binding site of GluN2B subunit containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 were pursued including the replacement of the benzylic OH moiety by a F-atom (13) and introduction of fluoroethoxy moieties at different positions (14, 17 18a-c). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a represent the most promising ligands...
March 9, 2018: ChemMedChem
Panos Zanos, Scott M Thompson, Ronald S Duman, Carlos A Zarate, Todd D Gould
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites...
March 7, 2018: CNS Drugs
Laura Fedele, Joseph Newcombe, Maya Topf, Alasdair Gibb, Robert J Harvey, Trevor G Smart
Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg2+ block. In addition, we provide new views on Mg2+ and NMDA channel blocker binding sites...
March 6, 2018: Nature Communications
Yang Yang, Wei-Gang Ji, Zhi-Ru Zhu, Yu-Ling Wu, Zhi-Yang Zhang, Shao-Chen Qu
Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid β protein (Aβ) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Aβ-induced neurotoxicity. However, whether RIN can prevent soluble Aβ1-42 -induced impairments in spatial cognitive function and synaptic plasticity is still unclear...
March 3, 2018: Neuropharmacology
Yanhong Duan, Qi Wang, Qingwen Zeng, Jiayue Wang, Zhenzhen Chen, Meichen Xu, Yale Duan, Zheng Zhao, Qingsheng Xue, Xiaohua Cao
Although the striatum has a well-documented role in procedural learning and memory, the underlying mechanisms remain poorly understood. GluN2B subunit is abundantly expressed in striatum, however, the function of striatal GluN2B subunit in striatum-related learning is also unclear. In the present study, using transgenic mice with forebrain-specific overexpression of the GluN2B subunit, we observed that up-regulation of GluN2B subunit expression results in enhanced dorsal striatum-related motor skill learning and stimulus-response (S-R) learning as well as cortico-dorsomedial striatal (cortico-DMS) long-term potentiation (LTP)...
March 2, 2018: Neuropharmacology
Marta Portero-Tresserra, Margarita Martí-Nicolovius, Mireia Tarrés-Gatius, Ana Candalija, Gemma Guillazo-Blanch, Anna Vale-Martínez
RATIONALE: Aging is characterized by a decrease in N-methyl-D-aspartate receptors (NMDARs) in the hippocampus, which might be one of the factors involved in the age-dependent cognitive decline. D-Cycloserine (DCS), a partial agonist of the NMDAR glycine recognition site, could improve memory deficits associated to neurodegenerative disorders and cognitive deficits observed in normal aging. OBJECTIVES AND METHODS: The aim of the present study was to explore whether DCS would reverse age-dependent memory deficits and decreases in NMDA receptor subunits (GluN1, GluN2A, and GluN2B) and the presynaptic protein synaptophysin in Wistar rats...
February 28, 2018: Psychopharmacology
Feng Yi, Linda G Zachariassen, Katherine N Dorsett, Kasper B Hansen
NMDA-type glutamate receptors mediate excitatory synaptic transmission in the central nervous system and play critical roles in many neuronal processes. The physiological roles of NMDA receptors are shaped by their functional properties, which are highly dependent on subunit composition. Most NMDA receptors are assembled from two GluN1 and two GluN2 subunits, but diversity in subunit composition is made possible by eight GluN1 splice variants (i.e. isoforms) and four distinct GluN2 subunits (GluN2A-D). We demonstrate using FRET-FLIM that GluN1-1a and GluN1-1b isoforms, which includes or lacks residues encoded by exon 5, form triheteromeric GluN1-1a/GluN1-1b/GluN2A (1a/1b/2A) and GluN1-1a/GluN1-1b/GluN2B (1a/1b/2B) receptors...
February 26, 2018: Molecular Pharmacology
Natasha Warikoo, Samuel J Brunwasser, Ann Benz, Hong-Jin Shu, Steven M Paul, Michael Lewis, James Doherty, Michael Quick, Laura Piccio, Charles F Zorumski, Gregory S Day, Steven Mennerick
N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the central nervous system associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to cerebrospinal fluid (CSF) from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs...
February 23, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
J Jane Zhang, Josué Haubrich, Matteo Bernabo, Peter S B Finnie, Karim Nader
Reconsolidation, a process by which long-term memories are rendered malleable following retrieval, has been shown to occur across many different species and types of memory. However, there are conditions under which memories do not reconsolidate, and the reasons for this are poorly understood. One emerging theory is that these boundary conditions are mediated by a form of metaplasticity: cellular changes through which experience can affect future synaptic plasticity. We review evidence that N-methyl-D-aspartate receptors (NMDARs) might contribute to this phenomenon, and hypothesize that resistance to memory destabilization may be mediated by the ratio of GluN2A/GluN2B subunits that make up these receptors...
February 20, 2018: Neurobiology of Learning and Memory
Kenneth J O'Riordan, Neng-Wei Hu, Michael J Rowan
Promotion of long-term depression (LTD) mechanisms by synaptotoxic soluble oligomers of amyloid-β (Aß) has been proposed to underlie synaptic dysfunction in Alzheimer's disease (AD). Previously, LTD was induced by relatively non-specific electrical stimulation. Exploiting optogenetics, we studied LTD using a more physiologically diffuse spatial pattern of selective pathway activation in the rat hippocampus in vivo. This relatively sparse synaptic LTD requires both the ion channel function and GluN2B subunit of the NMDA receptor but, in contrast to electrically induced LTD, is not facilitated by boosting endogenous muscarinic acetylcholine or metabotropic glutamate 5 receptor activation...
February 20, 2018: Cell Reports
Pâmella K Frühauf-Perez, Fernanda R Temp, Micheli M Pillat, Cristiane Signor, Arithane Lorena Wendel, Henning Ulrich, Carlos F Mello, Maribel A Rubin
Lipopolysaccharide (LPS) has been long known to promote neuroinflammation and learning and memory deficits. Since spermine, one of the main natural polyamines in the central nervous system, protects from LPS-induced memory deficit by a mechanism that comprises GluN2B receptors, the aim of the present study was to determine whether brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) receptor and cAMP response element binding (CREB) are involved in this protective effect of spermine...
February 16, 2018: Neurobiology of Learning and Memory
Ioana Neagoe, Chang Liu, Alexander Stumpf, Yanmei Lu, Dongping He, Ross Francis, Jun Chen, Paul Reynen, Moulay Hicham Alaoui-Ismaili, Hirokazu Fukui
Abnormal signaling pathways mediated by N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathogenesis of various CNS disorders and have been long considered as promising points of therapeutic intervention. However, few efforts have been previously described concerning evaluation of therapeutic modulators of NMDARs and their downstream pathways in human neurons with endogenous expression of NMDARs. In the present study, we assessed expression, functionality, and subunit composition of endogenous NMDARs in human induced pluripotent stem cell (hiPSC)-derived cortical neurons (iCell Neurons and iCell GlutaNeurons)...
February 8, 2018: Stem Cell Research
Mi Zhou, Zhao Liu, Jia Yu, Shuiming Li, Min Tang, Li Zeng, Haiyang Wang, Hong Xie, Li Peng, Haojun Huang, Chanjuan Zhou, Peng Xie, Jian Zhou
The amygdala plays a key role in the pathophysiology of depression, but the molecular mechanisms underlying amygdalar hyperactivity in depression remain unclear. In this study, we used a chronic mild stress (CMS) protocol to separate susceptible and insusceptible rat subgroups. Proteomes in the amygdalae were analyzed differentially across subgroups based on labeling with isobaric tags for relative and absolute quantitation (iTRAQ) combined with mass spectrometry. Of 2562 quantified proteins, 102 were differentially expressed...
February 13, 2018: Neuroscience
Jiali Chen, Yunlong Ma, Rongli Fan, Zhongli Yang, Ming D Li
Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes...
February 10, 2018: Molecular Neurobiology
Lucas Taoro-Gonzalez, Yaiza M Arenas, Andrea Cabrera-Pastor, Vicente Felipo
BACKGROUND: Hyperammonemic rats reproduce the cognitive alterations of patients with hepatic encephalopathy, including altered spatial memory, attributed to altered membrane expression of AMPA receptor subunits in hippocampus. Neuroinflammation mediates these cognitive alterations. We hypothesized that hyperammonemia-induced increase in IL-1β in hippocampus would be responsible for the altered GluA1 and GluA2 membrane expression. The aims of this work were to (1) assess if increased IL-1β levels and activation of its receptor are responsible for the changes in GluA1 and/or GluA2 membrane expression in hyperammonemia and (2) identify the mechanisms by which activation of IL-1 receptor leads to altered membrane expression of GluA1 and GluA2...
February 8, 2018: Journal of Neuroinflammation
Alessandro Piva, Elisabetta Gerace, Marzia Di Chio, Lisa Osanni, Laura Padovani, Lucia Caffino, Fabio Fumagalli, Domenico E Pellegrini-Giampietro, Cristiano Chiamulera
Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation...
January 31, 2018: Neurobiology of Learning and Memory
Bernhard Wünsch, Louisa Temme, Dirk Schepmann, Julian A Schreiber, Bastian Frehland
Since only a few studies investigated the affinity and functional activity of NMDA receptor open channel blockers under same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activity of MK-801, phencyclidine, dexoxadrol, etoxadrol, (S)- and (R)-ketamine, dextromethorphan, memantine and amantadine was analyzed under same uniform assay conditions. The affinity towards the PCP and ifenprodil binding sites was recorded in radioligand binding assays...
January 27, 2018: ChemMedChem
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