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https://www.readbyqxmd.com/read/28299629/inhibition-of-calcineurin-a-by-fk506-suppresses-seizures-and-reduces-the-expression-of-glun2b-in-membrane-fraction
#1
Yuetao Wen, Pengfei Fu, Kunlun Wu, Kaichuang Si, Yanfeng Xie, Wei Dan, Yan Zhan, Quanhong Shi
FK506, a calcineurin inhibitor, shows neuroprotective effects and has been associated with neurodegenerative diseases. Calcineurin A (CaNA), a catalytic subunit of calcineurin, mediates the dephosphorylation of various proteins. N-methyl-D-aspartate receptor (GluN) is closely related to epileptogenesis, and various phosphorylation sites of GluN2B, a regulatory subunit of the GluN complex, have different functions. Thus, we hypothesized that one of the potential anti-epileptic mechanisms of FK506 is mediated by its ability to promote the phosphorylation of GluN2B and reduce the expression of GluN2B in membrane fraction by down-regulating CaNA...
March 15, 2017: Neurochemical Research
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
#2
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...
March 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28273943/increased-nrg1-erbb4-signaling-in-human-symptomatic-epilepsy
#3
Jun-Ming Zhu, Ke-Xin Li, Shu-Xia Cao, Xiao-Juan Chen, Chen-Jie Shen, Ying Zhang, Hong-Yan Geng, Bi-Qing Chen, Hong Lian, Jian-Min Zhang, Xiao-Ming Li
Previous studies have shown that the neuregulin 1 (NRG1)-ErbB4 signaling pathway may regulate the excitability of fast-spiking neurons in the frontal cortex and participate in primary epilepsy pathogenesis. However, the exact roles and mechanism for NRG1/ErbB4 in human symptomatic epilepsy are still unclear. Using fresh human symptomatic epilepsy tissues, we found that the protein levels of NRG1 and ErbB4 were significantly increased in the temporal cortex. In addition, NRG1-ErbB4 signaling suppressed phosphorylation of GluN2B at position 1472 by Src kinase, and decreased levels of phosphorylation level of GluN2B and Src were detected in human symptomatic epilepsy tissues...
December 2017: Scientific Reports
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
#4
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
#5
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
https://www.readbyqxmd.com/read/28246062/epilepsy-with-myoclonic-atonic-seizures-and-chronic-cerebellar-symptoms-associated-with-antibodies-against-glutamate-receptors-n2b-and-d2-in-serum-and-cerebrospinal-fluid
#6
Ryuki Matsuura, Shin-Ichiro Hamano, Satoru Ikemoto, Yuko Hirata, Kotoko Suzuki, Kenjiro Kikuchi, Yukitoshi Takahashi
A 3-year-old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti-C-terminal GluN2B and anti-N terminal GluD2 antibodies in the serum, and anti-N terminal GluN2B and anti-C terminal GluD2 antibodies in the cerebrospinal fluid (CSF)...
February 27, 2017: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/28240721/cucurbitacin-iia-exerts-antidepressant-like-effects-on-mice-exposed-to-chronic-unpredictable-mild-stress
#7
Shi-Meng Zhou, Shao-Yu Guan, Le Yang, Liu-Kun Yang, Lu Wang, Hui-Fang Nie, Xiang Li, Ming-Gao Zhao, Qi Yang, Hong Wu
Cucurbitacin IIa (CuIIa) is the major active component of the Helmseya amabilis root and is known to have antiviral and anti-inflammatory effects. In this study, we examined the antidepressant-like effects of CuIIa in a mouse model of chronic unpredictable mild stress (CUMS) and investigated the possible underlying mechanisms. To evaluate the antidepressant-like effects of CuIIa on depression-like behaviors, mice were subjected to the open-field test, the elevated plus-maze test, the forced-swimming test, and the tail-suspension test...
February 24, 2017: Neuroreport
https://www.readbyqxmd.com/read/28228639/grin1-mutation-associated-with-intellectual-disability-alters-nmda-receptor-trafficking-and-function
#8
Wenjuan Chen, Christine Shieh, Sharon A Swanger, Anel Tankovic, Margaret Au, Marianne McGuire, Michele Tagliati, John M Graham, Suneeta Madan-Khetarpal, Stephen F Traynelis, Hongjie Yuan, Tyler Mark Pierson
N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties...
February 23, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28228087/beyond-ketamine-new-approaches-to-the-development-of-safer-antidepressants
#9
Shigeyuki Chaki
Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice. Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention...
February 20, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28225710/chronic-stress-exacerbates-neuropathic-pain-via-the-integration-of-stress-affect-related-information-with-nociceptive-information-in-the-central-nucleus-of-the-amygdala
#10
Ming-Jia Li, Ling-Yu Liu, Lin Chen, Jie Cai, You Wan, Guo-Gang Xing
Exacerbation of pain by chronic stress and comorbidity of pain with stress-related psychiatric disorders, including anxiety and depression, represent significant clinical challenges. However, the underlying mechanisms still remain unclear. Here, we investigated whether chronic forced swim stress (CFSS)-induced exacerbation of neuropathic pain is mediated by the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala (CeA). We first demonstrated that CFSS indeed produces both depressive-like behaviors and exacerbation of spared nerve injury (SNI)-induced mechanical allodynia in rats...
April 2017: Pain
https://www.readbyqxmd.com/read/28185898/sirt2-inhibition-modulate-glutamate-and-serotonin-systems-in-the-prefrontal-cortex-and-induces-antidepressant-like-action
#11
Mercedes Erburu, Irene Muñoz-Cobo, Teresa Diaz-Perdigon, Paolo Mellini, Takayoshi Suzuki, Elena Puerta, Rosa M Tordera
Growing evidence suggests that changes in histone acetylation in specific sites of the chromatin modulate neuronal plasticity and contribute to antidepressant-like action. Sirtuin 2 (SIRT2) is a class III NAD(+)-dependent histone deacetylase involved in transcriptional repression of genes regulating synaptic plasticity. Importantly, a key role for the glutamate system in prefrontal cortex (PFC) synaptic plasticity changes induced by antidepressants has been suggested. Here, we asked whether SIRT2 could be a pharmacological target for depression therapy...
February 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28174113/involvement-of-glun2b-subunit-containing-n-methyl-d-aspartate-nmda-receptors-in-mediating-the-acute-and-chronic-synaptotoxic-effects-of-oligomeric-amyloid-beta-a%C3%AE-in-murine-models-of-alzheimer-s-disease-ad
#12
Gerhard Rammes, Corinna Mattusch, Matthias Wulff, Franziska Seeser, Matthias Kreuzer, Kaichuan Zhu, Jan M Deussing, Jochen Herms, Chris G Parsons
To elucidate whether a permanent reduction of the GluN2B subunit affects the pathology of Alzheimer's disease (AD), we cross-bred mice heterozygous for GluN2B receptors in the forebrain (hetGluN2B) with a mouse model for AD carrying a mutated amyloid precursor protein with the Swedish and Arctic mutation (mAPP) resulting in a hetGluN2B/mAPP transgenic. By means of voltage-sensitive dye imaging (VSDI) in the di-synaptic hippocampal pathway and the recording of field excitatory postsynaptic potentials (fEPSPs), hippocampal slices of all genotypes (WT, hetGluN2B, mAPP and hetGluN2B/mAPP, age 9-18 months) were tested for spatiotemporal activity propagation and LTP induction...
February 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28157099/sex-impact-on-tau-aggregation-and-postsynaptic-protein-levels-in-the-p301l-mouse-model-of-tauopathy
#13
Lucia Buccarello, Giuliano Grignaschi, Anna Maria Castaldo, Alessia Di Giancamillo, Cinzia Domeneghini, Roberto Cosimo Melcangi, Tiziana Borsello
P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interactions among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented a lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28134307/fingolimod-limits-acute-a%C3%AE-neurotoxicity-and-promotes-synaptic-versus-extrasynaptic-nmda-receptor-functionality-in-hippocampal-neurons
#14
Pooja Joshi, Martina Gabrielli, Luisa Ponzoni, Silvia Pelucchi, Matteo Stravalaci, Marten Beeg, Sonia Mazzitelli, Daniela Braida, Mariaelvina Sala, Enrica Boda, Annalisa Buffo, Marco Gobbi, Fabrizio Gardoni, Michela Matteoli, Elena Marcello, Claudia Verderio
Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer's disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons...
January 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28109345/reduced-ethanol-drinking-following-selective-cortical-interneuron-deletion-of-the-glun2b-nmda-receptors-subunit
#15
Anna K Radke, Nicholas J Jury, Eric Delpire, Kazu Nakazawa, Andrew Holmes
N-Methyl-d-aspartate receptors (NMDAR) are involved in the regulation of alcohol drinking, but the contribution of NMDAR subunits located on specific neuronal populations remains incompletely understood. The current study examined the role of GluN2B-containing NMDARs expressed on cortical principal neurons and cortical interneurons in mouse ethanol drinking. Consumption of escalating concentrations of ethanol was measured in mice with GluN2B gene deletion in either cortical principal neurons (GluN2B(CxNULL)) or interneurons (GluN2B(InterNULL)), using a two-bottle choice paradigm...
February 2017: Alcohol
https://www.readbyqxmd.com/read/28107590/endocannabinoid-activation-of-cb1-receptors-contributes-to-long-lasting-reversal-of-neuropathic-pain-by-repetitive-spinal-cord-stimulation
#16
L Sun, L Tai, Q Qiu, R Mitchell, S Fleetwood-Walker, E A Joosten, C W Cheung
BACKGROUND: Spinal cord stimulation (SCS) has been shown to be effective in the management of certain neuropathic pain conditions, however, the underlying mechanisms are incompletely understood. In this study, we investigated repetitive SCS in a rodent neuropathic pain model, revealing long-lasting and incremental attenuation of hyperalgesia and a mechanism of action involving endocannabinoids. METHOD: Animals were implanted with monopolar electrodes at the time of partial sciatic nerve injury...
January 20, 2017: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/28106041/glutamatergic-projections-from-the-entorhinal-cortex-to-dorsal-dentate-gyrus-mediate-context-induced-reinstatement-of-heroin-seeking
#17
Feifei Ge, Na Wang, Cailian Cui, Yijing Li, Yan Liu, Yaoying Ma, Shuli Liu, Haolin Zhang, Xiaowei Sun
Re-exposure to the context associated with heroin intake provokes relapse to drug taking after abstinence. The dorsal dentate gyrus (dDG) and entorhinal cortex (EC) have been implicated in contextual memory processing, but the underlying circuit mechanisms in context-induced relapse remains poorly understood. In this study, using a self-administration rat model, we found that activation and synaptic transmission of glutamatergic projections from the EC to the upper blade of dentate gyrus (dDGub) were significantly enhanced during context-induced reinstatement of heroin seeking...
January 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28098256/dopamine-promotes-nmda-receptor-hypofunction-in-the-retina-through-d1-receptor-mediated-csk-activation-src-inhibition-and-decrease-of-glun2b-phosphorylation
#18
Renato Socodato, Felipe N Santiago, Camila C Portugal, Ivan Domith, Thaísa G Encarnação, Erick C Loiola, Ana L M Ventura, Marcelo Cossenza, João B Relvas, Newton G Castro, Roberto Paes-de-Carvalho
Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1 receptors (D1Rs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between D1Rs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated D1R stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28095420/molecular-mechanism-of-disease-associated-mutations-in-the-pre-m1-helix-of-nmda-receptors-and-potential-rescue-pharmacology
#19
Kevin K Ogden, Wenjuan Chen, Sharon A Swanger, Miranda J McDaniel, Linlin Z Fan, Chun Hu, Anel Tankovic, Hirofumi Kusumoto, Gabrielle J Kosobucki, Anthony J Schulien, Zhuocheng Su, Joseph Pecha, Subhrajit Bhattacharya, Slavé Petrovski, Adam E Cohen, Elias Aizenman, Stephen F Traynelis, Hongjie Yuan
N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28094500/chronic-mild-stress-induced-alterations-of-local-protein-synthesis-a-role-for-cognitive-impairment
#20
Francesca Calabrese, Paola Brivio, Piotr Gruca, Magdalena Lason-Tyburkiewicz, Mariusz Papp, Marco A Riva
Depression, a major cause of disability worldwide, is characterized by a complex and heterogeneous symptomatology. With this respect, cognitive deterioration represents a major problem that has a strong impact on a patient's function. Thus, within the context of a depressive phenotype, it is important to characterize the mechanisms that sustain cognitive dysfunctions and may represent an important target for pharmacological intervention. Here, using the chronic mild stress (CMS) paradigm of depression, we found that, independently from the anhedonic phenotype, CMS rats showed a deficit in the novel object recognition (NOR) test, which is associated with an inability to phosphorylate GluN2B subunit on Ser1303 and to activate the mTOR pathway...
February 3, 2017: ACS Chemical Neuroscience
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