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https://www.readbyqxmd.com/read/27926876/potentiation-of-synaptic-glun2b-nmdar-currents-by-fyn-kinase-is-gated-through-bdnf-mediated-disinhibition-in-spinal-pain-processing
#1
Michael E Hildebrand, Jian Xu, Annemarie Dedek, Yi Li, Ameet S Sengar, Simon Beggs, Paul J Lombroso, Michael W Salter
In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27917110/adolescent-mice-are-resilient-to-alcohol-withdrawal-induced-anxiety-and-changes-in-indices-of-glutamate-function-within-the-nucleus-accumbens
#2
Kaziya M Lee, Michal A Coelho, Hadley A McGregor, Noah R Solton, Matan Cohen, Karen K Szumlinski
Binge-drinking is the most prevalent form of alcohol abuse and while an early life history of binge-drinking is a significant risk factor for subsequent alcoholism and co-morbid affective disorders, relatively little is known regarding the biobehavioral impact of binge-drinking during the sensitive neurodevelopmental period of adolescence. In adult mice, a month-long history of binge-drinking elicits a hyper-glutamatergic state within the nucleus accumbens (Acb), coinciding with hyper-anxiety. Herein, we employed a murine model of binge-drinking to determine whether or not: (1) withdrawal-induced changes in brain and behavior differ between adult and adolescent bingers; and (2) increased behavioral signs of negative affect and changes in Acb expression of glutamate-related proteins would be apparent in adult mice with less chronic binge-drinking experience (14 days, approximating the duration of mouse adolescence)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27916457/molecular-basis-for-subtype-specificity-and-high-affinity-zinc-inhibition-in-the-glun1-glun2a-nmda-receptor-amino-terminal-domain
#3
Annabel Romero-Hernandez, Noriko Simorowski, Erkan Karakas, Hiro Furukawa
Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure...
November 21, 2016: Neuron
https://www.readbyqxmd.com/read/27888019/ifenprodil-infusion-in-agranular-insular-cortex-alters-social-behavior-and-vocalizations-in-rats-exposed-to-moderate-levels-of-ethanol-during-prenatal-development
#4
Clark W Bird, Daniel Barto, Christy M Magcalas, Carlos I Rodriguez, Tia Donaldson, Suzy Davies, Daniel D Savage, Derek A Hamilton
Moderate exposure to alcohol during development leads to subtle neurobiological and behavioral effects classified under the umbrella term fetal alcohol spectrum disorders (FASDs). Alterations in social behaviors are a frequently observed consequence of maternal drinking, as children with FASDs display inappropriate aggressive behaviors and altered responses to social cues. Rodent models of FASDs mimic the behavioral alterations seen in humans, with rats exposed to ethanol during development displaying increased aggressive behaviors, decreased social investigation, and altered play behavior...
November 22, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27881781/blocking-the-interaction-between-ephb2-and-addls-by-a-small-peptide-rescues-impaired-synaptic-plasticity-and-memory-deficits-in-a-mouse-model-of-alzheimer-s-disease
#5
Xiao-Dong Shi, Kai Sun, Rui Hu, Xiao-Ya Liu, Qiu-Mei Hu, Xiao-Yu Sun, Bin Yao, Nan Sun, Jing-Ru Hao, Pan Wei, Yuan Han, Can Gao
: Soluble amyloid-β (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aβ oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27871866/effects-of-the-glun2b-nmda-receptor-antagonist-ro-25-6981-on-two-types-of-behavioral-flexibility-in-rats
#6
Emma Clark, Kristen Antoniak, Alyssandra Feniquito, Hans C Dringenberg
Recent evidence has implicated N-methyl-d-aspartate receptors (NMDARs) in several aspects of learning and behavioral flexibility in rodents. Here, we examined the effects of treatment with Ro 25-6981, a selective antagonist of NMDARs containing GluN2B subunits, on two types of behavioral flexibility in rats, spatial reversal learning and set-shifting (spatial vs. motor strategy). To examine spatial reversal learning, rats were trained to swim to a hidden platform in a water maze over four days. On the following day, the platform was moved to a new location in the maze...
November 18, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27865917/the-co-expression-of-glun2b-subunits-of-the-nmda-receptors-and-glucocorticoid-receptors-after-chronic-restraint-stress-in-low-and-high-anxiety-rats
#7
Małgorzata Lehner, Aleksandra Wisłowska-Stanek, Marek Gryz, Alicja Sobolewska, Danuta Turzyńska, Natalia Chmielewska, Paweł Krząścik, Anna Skórzewska, Adam Płaźnik
The aim of this study was to assess the mechanisms underlying behavioural differences between high- (HR) and low- (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of the freezing response was used as a discriminating variable), after a chronic restraint procedure (21days, 3h daily). We analysed the expression of the GluN2B subunits of the NMDA and glucocorticoid receptors (GRs) in selected brain structures (immunofluorescence). Following chronic restraint stress in the HR rats, we observed a decrease in the expression of the GRs and GluN2B subunits of the NMDA receptor in the prefrontal cortical areas and the hippocampus compared to the HR-control and the LR-restraint groups...
November 16, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27865768/regulation-of-extrasynaptic-signaling-by-polysialylated-ncam-impact-for-synaptic-plasticity-and-cognitive-functions
#8
REVIEW
Hristo Varbanov, Alexander Dityatev
The activation of synaptic N-methyl-d-aspartate-receptors (NMDARs) is crucial for induction of synaptic plasticity and supports cell survival, whereas activation of extrasynaptic NMDARs inhibits long-term potentiation and triggers neurodegeneration. A soluble polysialylated form of the neural cell adhesion molecule (polySia-NCAM) suppresses signaling through peri-/extrasynaptic GluN2B-containing NMDARs. Genetic or enzymatic manipulations blocking this mechanism result in impaired synaptic plasticity and learning, which could be repaired by reintroduction of polySia, or inhibition of either GluN1/GluN2B receptors or downstream signaling through RasGRF1 and p38 MAP kinase...
November 16, 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27847466/glun2a-subunit-containing-nmda-receptors-are-the-preferential-neuronal-targets-of-homocysteine
#9
Dmitry A Sibarov, Polina A Abushik, Rashid Giniatullin, Sergei M Antonov
Homocysteine (HCY) is an endogenous redox active amino acid, best known as contributor to various neurodegenerative disorders. Although it is known that HCY can activate NMDA receptors (NMDARs), the mechanisms of its action on receptors composed of different NMDA receptor subunits remains almost unknown. In this study, using imaging and patch clamp technique in cultured cortical neurons and heterologous expression in HEK293T cells we tested the agonist activity of HCY on NMDARs composed of GluN1 and GluN2A subunits (GluN1/2A receptors) and GluN1 and GluN2B subunits (GluN1/2B receptors)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27845401/neuroprotection-mediated-through-glun2c-containing-n-methyl-d-aspartate-nmda-receptors-following-ischemia
#10
Connie Chung, John D Marson, Quan-Guang Zhang, Jimok Kim, Wei-Hua Wu, Darrell W Brann, Bo-Shiun Chen
Post-ischemic activation of NMDA receptors (NMDARs) has been linked to NMDAR subunit-specific signaling that mediates pro-survival or pro-death activity. Although extensive studies have been performed to characterize the role of GluN2A and GluN2B following ischemia, there is less understanding regarding the regulation of GluN2C. Here, we show that GluN2C expression is increased in acute hippocampal slices in response to ischemia. Strikingly, GluN2C knockout mice, following global cerebral ischemia, exhibit greater neuronal death in the CA1 area of the hippocampus and reduced spatial working memory compared to wild-type mice...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27845197/sustained-morphine-administration-induces-trpm8-dependent-cold-hyperalgesia
#11
Kerui Gong, Luc Jasmin
: It is not uncommon for patients chronically treated with opioids to exhibit opioid induced hyperalgesia (OIH), and this has been widely reported both clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate (NMDA) receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small diameter primary sensory neurons only...
November 11, 2016: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/27818632/afferent-input-selects-nmda-receptor-subtype-to-determine-the-persistency-of-hippocampal-ltp-in-freely-behaving-mice
#12
Jesús J Ballesteros, Arne Buschler, Georg Köhr, Denise Manahan-Vaughan
The glutamatergic N-methyl-D-aspartate receptor (NMDAR) is critically involved in many forms of hippocampus-dependent memory that may be enabled by synaptic plasticity. Behavioral studies with NMDAR antagonists and NMDAR subunit (GluN2) mutants revealed distinct contributions from GluN2A- and GluN2B-containing NMDARs to rapidly and slowly acquired memory performance. Furthermore, studies of synaptic plasticity, in genetically modified mice in vitro, suggest that GluN2A and GluN2B may contribute in different ways to the induction and longevity of synaptic plasticity...
2016: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/27818011/human-grin2b-variants-in-neurodevelopmental-disorders
#13
REVIEW
Chun Hu, Wenjuan Chen, Scott J Myers, Hongjie Yuan, Stephen F Traynelis
The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-d-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia...
October 2016: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/27816787/gastrodin-relieved-complete-freund-s-adjuvant-induced-spontaneous-pain-by-inhibiting-inflammatory-response
#14
Ting Sun, Jian Wang, Xiang Li, Yu-Jiao Li, Dan Feng, Wen-Long Shi, Ming-Gao Zhao, Jian-Bo Wang, Yu-Mei Wu
The analgesic effects of gastrodin (GAS), an active component derived from the Chinese herb Tian ma (Gastrodia elata Blume), on chronic inflammatory pain of mice and the involved molecular mechanisms were investigated. GAS significantly attenuated mice chronic inflammatory pain induced by hindpaw injection of complete Freund's adjuvant (CFA) and the accompanying anxiety-like behaviors. GAS administration reduced CFA-induced up-regulation of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, GluN2A- and GluN2B-containing N-methyl-d-aspartate (NMDA) receptors, and Ca(2+)/calmodulin-dependent protein kinase II-alpha (CaMKII-α) in the anterior cingulate cortex (ACC)...
November 3, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27814790/differential-effects-of-tm4-tryptophan-mutations-on-inhibition-of-n-methyl-d-aspartate-receptors-by-ethanol-and-toluene
#15
C Thetford Smothers, John J Woodward
The voluntary use and abuse of alcohol and inhalants is a recognized health problem throughout the world. Previous studies have shown that these agents affect brain function in a variety of ways including direct inhibition of key ion channels that regulate neuronal excitability. Among these, the N-methyl-d-aspartate (NMDA) receptor is particularly important given its key role in glutamatergic synaptic transmission, neuronal plasticity and learning and memory. Previous studies from this laboratory and others have identified key residues within transmembrane (TM) domains of the NMDA receptor that appear to regulate its sensitivity to alcohol and anesthetics...
November 2016: Alcohol
https://www.readbyqxmd.com/read/27810933/nmdars-adapt-to-neurotoxic-hiv-protein-tat-downstream-of-a-glun2a-ubiquitin-ligase-signaling-pathway
#16
Matthew V Green, Stanley A Thayer
: HIV-associated neurocognitive disorder (HAND) affects about half of HIV-infected patients. Infected non-neuronal cells release neurotoxic factors such as the viral protein, transactivator of transcription (Tat), that potentiate NMDAR function. NMDARs regulate synaptic changes observed following exposure to HIV proteins, which may underlie cognitive impairment in HAND patients. Here we used patch-clamp recording to measure NMDAR-mediated currents in rat hippocampal cultures following exposure to Tat...
November 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27807405/glycine-potentiates-ampa-receptor-function-through-metabotropic-activation-of-glun2a-containing-nmda-receptors
#17
Li-Jun Li, Rong Hu, Brendan Lujan, Juan Chen, Jian-Jian Zhang, Yasuko Nakano, Tian-Yuan Cui, Ming-Xia Liao, Jin-Cao Chen, Heng-Ye Man, Hua Feng, Qi Wan
NMDA receptors are Ca(2+)-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27807157/the-role-of-glun2c-containing-nmda-receptors-in-ketamine-s-psychotogenic-action-and-in-schizophrenia-models
#18
Elizaveta Khlestova, Jon W Johnson, John H Krystal, John Lisman
The NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia is supported by multiple lines of evidence. Notably, administration of the NMDAR antagonist, ketamine, to healthy human subjects has psychotogenic action, producing both positive and negative symptoms associated with schizophrenia. NMDARs have multiple subtypes, but the subtypes through which ketamine produces its psychotogenic effects are not known. Here we address this question using quantitative data that characterize ketamine's ability to block different NMDAR subtypes...
November 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27796759/increased-src-family-kinase-activity-disrupts-excitatory-synaptic-transmission-and-impairs-remote-fear-memory-in-forebrain-shp2-deficient-mice
#19
Xunyi Yan, Bin Zhang, Wen Lu, Lin Peng, Qian Yang, Wei Cao, Shen Lin, Wenyue Yu, Xiaoming Li, Yuehai Ke, Shengtian Li, Wei Yang, Jianhong Luo
Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory...
October 29, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27785460/involvement-of-brain-enriched-guanylate-kinase-associated-protein-begain-in-chronic-pain-after-peripheral-nerve-injury
#20
Tayo Katano, Masafumi Fukuda, Hidemasa Furue, Maya Yamazaki, Manabu Abe, Masahiko Watanabe, Kazuhiko Nishida, Ikuko Yao, Akihiro Yamada, Yutaka Hata, Nobuaki Okumura, Takanobu Nakazawa, Tadashi Yamamoto, Kenji Sakimura, Toshifumi Takao, Seiji Ito
Maintenance of neuropathic pain caused by peripheral nerve injury crucially depends on the phosphorylation of GluN2B, a subunit of the N-methyl-d-aspartate (NMDA) receptor, at Tyr1472 (Y1472) and subsequent formation of a postsynaptic density (PSD) complex of superficial spinal dorsal horn neurons. Here we took advantage of comparative proteomic analysis based on isobaric stable isotope tags (iTRAQ) between wild-type and knock-in mice with a mutation of Y1472 to Phe of GluN2B (Y1472F-KI) to search for PSD proteins in the spinal dorsal horn that mediate the signaling downstream of phosphorylated Y1472 GluN2B...
September 2016: ENeuro
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