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https://www.readbyqxmd.com/read/28731405/pro-death-nmda-receptor-signaling-is-promoted-by-the-glun2b-c-terminus-independently-of-dapk1
#1
Jamie McQueen, Tomas J Ryan, Sean McKay, Katie Fm Marwick, Paul E Baxter, Sarah M Carpanini, Thomas M Wishart, Thomas H Gillingwater, Jean C Manson, David Ja Wyllie, Seth Gn Grant, Barry McColl, Noboru Komiyama, Giles E Hardingham
Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by DAPK1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by DAPK1 deficiency in vitro or following ischemia in vivo...
July 21, 2017: ELife
https://www.readbyqxmd.com/read/28730861/comparative-outcomes-in-children-and-adults-with-anti-n-methyl-d-aspartate-anti-nmda-receptor-encephalitis
#2
Eliza Gordon-Lipkin, Anusha K Yeshokumar, Deanna Saylor, Ana Arenivas, John C Probasco
This study compared neurologic disability and adaptive function in children and adults >1 year following anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis diagnosis. Retrospective record review identified 12 patients with anti-NMDAR encephalitis. At last follow-up, all surviving patients had "good" modified Rankin Score (0-2). Four children, 6 adults, and their families participated in a telephone interview. Median duration since diagnosis was similar for children (2.42 years, interquartile range 2...
January 1, 2017: Journal of Child Neurology
https://www.readbyqxmd.com/read/28729220/cognitive-enhancement-and-antipsychotic-like-activity-following-repeated-dosing-with-the-selective-m4-pam-vu0467154
#3
Robert W Gould, Michael D Grannan, Barak W Gunter, Jacob Ball, Michael Bubser, Thomas M Bridges, Jurgen Wess, Michael W Wood, Nicholas J Brandon, Mark E Duggan, Colleen M Niswender, Craig W Lindsley, P Jeffrey Conn, Carrie K Jones
Although selective activation of the M1 muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M4 mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M4 mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms...
July 17, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28726484/annals-express-experience-with-newer-central-nervous-system-autoantibodies
#4
Abid Karim, Saiju Jacob
In the last decade, a large number of neuronal cell-surface antibodies have been described which are responsible for a range of neuroimmunological central nervous system disorders. Unlike the paraneoplastic antibodies which target intracellular antigens, these antibodies appear to be pathogenic and hence identification and prompt treatment can make a substantial impact on clinical outcomes of these patients. We review the common antibodies against the ionotropic Glutamate receptors (NMDAR, AMPAR), metabotropic Glutamate receptors (mGluR1 and mGluR5), voltage gated potassium channel-complex proteins (LGI1, CASPR2), and other antibodies targeted against Glycine receptor, Glutamic acid decarboxylase (GAD), Gamma Amino Butyric Acid B (GABAB), Dopamine-2-receptor (D2R) and Dipeptidyl-peptidase-like protein 6 (DPPX)...
January 1, 2017: Annals of Clinical Biochemistry
https://www.readbyqxmd.com/read/28721398/calcium-stimulated-adenylyl-cyclase-subtype-1-ac1-contributes-to-ltp-in-the-insular-cortex-of-adult-mice
#5
Manabu Yamanaka, Takanori Matsuura, Haili Pan, Min Zhuo
Long-term potentiation (LTP) of synaptic transmission in the central nervous system is a key form of cortical plasticity. The insular cortex (IC) is known to play important roles in pain perception, aversive memory and mood disorders. LTP has been recently reported in the IC, however, the signaling pathway for IC LTP remains unknown. Here, we investigated the synaptic mechanism of IC LTP. We found that IC LTP induced by the pairing protocol was N-methyl-D-aspartate receptors (NMDARs) dependent, and expressed postsynaptically, since paired-pulse ratio (PPR) was not affected...
July 2017: Heliyon
https://www.readbyqxmd.com/read/28720858/gsk-3%C3%AE-deletion-in-dentate-gyrus-excitatory-neuron-impairs-synaptic-plasticity-and-memory
#6
Enjie Liu, Ao-Ji Xie, Qiuzhi Zhou, Mengzhu Li, Shujuan Zhang, Shihong Li, Weijin Wang, Xiaochuan Wang, Qun Wang, Jian-Zhi Wang
Increasing evidence suggests that glycogen synthase kinase-3β (GSK-3β) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3β also shows detrimental effects. Currently, the function of GSK-3β in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre-2A-eGFP into GSK-3β(lox/lox) mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28719878/the-effects-of-fluoride-on-neuronal-function-occurs-via-cytoskeleton-damage-and-decreased-signal-transmission
#7
Lingli Chen, Hongmei Ning, Zhihong Yin, Xiaochao Song, Yongchao Feng, Hao Qin, Yi Li, Jundong Wang, Yaming Ge, Wenkui Wang
It has been reported that fluoride exposure may cause serious public health problems, particularly neurotoxicity. However, the underlying mechanisms remain unclear. This study used Neuro-2A cells to investigate the effects of fluoride on the cytoskeleton. The Neuro-2A cells were exposed to 0, 1, 2, 4 and 6 mM sodium fluoride (NaF) for 24 h. Cell viability and lactate dehydrogenase (LDH) release were examined. It was observed that exposure to NaF reduced cell viability, disrupted cellular membrane integrity, and high levels of LDH were released...
June 30, 2017: Chemosphere
https://www.readbyqxmd.com/read/28719605/extracellular-phosphorylation-of-a-receptor-tyrosine-kinase-controls-synaptic-localization-of-nmda-receptors-and-regulates-pathological-pain
#8
Kenji Hanamura, Halley R Washburn, Sean I Sheffler-Collins, Nan L Xia, Nathan Henderson, Dipti V Tillu, Shayne Hassler, Daniel S Spellman, Guoan Zhang, Thomas A Neubert, Theodore J Price, Matthew B Dalva
Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2...
July 2017: PLoS Biology
https://www.readbyqxmd.com/read/28716964/a-glun2b-selective-nmdar-antagonist-reverses-synapse-loss-and-cognitive-impairment-produced-by-the-hiv-1-protein-tat
#9
Jonathan D Raybuck, Nicholas J Hargus, Stanley A Thayer
HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both in vitro and in vivo and has been linked to impaired neurocognitive function in humans. In vitro studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat...
July 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28711909/h2o2-attenuates-igf-1r-tyrosine-phosphorylation-and-its-survival-signaling-properties-in-neuronal-cells-via-nr2b-containing-nmda-receptor
#10
Zhiwen Zeng, Dejun Wang, Uma Gaur, Liao Rifang, Haitao Wang, Wenhua Zheng
Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H2O2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H2O2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28711661/mechanisms-of-action-and-clinical-efficacy-of-nmda-receptor-modulators-in-mood-disorders
#11
REVIEW
Mehdi Ghasemi, Cristy Phillips, Atoossa Fahimi, Margaret Windy McNerney, Ahmad Salehi
Although the biogenic amine models have provided meaningful links between clinical phenomena and pharmacological management of with mood disorders (MDs), the onset of action of current treatments is slow and a proportion of individuals fail to adequately respond. A growing number of investigations have focused on the glutamatergic system as a viable target. Herein we review the putative role of N-methyl-D-aspartate (NMDA) signaling in the pathophysiology of MDs. Prompting this focus are several lines of evidence: 1) altered glutamate and NMDA receptor (NMDAR) expression and functioning; 2) antidepressant effects of NMDAR signaling blockers; 3) interaction between conventional therapeutic regimens and NMDAR signaling modulators; 4) biochemical evidence of interaction between monoaminergic system and NMDAR signaling; 5) interaction between neurotrophic factors and NMDAR signaling in mood regulation; 6) cross-talk between NMDAR signaling and inflammatory processes; and 7) antidepressant effects of a number of NMDA modulators in recent clinical trials...
July 12, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28711472/interactive-effects-of-an-n-methyl-d-aspartate-receptor-antagonist-and-a-nicotinic-acetylcholine-receptor-agonist-on-mismatch-negativity-implications-for-schizophrenia
#12
Holly K Hamilton, Deepak C D'Souza, Judith M Ford, Brian J Roach, Naomi S Kort, Kyung-Heup Ahn, Savita Bhakta, Mohini Ranganathan, Daniel H Mathalon
N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities...
July 12, 2017: Schizophrenia Research
https://www.readbyqxmd.com/read/28709671/mechanism-and-properties-of-positive-allosteric-modulation-of-n-methyl-d-aspartate-receptors-by-6-alkyl-2-naphthoic-acid-derivatives
#13
Kiran Sapkota, Mark W Irvine, Guangyu Fang, Erica S Burnell, Neil Bannister, Arturas Volianskis, Georgia R Culley, Shashank M Dravid, Graham L Collingridge, David E Jane, Daniel T Monaghan
The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs...
July 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28701927/activation-of-the-creb-c-fos-pathway-during-long-term-synaptic-plasticity-in-the-cerebellum-granular-layer
#14
Daniela Gandolfi, Silvia Cerri, Jonathan Mapelli, Mariarosa Polimeni, Simona Tritto, Marie-Therese Fuzzati-Armentero, Albertino Bigiani, Fabio Blandini, Lisa Mapelli, Egidio D'Angelo
The induction of long-term potentiation and depression (LTP and LTD) is thought to trigger gene expression and protein synthesis, leading to consolidation of synaptic and neuronal changes. However, while LTP and LTD have been proposed to play important roles for sensori-motor learning in the cerebellum granular layer, their association with these mechanisms remained unclear. Here, we have investigated phosphorylation of the cAMP-responsive element binding protein (CREB) and activation of the immediate early gene c-Fos pathway following the induction of synaptic plasticity by theta-burst stimulation (TBS) in acute cerebellar slices...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28698711/anti-n-methyl-d-aspartate-receptor-encephalitis-a-severe-potentially-reversible-autoimmune-encephalitis
#15
REVIEW
Cai-Yun Liu, Jie Zhu, Xiang-Yu Zheng, Chi Ma, Xu Wang
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28695335/glutamatergic-system-and-mtor-signaling-pathway-participate-in-the-antidepressant-like-effect-of-inosine-in-the-tail-suspension-test
#16
Filipe Marques Gonçalves, Vivian Binder Neis, Débora Kurrle Rieger, Tanara V Peres, Mark William Lopes, Isabella A Heinrich, Ana Paula Costa, Ana Lúcia S Rodrigues, Manuella P Kaster, Rodrigo Bainy Leal
Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice...
July 10, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28683723/case-report-anaesthetic-management-of-radical-gastrectomy-for-gastric-cancer-associated-with-anti-n-methyl-d-aspartate-receptor-encephalitis
#17
Lei Ding, Hongyu Tan, Ziyu Li, Jiafu Ji, Xuejun Song
BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare neurological disorder that is caused by the production of antibodies against NMDARs. As many anaesthetic drugs interact with NMDARs and may worsen the disease and because the disease poses risks, such as cardiovascular events, hyperthermia and respiratory insufficiency, while under anaesthesia, administering anaesthesia to patients with this disorder is clinically challenging. CASE PRESENTATION: A 55-year-old man with gastric cancer associated with anti-NMDAR encephalitis who was diagnosed 8 months prior was admitted to Peking University Cancer Hospital for tumour resection...
July 6, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/28682239/physiological-and-pathophysiological-control-of-synaptic-glun2b-nmda-receptors-by-the-c-terminal-domain-of-amyloid-precursor-protein
#18
Paula A Pousinha, Xavier Mouska, Elisabeth F Raymond, Carole Gwizdek, Ghien Dhib, Gwenola Poupon-Silvestre, Laure-Emmanuelle Zaragosi, Camilla Giudici, Ingrid Bethus, Emilie Pacary, Michael Willem, Hélène Marie
The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer's disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in-vivo AICD expression, ex-vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism...
July 6, 2017: ELife
https://www.readbyqxmd.com/read/28679049/role-of-mglu5-receptors-and-inhibitory-neurotransmission-in-m1-dependent-muscarinic-ltd-in-the-prefrontal-cortex-implications-in-schizophrenia
#19
Ayan Ghoshal, Sean P Moran, Jonathan W Dickerson, Max E Joffe, Brad A Grueter, Zixiu Xiang, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Selective potentiation of the mGlu5 subtype of metabotropic glutamate (mGlu) receptor using positive allosteric modulators (PAMs) has robust cognition-enhancing effects in rodent models that are relevant for schizophrenia. Until recently, these effects were thought to be due to potentiation of mGlu5-induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu5 PAMs that do not potentiate mGlu5 effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu5 PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions...
July 5, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28676240/local-nmda-receptor-hypofunction-evokes-generalized-effects-on-gamma-and-high-frequency-oscillations-and-behavior
#20
Jaime Lee, Matthew R Hudson, Terence J O'Brien, Jess Nithianantharajah, Nigel C Jones
The NMDA receptor (NMDAr) hypofunction theory of schizophrenia suggests that aberrant signaling through NMDAr underlies the pathophysiology of this disease. This is commonly modeled in rodents via treatment with NMDAr antagonists, which causes a range of behavioral effects that represent endophenotypes related to schizophrenia. These drugs also disrupt high-frequency neural oscillations within the brain, also potentially relevant to disease. We studied the effect of localized NMDAr hypofunction on the generation of neural oscillations occurring both locally and in distant brain regions, and on behaviors routinely used as endophenotypes to model psychosis in rodents...
July 1, 2017: Neuroscience
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