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Erik Nylander, Alfhild Grönbladh, Sofia Zelleroth, Shanti Diwakarla, Fred Nyberg, Mathias Hallberg
Human growth hormone (GH) displays promising protective effects in the central nervous system after damage caused by various insults. Current evidence suggests that these effects may involve N-methyl-D-aspartate (NMDA) receptor function, a receptor that also is believed to play a role in opioid-induced neurotoxicity. The aims of the present study were to examine the acute toxic effects of methadone, an opioid receptor agonist and NMDA receptor antagonist, as well as to evaluate the protective properties of recombinant human GH (rhGH) on methadone-induced toxicity...
October 13, 2016: Neuroscience
Rong Hu, Juan Chen, Brendan Lujan, Ruixue Lei, Mi Zhang, Zefen Wang, Mingxia Liao, Zhiqiang Li, Yu Wan, Fang Liu, Hua Feng, Qi Wan
Ionotropic activation of NMDA receptors (NMDARs) requires agonist glutamate and co-agonist glycine. Here we show that glycine enhances the activation of cell survival-promoting kinase Akt in cultured cortical neurons in which both the channel activity of NMDARs and the glycine receptors are pre-inhibited. The effect of glycine is reduced by shRNA-mediated knockdown of GluN2A subunit-containing NMDARs (GluN2ARs), suggesting that a non-ionotropic activity of GluN2ARs mediates glycine-induced Akt activation. In support of this finding, glycine enhances Akt activation in HEK293 cells over-expressing GluN2ARs...
October 3, 2016: Scientific Reports
Anna Rafalo-Ulinska, Joanna Piotrowska, Agata Kryczyk, Włodzimierz Opoka, Magdalena Sowa-Kucma, Paulina Misztak, Grazyna Rajkowska, Craig A Stockmeier, Wojciech Datka, Gabriel Nowak, Bernadeta Szewczyk
BACKGROUND: Major depressive disorder (MDD) is a serious psychiatric illness, associated with an increasing rate of suicide. The pathogenesis of depression may be associated with the disruption of zinc (Zn) homeostasis. In the brain, several proteins that regulate Zn homeostasis are present, including Zn transporters (ZnTs) which remove Zn from the cytosol. The present study was designed to investigate whether depression and suicide are associated with alterations in the expression of the ZnTs protein...
September 13, 2016: Journal of Psychiatric Research
Andrew J Samson, Graham Robertson, Michele Zagnoni, Christopher N Connolly
Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients...
2016: Scientific Reports
Riley Edward Perszyk, John O DiRaddo, Katie L Strong, Chian-Ming Low, Kevin K Ogden, Alpa Khatri, Geoffrey A Vargish, Kenneth A Pelkey, Ludovic Tricoire, Dennis C Liotta, Yoland Smith, Chris J McBain, Stephen F Traynelis
NMDA receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus...
September 13, 2016: Molecular Pharmacology
Feng Yi, Tung-Chung Mou, Katherine N Dorsett, Robert A Volkmann, Frank S Menniti, Stephen R Sprang, Kasper B Hansen
NMDA receptors mediate excitatory synaptic transmission and regulate synaptic plasticity in the central nervous system, but their dysregulation is also implicated in numerous brain disorders. Here, we describe GluN2A-selective negative allosteric modulators (NAMs) that inhibit NMDA receptors by stabilizing the apo state of the GluN1 ligand-binding domain (LBD), which is incapable of triggering channel gating. We describe structural determinants of NAM binding in crystal structures of the GluN1/2A LBD heterodimer, and analyses of NAM-bound LBD structures corresponding to active and inhibited receptor states reveal a molecular switch in the modulatory binding site that mediate the allosteric inhibition...
September 21, 2016: Neuron
Roopashri Holehonnur, Aarron J Phensy, Lily J Kim, Milica Milivojevic, Dat Vuong, Delvin K Daison, Saira Alex, Michael Tiner, Lauren E Jones, Sven Kroener, Jonathan E Ploski
UNLABELLED: Reconsolidation updating is a form of memory modification in which an existing memory can become destabilized upon retrieval and subsequently be modified via protein-synthesis-dependent reconsolidation. However, not all memories appear to destabilize upon retrieval and thus are not modifiable via reconsolidation updating approaches and the neurobiological basis for this remains poorly understood. Here, we report that auditory fear memories created with 10 tone-shock pairings are resistant to retrieval-dependent memory destabilization and are associated with an increase in the synaptic GluN2A/GluN2B ratio in neurons of the basal and lateral amygdala (BLA) compared with weaker fear memories created via one or three tone-shock pairings...
September 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Assaf Yacobi, Yael Stern Bach, Michal Horowitz
Long-term heat acclimation (34 °C, 30d) alters the physiological responses and the metabolic state of organisms. It also improves ability to cope with hypoxic stress via a cross-tolerance mechanism. Within the brain, the hippocampal and frontal cortex neurons are the most sensitive to hypoxia and cell death is mainly caused by calcium influx via glutamate-gated ion channels, specifically NMDA and AMPA receptors. GluN1 subunit levels of NMDA-R correspond to NMDA-R levels. GluN2B/GluN2A subunit ratio is a qualitative index of channel activity; a higher ratio implies lower calcium permeability...
April 2014: Temperature: Multidisciplinary Biomedical Journal
Alessia Luoni, Peter Gass, Paolo Brambilla, Mirella Ruggeri, Marco A Riva, Dragos Inta
The evidence underlying the so-called glutamatergic hypothesis ranges from NMDA receptor hypofunction to an imbalance between excitatory and inhibitory circuits in specific brain structures. Among all glutamatergic system components, metabotropic receptors play a main role in regulating neuronal excitability and synaptic plasticity. Here, we investigated, using qRT-PCR and western blot, consequences in the hippocampus and prefrontal/frontal cortex (PFC/FC) of mice with a genetic deletion of the metabotropic glutamate receptor 5 (mGlu5), addressing key components of the GABAergic and glutamatergic systems...
August 31, 2016: European Archives of Psychiatry and Clinical Neuroscience
Yuan-Jian Yang, Ying Zhao, Bin Yu, Guo-Gang Xu, Wei Wang, Jin-Qiong Zhan, Zhen-Yu Tang, Ting Wang, Bo Wei
Alzheimer's disease (AD) is the most common type of clinical dementia. Previous studies have demonstrated that hydrogen sulfide (H2S) is implicated with the pathology of AD, and exogenous H2S attenuates spatial memory impairments in AD animal models. However, the molecular mechanism by which H2S improves cognition in AD has not been fully explored. Here, we report that chronic administration of sodium hydrosulfide (NaHS, a H2S donor) elevated hippocampal H2S levels and enhanced hippocampus-dependent contextual fear memory and novel object recognition in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice...
October 29, 2016: Neuroscience
Timothy J Wilding, Melany N Lopez, James E Huettner
UNLABELLED: NMDA receptors are ligand-gated ion channels that underlie transmission at excitatory synapses and play an important role in regulating synaptic strength and stability. Functional NMDA receptors require two copies of the GluN1 subunit coassembled with GluN2 (and/or GluN3) subunits into a heteromeric tetramer. A diverse array of allosteric modulators can upregulate or downregulate NMDA receptor activity. These modulators include both synthetic compounds and endogenous modulators, such as cis-unsaturated fatty acids, 24(S)-hydroxycholesterol, and various neurosteroids...
August 24, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Grace France, Diego Fernández-Fernández, Erica S Burnell, Mark W Irvine, Daniel T Monaghan, David E Jane, Zuner A Bortolotto, Graham L Collingridge, Arturas Volianskis
In the CA1 area of the hippocampus N-methyl-d-aspartate receptors (NMDARs) mediate the induction of long-term depression (LTD), short-term potentiation (STP) and long-term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in the juvenile hippocampal slices but the involvement of particular NMDAR-subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP-AAM077, Ro 25-6981 and UBP145 to target GluN2A-, 2B- and 2D-containing NMDARs respectively, we show that GluN2B-containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus...
August 11, 2016: Neuropharmacology
Yan Li, Lirong Chang, Yizhi Song, Xianghong Gao, Francesco Roselli, Jinping Liu, Wei Zhou, Yuan Fang, Wei Ling, Hui Li, Osborne F X Almeida, Yan Wu
Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection...
August 1, 2016: Journal of Alzheimer's Disease: JAD
Karen K Szumlinski, Melissa G Wroten, Bailey W Miller, Arianne D Sacramento, Matan Cohen, Osnat Ben-Shahar, Tod E Kippin
Cue-elicited drug-craving correlates with hyperactivity within prefrontal cortex (PFC), which is theorized to result from dysregulated excitatory neurotransmission. The NMDA glutamate receptor is highly implicated in addiction-related neuroplasticity. As NMDA receptor function is regulated critically by its GluN2 subunits, herein, we assayed the relation between incubated cue-elicited cocaine-seeking following extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) and the expression of GluN2A/B receptor subunits within PFC sub regions during early versus late withdrawal (respectively, 3 vs...
2016: Journal of Drug Abuse
Jing-Dun Xie, Shao-Rui Chen, Hong Chen, Wei-An Zeng, Hui-Lin Pan
Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-d-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices...
September 9, 2016: Journal of Biological Chemistry
Zhen-Zhen Duan, Feng Zhang, Feng-Ying Li, Yi-Fei Luan, Peng Guo, Yi-Hang Li, Yong Liu, Su-Hua Qi
It has been demonstrated that Src could modulate NMDA receptor, and PAR1 could also affect NMDAR signaling. However, whether PAR1 could regulate NMDAR through Src under ICH has not yet been investigated. In this study, we demonstrated the role of Src-PSD95-GluN2A signaling cascades in rat ICH model and in vitro thrombin challenged model. Using the PAR1 agonist SFLLR, antagonist RLLFS and Src inhibitor PP2, electrophysiological analysis showed that PAR1 regulated NMDA-induced whole-cell currents (INMDA) though Src in primary cultured neurons...
2016: Scientific Reports
Torrian L Green, Jessica A Burket, Stephen I Deutsch
NMDA receptor-mediated neurotransmission is implicated in the regulation of normal sociability in mice. The heterotetrameric NMDA receptor is composed of two obligatory GluN1 and either two "modulatory" GluN2A or GluN2B receptor subunits. GluN2A and GluN2B-containing receptors differ in terms of their developmental expression, distribution between synaptic and extrasynaptic locations, and channel kinetic properties, among other differences. Because age-dependent differences in disruptive effects of GluN2A and GluN2B subtype-selective antagonists on sociability and locomotor activity have been reported in rats, the current investigation explored age-dependent effects of PEAQX, a GluN2A subtype-selective antagonist, on sociability, stereotypic behaviors emerging during social interaction, and spatial working memory in 4- and 8-week old male Swiss Webster mice...
July 2016: Brain Research Bulletin
Lunxu Li, Zhengqian Li, Yiyun Cao, Dongsheng Fan, Dehua Chui, Xiangyang Guo
There is increasing concern regarding the postoperative cognitive dysfunction (POCD) in the aging population, and general anesthetics are believed to be involved. Isoflurane exposure induced increased N-methyl-D-aspartic acid receptor (NMDAR) GluN2B subunit expression following anesthesia, which was accompanied by alteration of the cognitive function. However, whether isoflurane affects this expression in different subcellular compartments, and is involved in the development of POCD remains to be elucidated...
July 2016: Experimental and Therapeutic Medicine
Deebika Balu, John R Larson, Jennifer V Schmidt, David Wirtshafter, Aleksey Yevtodiyenko, John P Leonard
Activity-dependent plasticity in NMDA receptor-containing synapses can be regulated by phosphorylation of serines and tyrosines in the C-terminal domain of the receptor subunits by various kinases. We have previously identified S1291/S1312 as important sites for PKC phosphorylation; while Y1292/Y1312 are the sites indirectly phosphorylated by PKC via Src kinase. In the oocyte expression system, mutation of those Serine sites to Alanine (that cannot be phosphorylated) in the GluN2A subunit, resulted in a decreased PKC stimulated current enhancement through the receptors compared to wild-type NMDA receptors...
September 1, 2016: Brain Research
Benjamin Serraz, Teddy Grand, Pierre Paoletti
Recent human genetic studies have identified a surprisingly high number of alterations in genes encoding NMDA receptor (NMDAR) subunits in several common brain diseases. Among NMDAR subunits, the widely-expressed GluN2A subunit appears particularly affected, with tens of de novo or inherited mutations associated with neurodevelopmental conditions including childhood epilepsies and cognitive deficits. Despite the increasing identification of NMDAR mutations of clinical interest, there is still little information about the effects of the mutations on receptor and network function...
October 2016: Neuropharmacology
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