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Sample records for activation augments nmda

  1. NMDA receptor activity in neuropsychiatric disorders

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    Shaheen E Lakhan

    2013-06-01

    Full Text Available N-Methyl-D-aspartate (NMDA receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington's disease, Alzheimer's disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.

  2. Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain.

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    Forsyth, Jennifer K; Bachman, Peter; Mathalon, Daniel H; Roach, Brian J; Asarnow, Robert F

    2015-12-15

    Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-d-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using d-cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high-frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activity-dependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers.

  3. A quantitative method to assess extrasynaptic NMDA receptor function in the protective effect of synaptic activity against neurotoxicity

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    Bading Hilmar

    2008-01-01

    Full Text Available Abstract Background Extrasynaptic NMDA receptors couple to a CREB shut-off pathway and cause cell death, whereas synaptic NMDA receptors and nuclear calcium signaling promote CREB-mediated transcription and neuronal survival. The distribution of NMDA receptors (synaptic versus extrasynaptic may be an important parameter that determines the susceptibility of neurons to toxic insults. Changes in receptor surface expression towards more extrasynaptic NMDA receptors may lead to neurodegeneration, whereas a reduction of extrasynaptic NMDA receptors may render neurons more resistant to death. A quantitative assessment of extrasynaptic NMDA receptors in individual neurons is needed in order to investigate the role of NMDA receptor distribution in neuronal survival and death. Results Here we refined and verified a protocol previously used to isolate the effects of extrasynaptic NMDA receptors using the NMDA receptor open channel blocker, MK-801. Using this method we investigated the possibility that the known neuroprotective shield built up in hippocampal neurons after a period of action potential bursting and stimulation of synaptic NMDA receptors is due to signal-induced trafficking of extrasynaptic NMDA receptors or a reduction in extrasynaptic NMDA receptor function. We found that extrasynaptic NMDA receptor-mediated calcium responses and whole cell currents recorded under voltage clamp were surprisingly invariable and did not change even after prolonged (16 to 24 hours periods of bursting and synaptic NMDA receptor activation. Averaging a large number of calcium imaging traces yielded a small (6% reduction of extrasynaptic NMDA receptor-mediated responses in hippocampal neurons that were pretreated with prolonged bursting. Conclusion The slight reduction in extrasynaptic NMDA receptor function following action potential bursting and synaptic NMDA receptor stimulation could contribute to but is unlikely to fully account for activity

  4. Facilitation of neocortical presynaptic terminal development by NMDA receptor activation

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    Sceniak Michael P

    2012-02-01

    Full Text Available Abstract Background Neocortical circuits are established through the formation of synapses between cortical neurons, but the molecular mechanisms of synapse formation are only beginning to be understood. The mechanisms that control synaptic vesicle (SV and active zone (AZ protein assembly at developing presynaptic terminals have not yet been defined. Similarly, the role of glutamate receptor activation in control of presynaptic development remains unclear. Results Here, we use confocal imaging to demonstrate that NMDA receptor (NMDAR activation regulates accumulation of multiple SV and AZ proteins at nascent presynaptic terminals of visual cortical neurons. NMDAR-dependent regulation of presynaptic assembly occurs even at synapses that lack postsynaptic NMDARs. We also provide evidence that this control of presynaptic terminal development is independent of glia. Conclusions Based on these data, we propose a novel NMDAR-dependent mechanism for control of presynaptic terminal development in excitatory neocortical neurons. Control of presynaptic development by NMDARs could ultimately contribute to activity-dependent development of cortical receptive fields.

  5. mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway

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    Liao Pei-Fei

    2011-02-01

    Full Text Available Abstract Background In order to understand the interaction between the metabotropic glutamate subtype 5 (mGluR5 and N-methyl-D-aspartate (NMDA receptors, the influence of mGluR5 positive modulators in the inhibition of NMDA receptors by the noncompetitive antagonist ketamine, the competitive antagonist D-APV and the selective NR2B inhibitor ifenprodil was investigated. Methods This study used the multi-electrode dish (MED system to observe field potentials in hippocampal slices of mice. Results Data showed that the mGluR5 agonist (RS-2-chloro-5-hydroxyphenylglycine (CHPG, as well as the positive allosteric modulators 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB and 3,3'-difluorobenzaldazine (DFB alone did not alter the basal field potentials, but enhanced the amplitude of field potentials induced by NMDA. The inhibitory action of ketamine on NMDA-induced response was reversed by CHPG, DFB, and CDPPB, whereas the blockade of NMDA receptor by D-APV was restored by CHPG and CDPPB, but not by DFB. Alternatively, activation of NMDA receptors prior to the application of mGluR5 modulators, CHPG was able to enhance NMDA-induced field potentials and reverse the suppressive effect of ketamine and D-APV, but not ifenprodil. In addition, chelerythrine chloride (CTC, a protein kinase C (PKC inhibitor, blocked the regulation of mGluR5 positive modulators in enhancing NMDA receptor activation and recovering NMDA receptor inhibition. The PKC activator (PMA mimicked the effects of mGluR5 positive modulators on enhancing NMDA receptor activation and reversing NMDA antagonist-evoked NMDA receptor suppression. Conclusion Our results demonstrate that the PKC-dependent pathway may be involved in the positive modulation of mGluR5 resulting in potentiating NMDA receptor activation and reversing NMDA receptor suppression induced by NMDA antagonists.

  6. In vitro neuronal network activity in NMDA receptor encephalitis

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    Jantzen Sabine U

    2013-02-01

    Full Text Available Abstract Background Anti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma. Results We describe effects of cerebrospinal fluid (CSF from an anti-N-methyl-D-aspartate receptor (NMDAR encephalitis patient on in vitro neuronal network activity (ivNNA. In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA system. The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease. Conclusion Patient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

  7. Activation of nucleus accumbens NMDA receptors differentially affects appetitive or aversive taste learning and memory

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    Luis eNuñez-Jaramillo

    2012-04-01

    Full Text Available Taste memory depends on motivational and post-ingestional consequences; thus, it can be aversive (e.g., conditioned taste aversion, CTA if a novel, palatable taste is paired with visceral malaise, or it can be appetitive if no intoxication appears after novel taste consumption, and a taste preference is developed. The nucleus accumbens (NAc plays a role in hedonic reactivity to taste stimuli, and recent findings suggest that reward and aversion are differentially encoded by the activity of NAc neurons. The present study examined whether the requirement for NMDA receptors in the NAc core during rewarding appetitive taste learning differs from that during aversive taste conditioning, as well as during retrieval of appetitive versus aversive taste memory, using the taste preference or CTA model, respectively. Bilateral infusions of NMDA (1 μg/μl, 0.5 μl into the NAc core were performed before acquisition or before retrieval of taste preference or CTA. Activation of NMDA receptors before taste preference training or CTA acquisition did not alter memory formation. Furthermore, NMDA injections before aversive taste retrieval had no effect on taste memory; however, 24 h later, CTA extinction was significantly delayed. Also, NMDA injections, made before familiar appetitive memory retrieval, interrupted the development of taste preference and produced a preference delay 24 h later. These results suggest that memory formation for a novel taste produces neurochemical changes in the NAc core that have differential requirements for NMDA receptors during retrieval of appetitive or aversive memory.

  8. NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation

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    Fabio eCavaliere

    2013-12-01

    Full Text Available Multipotent cells from the juvenile subventricular zone (SVZ possess the ability to differentiate into new neural cells. Depending on local signals, SVZ can generate new neurons, astrocytes or oligodendrocytes. We previously demonstrated that activation of NMDA receptors in SVZ progenitors increases the rate of oligodendrocyte differentiation. Here we investigated the mechanisms involved in NMDA receptor-dependent differentiation. Using functional studies performed with the reporter gene luciferase we found that activation of NMDA receptor stimulates PKC. In turn, stimulation of PKC precedes the activation of NADPH oxidase (NOX as demonstrated by translocation of the p67phox subunit to the cellular membrane. We propose that NOX2 is involved in the transduction of the signal from NMDA receptors through PKC activation as the inhibitor gp91 reduced their pro-differentiation effect. In addition, our data and that from other groups suggest that signaling through the NMDA receptor/PKC/NOX2 cascade generates ROS that activate the PI3/mTOR pathway and finally leads to the generation of new oligodendrocytes.

  9. Nerve growth factor alters the sensitivity of rat masseter muscle mechanoreceptors to NMDA receptor activation.

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    Wong, Hayes; Dong, Xu-Dong; Cairns, Brian E

    2014-11-01

    Intramuscular injection of nerve growth factor (NGF) into rat masseter muscle induces a local mechanical sensitization that is greater in female than in male rats. The duration of NGF-induced sensitization in male and female rats was associated with an increase in peripheral N-methyl-d-aspartate (NMDA) receptor expression by masseter muscle afferent fibers that began 3 days postinjection. Here, we investigated the functional consequences of increased NMDA expression on the response properties of masseter muscle mechanoreceptors. In vivo extracellular single-unit electrophysiological recordings of trigeminal ganglion neurons innervating the masseter muscle were performed in anesthetized rats 3 days after NGF injection (25 μg/ml, 10 μl) into the masseter muscle. Mechanical activation threshold was assessed before and after intramuscular injection of NMDA. NMDA injection induced mechanical sensitization in both sexes that was increased significantly following NGF injection in the male rats but not in the female rats. However, in female but not male rats, further examination found that preadministration of NGF induced a greater sensitization in slow Aδ-fibers (2-7 m/s) than fast Aδ-fibers (7-12 m/s). This suggests that preadministration of NGF had a different effect on slowly conducting mechanoreceptors in the female rats compared with the male rats. Although previous studies have found an association between estrogenic tone and NMDA activity, no correlation was observed between NMDA-evoked mechanical sensitization and plasma estrogen level. This study suggests NGF alters NMDA-induced mechanical sensitization in the peripheral endings of masseter mechanoreceptors in a sexually dimorphic manner.

  10. Induction of Increased Intraceilular Calcium in Astrocytes by Glutamate through Activating NMDA and AMPA Receptors

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    张蕲; 胡波; 孙圣刚; 童萼塘

    2003-01-01

    To study the effect of glutamate on the intracellular calcium signal of pure cultured ratastrocytes and the role of NMDA and AMPA receptors in the procedure, the change of calcium sig-nal was investigated by monitoring the fluctuation of intracellular Ca2+ concentration ([Ca2+]i) onthe basis of Fura-2 single cell fluorescent ratio (F345/F380). The changes in the effect of glutamateon the intracellular calcium signal were observed after blockage of NMDA and(or) AMPA recep-tors. It was found that L-glutamate could induce an increased [Ca2+]i in most of the cells in concen-tration- and time-dependent manner. D-(-)-2-amino-5-phosphonopentanoic acid (D-AP-5, a selec-tive antagonist of the NMDA receptor) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selec-tive antagonist of the AMPA receptor) could abolish the effects of NMDA and AMPA respectively.Th.e treatment of D-AP-5 and CNQX simultaneously or respectively could attenuate the effect of L-glutamate at varying degrees. All these indicated that glutamate could modulate intracellular Ca2+of pure cultured rat astrocytes through different pathways. The activation of NMDA and AMPA re-ceptors took part in the complex mechanisms.

  11. Brain-derived neurotrophic factor activation of extracellular signal-regulated kinase is autonomous from the dominant extrasynaptic NMDA receptor extracellular signal-regulated kinase shutoff pathway.

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    Mulholland, P J; Luong, N T; Woodward, J J; Chandler, L J

    2008-01-24

    NMDA receptors bidirectionally modulate extracellular signal-regulated kinase (ERK) through the coupling of synaptic NMDA receptors to an ERK activation pathway that is opposed by a dominant ERK shutoff pathway thought to be coupled to extrasynaptic NMDA receptors. In the present study, synaptic NMDA receptor activation of ERK in rat cortical cultures was partially inhibited by the highly selective NR2B antagonist Ro25-6981 (Ro) and the less selective NR2A antagonist NVP-AAM077 (NVP). When Ro and NVP were added together, inhibition appeared additive and equal to that observed with the NMDA open-channel blocker MK-801. Consistent with a selective coupling of extrasynaptic NMDA receptors to the dominant ERK shutoff pathway, pre-block of synaptic NMDA receptors with MK-801 did not alter the inhibitory effect of bath-applied NMDA on ERK activity. Lastly, in contrast to a complete block of synaptic NMDA receptor activation of ERK by extrasynaptic NMDA receptors, activation of extrasynaptic NMDA receptors had no effect upon ERK activation by brain-derived neurotrophic factor. These results suggest that the synaptic NMDA receptor ERK activation pathway is coupled to both NR2A and NR2B containing receptors, and that the extrasynaptic NMDA receptor ERK inhibitory pathway is not a non-selective global ERK shutoff.

  12. NMDA receptor activation regulates sociability by its effect on mTOR signaling activity

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    Burket, Jessica A.; Benson, Andrew D.; Tang, Amy H.; Deutsch, Stephen I.

    2017-01-01

    Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORCl in neurons (e.g., cerebellar Purkinje cells). mTORCl is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORCl, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORCl overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORCl activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are “drivers” of mTORCl activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders. PMID:25703582

  13. NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.

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    Burket, Jessica A; Benson, Andrew D; Tang, Amy H; Deutsch, Stephen I

    2015-07-01

    Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.

  14. Bridge feedback for active damping augmentation

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    Chen, G.-S.; Lurie, B. J.

    1990-01-01

    A method is described for broadband damping augmentation of a structural system in which the active members (with feedback control) were developed such that their mechanical input impedance can be electrically adjusted to maximize the energy dissipation rate in the structural system. The active member consists of sensors, an actuator, and a control scheme. A mechanical/electrical analogy is described to model the passive structures and the active members in terms of their impedance representation. As a result, the problem of maximizing dissipative power is analogous to the problem of impedance matching in the electrical network. Closed-loop performance was demonstrated for single- and multiple-active-member controlled truss structure.

  15. Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-containing NMDA Receptors

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    Li-Jun Li

    2016-10-01

    Full Text Available NMDA receptors are Ca2+-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. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs, but not GluN2B-containing NMDA receptors (GluN2BRs, to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.

  16. Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-Containing NMDA Receptors

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    Li, Li-Jun; Hu, Rong; Lujan, Brendan; Chen, Juan; Zhang, Jian-Jian; Nakano, Yasuko; Cui, Tian-Yuan; Liao, Ming-Xia; Chen, Jin-Cao; Man, Heng-Ye; Feng, Hua; Wan, Qi

    2016-01-01

    NMDA receptors are Ca2+-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. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.

  17. Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors.

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    Pawlak, Robert; Melchor, Jerry P; Matys, Tomasz; Skrzypiec, Anna E; Strickland, Sidney

    2005-01-11

    Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for up-regulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1/2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors.

  18. NMDA receptors are the basis for persistent network activity in neocortex slices.

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    Castro-Alamancos, Manuel A; Favero, Morgana

    2015-06-01

    During behavioral quiescence the neocortex generates spontaneous slow oscillations that consist of Up and Down states. Up states are short epochs of persistent activity, but their underlying source is unclear. In neocortex slices of adult mice, we monitored several cellular and network variables during the transition between a traditional buffer, which does not cause Up states, and a lower-divalent cation buffer, which leads to the generation of Up states. We found that the resting membrane potential and input resistance of cortical cells did not change with the development of Up states. The synaptic efficacy of excitatory postsynaptic potentials mediated by non-NMDA receptors was slightly reduced, but this is unlikely to facilitate the generation of Up states. On the other hand, we identified two variables that are associated with the generation of Up states: an enhancement of the intrinsic firing excitability of cortical cells and an enhancement of NMDA-mediated responses evoked by electrical or optogenetic stimulation. The fact that blocking NMDA receptors abolishes Up states indicates that the enhancement in intrinsic firing excitability alone is insufficient to generate Up states. NMDA receptors have a crucial role in the generation of Up states in neocortex slices.

  19. Rhythmic delta activity represents a form of nonconvulsive status epilepticus in anti-NMDA receptor antibody encephalitis.

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    Kirkpatrick, McNeill P; Clarke, Charles D; Sonmezturk, Hasan H; Abou-Khalil, Bassel

    2011-02-01

    Anti-NMDA receptor antibody encephalitis is a limbic encephalitis with psychiatric manifestations, abnormal movements, coma, and seizures. The coma and abnormal movements are not typically attributed to seizure activity, and slow activity is the most common EEG finding. We report drug-resistant nonconvulsive status epilepticus as the basis for coma in a 19-year-old woman with anti-NMDA receptor antibodies and a mediastinal teratoma. The EEG showed generalized rhythmic delta activity, with evolution in morphology, frequency, and field typical of nonconvulsive status epilepticus. The status was refractory to antiepileptic drugs, repeated drug-induced coma, resection of the tumor, intravenous steroids, rituximab, and plasmapheresis. She awoke after the addition of felbamate, and the rhythmic delta activity ceased. The rhythmic delta activity described with coma in anti-NMDA receptor antibody encephalitis may represent a pattern of status epilepticus in some patients. Felbamate, which has NMDA receptor antagonist activity, should be studied as a therapeutic agent in this condition.

  20. Adenosine A1 receptor activation modulates N-methyl-d-aspartate (NMDA) preconditioning phenotype in the brain.

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    Constantino, Leandra C; Pamplona, Fabrício A; Matheus, Filipe C; Ludka, Fabiana K; Gomez-Soler, Maricel; Ciruela, Francisco; Boeck, Carina R; Prediger, Rui D; Tasca, Carla I

    2015-04-01

    N-methyl-d-aspartate (NMDA) preconditioning is induced by subtoxic doses of NMDA and it promotes a transient state of resistance against subsequent lethal insults. Interestingly, this mechanism of neuroprotection depends on adenosine A1 receptors (A1R), since blockade of A1R precludes this phenomenon. In this study we evaluated the consequences of NMDA preconditioning on the hippocampal A1R biology (i.e. expression, binding properties and functionality). Accordingly, we measured A1R expression in NMDA preconditioned mice (75mg/kg, i.p.; 24h) and showed that neither the total amount of receptor, nor the A1R levels in the synaptic fraction was altered. In addition, the A1R binding affinity to the antagonist [(3)H] DPCPX was slightly increased in total membrane extracts of hippocampus from preconditioned mice. Next, we evaluated the impact of NMDA preconditioning on A1R functioning by measuring the A1R-mediated regulation of glutamate uptake into hippocampal slices and on behavioral responses in the open field and hot plate tests. NMDA preconditioning increased glutamate uptake into hippocampal slices without altering the expression of glutamate transporter GLT-1. Interestingly, NMDA preconditioning also induced antinociception in the hot plate test and both effects were reversed by post-activation of A1R with the agonist CCPA (0.2mg/kg, i.p.). NMDA preconditioning or A1R modulation did not alter locomotor activity in the open field. Overall, the results described herein provide new evidence that post-activation of A1R modulates NMDA preconditioning-mediated responses, pointing to the importance of the cross-talk between glutamatergic and adenosinergic systems to neuroprotection.

  1. Progressive brain damage, synaptic reorganization and NMDA activation in a model of epileptogenic cortical dysplasia.

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    Francesca Colciaghi

    Full Text Available Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

  2. NMDA receptor activity and the transmission of sensory input into motor output in introverts and extraverts.

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    Rammsayer, Thomas H

    2003-05-01

    Recent research suggests that individual differences in brain dopamine functioning may be related to the personality dimension of extraversion. The major goal of the present study was to answer the question of whether a pharmacologically induced change in glutamatergic NMDA receptor activity would also differentially affect the transmission of sensory input into motor out-put in introverts and extraverts. Therefore, in a double-blind within-subjects design, either 30 mg of the NMDA receptor antagonist memantine or placebo were administered to 48 healthy male volunteers before performing a choice reaction-time task. In introverts, memantine caused a pronounced increase in lift-off time (i.e., the time required to lift the finger from a home button) compared to that in extraverts, whereas movement time (i.e., the time required to move the finger from the home button to a response button) was decreased in both groups. The pattern of results suggests that extraversion-related differential sensitivity to pharmacologically induced changes in NMDA receptor activity is limited to functions that involve an interaction between the glutamatergic and dopaminergic systems.

  3. β-Adrenergic activation enhances NMDA-induced current in pyramidal cells of the basolateral nucleus of amygdala

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    LIU Xinqiu; CAO Xiaohua; LI Bao-ming

    2005-01-01

    NMDA receptor (NMDA-R) in the amygdala complex is critical for both long-term potentiation (LTP) and formation of conditioned fear memory. It is reported that activation of β-adrenoceptors (β-AR) in the amygdala facilitates LTP and enhances memory consolidation. The present study examined the regulatory effect of β-AR activation on NMDA-R mediated current in pyramidal cells of the basolateral nucleus of amygdala (BLA), using whole-cell recording technique. Bath application of the β-AR agonist isoproterenol enhanced NMDA-induced current, and this facilitatory effect was blocked by co-administered propranolol, a β-AR antagonist. The facilitatory effect of isoproterenol on NMDA-induced current could not be induced when the protein kinase A (PKA) inhibitor Rp-cAMPs was added in electrode internal solution.The present results suggest that β-AR activation in the BLA could modulate NMDA-R activity directly and positively, probably via PKA.

  4. Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model.

    Directory of Open Access Journals (Sweden)

    Thomas J Brozoski

    Full Text Available Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(--2-amino-5-phosphonopentanoic acid (D-AP5 (0.5 mM, was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI. In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.

  5. Facilitation of neocortical presynaptic terminal development by NMDA receptor activation

    OpenAIRE

    2012-01-01

    Abstract Background Neocortical circuits are established through the formation of synapses between cortical neurons, but the molecular mechanisms of synapse formation are only beginning to be understood. The mechanisms that control synaptic vesicle (SV) and active zone (AZ) protein assembly at developing presynaptic terminals have not yet been defined. Similarly, the role of glutamate receptor activation in control of presynaptic development remains unclear. Results Here, we use confocal imag...

  6. PDI regulates seizure activity via NMDA receptor redox in rats.

    Science.gov (United States)

    Kim, Ji Yang; Ko, Ah-Rhem; Hyun, Hye-Won; Min, Su-Ji; Kim, Ji-Eun

    2017-02-15

    Redox modulation of cysteine residues is one of the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR). Protein disulfide isomerases (PDI), an endoplasmic reticulum (ER) chaperone, plays a crucial role in catalyzing disulfide bond formation, reduction, and isomerization. In the present study, we found that PDI bound to NMDAR in the normal hippocampus, and that this binding was increased in chronic epileptic rats. In vitro thiol reductase assay revealed that PDI increased the amount of thiols on full-length recombinant NR1 protein. PDI siRNA, 5-5'-dithio-bis(2-nitrobenzoic acid) (DTNB), bacitracin and PDI antibody reduced seizure susceptibility in response to pilocarpine. In addition, PDI knockdown effectively ameliorated spontaneous seizure activity in chronic epileptic rats. Anticonvulsive effects of PDI siRNA were correlated to the reduction of the amount of free- and nitrosothiols on NMDAR, accompanied by the inhibition of PDI activity. However, PDI knockdown did not lead to alteration in basal neurotransmission or ER stress under physiological condition. These findings provide mechanistic insight into sulfhydration of disulfide bonds on NMDAR by PDI, and suggest that PDI may represent a target of potential therapeutics for epilepsy, which avoids a possible side effect on physiological receptor functionality.

  7. Tissue plasminogen activator inhibits NMDA-receptor-mediated increases in calcium levels in cultured hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Samuel D Robinson

    2015-10-01

    Full Text Available NMDA receptors (NMDARs play a critical role in neurotransmission, acting as essential mediators of many forms of synaptic plasticity, and also modulating aspects of development, synaptic transmission and cell death. NMDAR-induced responses are dependent on a range of factors including subunit composition and receptor location. Tissue-type plasminogen activator (tPA is a serine protease that has been reported to interact with NMDARs and modulate NMDAR activity. In this study we report that tPA inhibits NMDAR-mediated changes in intracellular calcium levels in cultures of primary hippocampal neurons stimulated by low (5 μM but not high (50 μM concentrations of NMDA. tPA also inhibited changes in calcium levels stimulated by presynaptic release of glutamate following treatment with bicucculine/4-AP. Inhibition was dependent on the proteolytic activity of tPA but was unaffected by α2-antiplasmin, an inhibitor of the tPA substrate plasmin, and RAP, a pan-ligand blocker of the low-density lipoprotein receptor, two proteins previously reported to modulate NMDAR activity. These findings suggest that tPA can modulate changes in intracellular calcium levels in a subset of NMDARs expressed in cultured embryonic hippocampal neurons through a mechanism that involves the proteolytic activity of tPA and synaptic NMDARs.

  8. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus.

    Science.gov (United States)

    Weichel, O; Hilgert, M; Chatterjee, S S; Lehr, M; Klein, J

    1999-12-01

    In rat hippocampal slices superfused with magnesium-free buffer, glutamate (1 mM) caused the release of large amounts of choline due to phospholipid breakdown. This phenomenon was mimicked by N-methyl-D-aspartate (NMDA) in a calcium-sensitive manner and was blocked by NMDA receptor antagonists such as MK-801 and 7-chlorokynurenate. The NMDA-induced release of choline was not caused by activation of phospholipase D but was mediated by phospholipase A2 (PLA2) activation as the release of choline was accompanied by the formation of lyso-phosphatidylcholine (lyso-PC) and glycerophospho-choline (GPCh) and was blocked by 5-[2-(2-carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]pentano ic acid, a PLA2 inhibitor. Bilobalide, a constituent of Ginkgo biloba, inhibited the NMDA-induced efflux of choline with an IC50 value of 2.3 microM and also prevented the formation of lyso-PC and GPCh. NMDA also caused a release of choline in vivo when infused into the hippocampus of freely moving rats by retrograde dialysis. Again, the effect was completely inhibited by bilobalide which was administered systemically (20 mg/kg i.p.). Interestingly, convulsions which were observed in the NMDA-treated rats were almost totally suppressed by bilobalide. We conclude that release of choline is a sensitive marker for NMDA-induced phospholipase A2 activation and phospholipid breakdown. Bilobalide inhibited the glutamatergic excitotoxic membrane breakdown both in vitro and in vivo, an effect which may be beneficial in the treatment of brain hypoxia and/or neuronal hyperactivity.

  9. Active Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII Regulates NMDA Receptor Mediated Postischemic Long-Term Potentiation (i-LTP by Promoting the Interaction between CaMKII and NMDA Receptors in Ischemia

    Directory of Open Access Journals (Sweden)

    Ning Wang

    2014-01-01

    Full Text Available Active calcium/calmodulin-dependent protein kinase II (CaMKII has been reported to take a critical role in the induction of long-term potentiation (LTP. Changes in CaMKII activity were detected in various ischemia models. It is tempting to know whether and how CaMKII takes a role in NMDA receptor (NMDAR-mediated postischemic long-term potentiation (NMDA i-LTP. Here, we monitored changes in NMDAR-mediated field excitatory postsynaptic potentials (NMDA fEPSPs at different time points following ischemia onset in vitro oxygen and glucose deprivation (OGD ischemia model. We found that 10 min OGD treatment induced significant i-LTP in NMDA fEPSPs, whereas shorter (3 min or longer (25 min OGD treatment failed to induce prominent NMDA i-LTP. CaMKII activity or CaMKII autophosphorylation displays a similar bifurcated trend at different time points following onset of ischemia both in vitro OGD or in vivo photothrombotic lesion (PT models, suggesting a correlation of increased CaMKII activity or CaMKII autophosphorylation with NMDA i-LTP. Disturbing the association between CaMKII and GluN2B subunit of NMDARs with short cell-permeable peptides Tat-GluN2B reversed NMDA i-LTP induced by OGD treatment. The results provide support to a notion that increased interaction between NMDAR and CaMKII following ischemia-induced increased CaMKII activity and autophosphorylation is essential for induction of NMDA i-LTP.

  10. N-methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention?

    Science.gov (United States)

    Haddad, John J

    2005-11-01

    Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA and KA) receptors. Extracellular signals control diverse neuronal functions and are responsible for mediating activity-dependent changes in synaptic strength and neuronal survival. Influx of extracellular calcium ([Ca(2+)](e)) through the NMDA receptor (NMDAR) is required for neuronal activity to change the strength of many synapses. At the molecular level, the NMDAR interacts with signaling modules, which, like the mitogen-activated protein kinase (MAPK) superfamily, transduce excitatory signals across neurons. Recent burgeoning evidence points to the fact that MAPKs play a crucial role in regulating the neurochemistry of NMDARs, their physiologic and biochemical/biophysical properties, and their potential role in pathophysiology. It is the purpose of this review to discuss: (i) the MAPKs and their role in a plethora of cellular functions; (ii) the role of MAPKs in regulating the biochemistry and physiology of NMDA receptors; (iii) the kinetics of MAPK-NMDA interactions and their biologic and neurochemical properties; (iv) how cellular signaling pathways, related cofactors and intracellular conditions affect NMDA-MAPK interactions and (v) the role of NMDA-MAPK pathways in pathophysiology and the evolution of disease conditions. Given the versatility of the NMDA-MAPK interactions, the NMDA-MAPK axis will likely form a neurochemical target for therapeutic interventions.

  11. ARLearn: Learning activities and interaction in augmented reality

    NARCIS (Netherlands)

    Ternier, Stefaan; Tabuenca, Bernardo; Specht, Marcus

    2013-01-01

    Ternier, S., Tabuenca, B., & Specht, M. (2012). ARLearn: Learning activities and interaction in augmented reality. In M. Specht, J. Multisilta, & M. Sharples (Eds.), Proceedings of the Mobile Augmented Reality for Education Workshop (pp. 10-13). October, 16-17, 2012, Helsinki, Finland.

  12. ARLearn: Learning activities and interaction in augmented reality

    NARCIS (Netherlands)

    Ternier, Stefaan; Tabuenca, Bernardo; Specht, Marcus

    2013-01-01

    Ternier, S., Tabuenca, B., & Specht, M. (2012). ARLearn: Learning activities and interaction in augmented reality. In M. Specht, J. Multisilta, & M. Sharples (Eds.), Proceedings of the Mobile Augmented Reality for Education Workshop (pp. 10-13). October, 16-17, 2012, Helsinki, Finland.

  13. Rapid effect of stress concentration corticosterone on glutamate receptor and its subtype NMDA receptor activity in cultured hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    刘玲; 孙继虎; 王春安

    2003-01-01

    Objective:To study the rapid effect of glucocorticoids(GCs)on NMDA receptor activity in hippocampal neurons in stress and to elucidate its underlying probable membrane mechanisms.Methods:Whole-cell patch-clamp recording was used to assess the effect of stress concentration corticosterone(B)on the responses of cultured hippocampal neurons to glutamate and NMDA(N-methy-D-asparatic acid).To make clear the target of B,intracellular dialysis of B(10 μ mol/L)through patch pipette and extracellular application of bovine serum albumin-conjugated corticosterone(B-BSA,10 μmol/L)were carried out to observe their influence on peak amplitude of NMDA-evoked current.Results:B had a rapid,reversible and inhibitory effect on peak amplitude of GLU- or NMDA-evoked current in cultured hippocampal neurons.Furthermore,B-BSA had the inhibitory effect on INMDA as that of B,but intracellularly dialyzed B had no significant effect on INMDA.Conclusion:These results suggest that under the condition of stress,GCs may rapidly,negatively regulate excitatory synaptic receptors-glutamate receptors(GluRs),especially NMDA receptor(NMDAR)in central nervous system,which is mediated by rapid membrane mechanisms,but not by classical,genomic mechanisms.

  14. Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.

    Directory of Open Access Journals (Sweden)

    Zhao Han

    Full Text Available Excessive activation of the N-methyl-D-aspartic acid (NMDA type glutamate receptors (NMDARs causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl-2-imidazoline (2-BFI, an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10(-9 M(-1 sec(-1 and off rate (Koff = 0.67±0.02 sec(-1 than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment.

  15. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus

    DEFF Research Database (Denmark)

    Harvey, Brian H; Oosthuizen, Frasia; Brand, Linda

    2004-01-01

    activation. CONCLUSIONS: Stress-restress-mediated glucocorticoid release activates iNOS, followed by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. The role of NO in neuronal toxicity, and its regulation by glutamate and GABA has important implications...

  16. Current and calcium responses to local activation of axonal NMDA receptors in developing cerebellar molecular layer interneurons.

    Directory of Open Access Journals (Sweden)

    Bénédicte Rossi

    Full Text Available In developing cerebellar molecular layer interneurons (MLIs, NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca(2+ channels (VDCCs. Using Ca(2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg(2+ or by the addition of APV. Similar paradigms yielded restricted Ca(2+ transients in interneurons loaded with a Ca(2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca(2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca(2+-induced Ca(2+ release process mediated by presynaptic Ca(2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca(2+-mediated synaptic plasticity.

  17. Regulation of Neuronal Gene Expression and Survival by Basal NMDA Receptor Activity: A Role for Histone Deacetylase 4

    OpenAIRE

    Chen, Yelin; Wang, Yuanyuan; Modrusan, Zora; Sheng, Morgan; Kaminker, Joshua S.

    2014-01-01

    Neuronal gene expression is modulated by activity via calcium-permeable receptors such as NMDA receptors (NMDARs). While gene expression changes downstream of evoked NMDAR activity have been well studied, much less is known about gene expression changes that occur under conditions of basal neuronal activity. In mouse dissociated hippocampal neuronal cultures, we found that a broad NMDAR antagonist, AP5, induced robust gene expression changes under basal activity, but subtype-specific antagoni...

  18. Active member bridge feedback control for damping augmentation

    Science.gov (United States)

    Chen, Gun-Shing; Lurie, Boris J.

    1992-01-01

    An active damping augmentation approach using active members in a structural system is described. The problem of maximizing the vibration damping in a lightly damped structural system is considered using the analogy of impedance matching between the load and source impedances in an electrical network. The proposed active damping augmentation approach therefore consists of finding the desired active member impedances that maximize the vibration damping, and designing a feedback control in order to achieve desired active member impedances. This study uses a bridge feedback concept that feeds back a combination of signals from sensors of the axial force and relative velocity across the active member to realize the desired active member impedance. The proposed active damping augmentation approach and bridge feedback concept were demonstrated on a three-longeron softly suspended truss structure.

  19. Relief learning requires a coincident activation of dopamine D1 and NMDA receptors within the nucleus accumbens.

    Science.gov (United States)

    Bergado Acosta, Jorge R; Kahl, Evelyn; Kogias, Georgios; Uzuneser, Taygun C; Fendt, Markus

    2017-03-01

    Relief learning is the association of a stimulus with the offset of an aversive event. Later, the now conditioned relief stimulus induces appetitive-like behavioral changes. We previously demonstrated that the NMDA receptors within the nucleus accumbens (NAC) are involved in relief learning. The NAC is also important for reward learning and it has been shown that reward learning is mediated by an interaction of accumbal dopamine and NMDA glutamate receptors. Since conditioned relief has reward-like properties, we hypothesized that (a) acquisition of relief learning requires the activation of dopamine D1 receptors in the NAC, and (b) if D1 receptors are involved in this process as expected, a concurrent dopamine D1 and NMDA receptor activation may mediate this learning. The present study tested these hypotheses. Therefore, rats received intra-NAC injections of the dopamine D1 receptor antagonist SCH23390 and the NMDA antagonist AP5, either separately or together, at different time points of a relief conditioning procedure. First, we showed that SCH23390 dose-dependently blocked acquisition and the expression of conditioned relief. Next, we demonstrated that co-injections of SCH23390 and AP5 into the NAC, at doses that were ineffective when applied separately, blocked acquisition but not consolidation or expression of relief learning. Notably, neither of the injections affected the locomotor response of the animals to the aversive stimuli suggesting that their perception is not changed. This data indicates that a co-activation of dopamine D1 and NMDA receptors in the NAC is required for acquisition of relief learning. Copyright © 2016. Published by Elsevier Ltd.

  20. Functional neurokinin and NMDA receptor activity in an animal naturally lacking substance P: the naked mole-rat.

    Directory of Open Access Journals (Sweden)

    Antje Brand

    Full Text Available Naked mole-rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP. In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intrathecal application of: 1 SP, 2 an SP antagonist (GR-82334, and 3 an NMDA antagonist (APV on heat-evoked foot withdrawal. In the naked mole-rat, at a high enough concentration, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naïve animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in naked mole-rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.

  1. A Clickable Analogue of Ketamine Retains NMDA Receptor Activity, Psychoactivity, and Accumulates in Neurons

    Science.gov (United States)

    Emnett, Christine; Li, Hairong; Jiang, Xiaoping; Benz, Ann; Boggiano, Joseph; Conyers, Sara; Wozniak, David F.; Zorumski, Charles F.; Reichert, David E.; Mennerick, Steven

    2016-01-01

    Ketamine is a psychotomimetic and antidepressant drug. Although antagonism of cell-surface NMDA receptors (NMDARs) may trigger ketamine’s psychoactive effects, ketamine or its major metabolite norketamine could act intracellularly to produce some behavioral effects. To explore the viability of this latter hypothesis, we examined intracellular accumulation of novel visualizable analogues of ketamine/norketamine. We introduced an alkyne “click” handle into norketamine (alkyne-norketamine, A-NK) at the key nitrogen atom. Ketamine, norketamine, and A-NK, but not A-NK-amide, showed acute and persisting psychoactive effects in mice. This psychoactivity profile paralleled activity of the compounds as NMDAR channel blockers; A-NK-amide was inactive at NMDARs, and norketamine and A-NK were active but ~4-fold less potent than ketamine. We incubated rat hippocampal cells with 10 μM A-NK or A-NK-amide then performed Cu2+ catalyzed cycloaddition of azide-Alexa Fluor 488, which covalently attaches the fluorophore to the alkyne moiety in the compounds. Fluorescent imaging revealed intracellular localization of A-NK but weak A-NK-amide labeling. Accumulation was not dependent on membrane potential, NMDAR expression, or NMDAR activity. Overall, the approach revealed a correlation among NMDAR activity, intracellular accumulation/retention, and behavioral effects. Thus, we advance first generation chemical biology tools to aid in the identification of ketamine targets. PMID:27982047

  2. Glutamatergic synaptic inputs activate neurons in the subfornical organ through non-NMDA receptors.

    Science.gov (United States)

    Xu, S H; Inenaga, K; Honda, E; Yamashita, H

    2000-01-14

    The subfornical organ (SFO) plays an important role in central regulation of the autonomic nervous system. The synaptic transmission properties of neurons in the SFO were studied with intracellular and whole-cell patch clamp recordings in the rat slice preparations. Both the spontaneous and evoked excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) were almost completely suppressed by the glutamate receptor antagonist kynurenic acid and the non-NMDA (N-methyl-D-aspartic acid) antagonist CNQX. The non-NMDA agonist kainic acid depolarized the membrane most potently, compared with NMDA and quisqualic acid. These suggest that glutamate is a main excitatory neurotransmitter in the SFO and that its action is at least partly mediated through non-NMDA receptors.

  3. Selective 5-HT7 Receptor Activation May Enhance Synaptic Plasticity Through N-methyl-D-aspartate (NMDA) Receptor Activity in the Visual Cortex.

    Science.gov (United States)

    Xiang, Kangjian; Zhao, Xuefei; Li, Youjun; Zheng, Liang; Wang, Jue; Li, Yan-Hai

    2016-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist). A specific antagonist for the 5-HT7 receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HT1A receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HT7 receptors, but not 5-HT1A receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

  4. Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury.

    Science.gov (United States)

    Kulkarni, Miriam; Armstead, William M

    2002-08-01

    Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2

  5. Synthesis and structure-activity studies on acidic amino acids and related diacids as NMDA receptor ligands

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1994-01-01

    , of (S)-glutamic acid (1) receptors. A number of amino acids and diacids structurally related to AMAA were synthesized and tested electrophysiologically and in receptor-binding assays. The hydroxymethyl analogue 7c of AMAA was an NMDA agonist approximately equipotent with AMAA in the [3H......]CPP-binding assay (IC50 = 7 +/- 3 microM) and electropharmacologically in the rat cortical wedge model (EC50 = 8 +/- 2 microM). In contrast to this, the tertbutyl analogue 7a of AMAA turned out to be an antagonist at NMDA and AMPA receptors. The conformational characteristics of AMAA and 7a, c were studied...... by molecular mechanics calculations. Compound 7a possesses extra steric bulk and shows significant restriction of conformational flexibility compared to AMAA and 7c, which may be determining factors for the observed differences in biological activity. Although the nitrogen atom of quinolinic acid (6) has very...

  6. NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs during inflammation induced visceral hypersensitivity

    Directory of Open Access Journals (Sweden)

    Caudle Robert M

    2009-09-01

    Full Text Available Abstract Background Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs, co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG neurons expressing the transient receptor potential vanilloid-1 (TRPV1 receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX prior to inflammation and behavioural testing. Results CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Conclusion Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned

  7. Relief learning is dependent on NMDA receptor activation in the nucleus accumbens

    Science.gov (United States)

    Mohammadi, Milad; Fendt, Markus

    2015-01-01

    Background and Purpose Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning. Experimental Approach The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested. Key Results Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections. Conclusion and Implication The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory. PMID:25572550

  8. Orchestration Framework for Learning Activities in Augmented Reality Environments

    OpenAIRE

    Ibáñez, María Blanca; Delgado Kloos, Carlos; Di Serio, Angela

    2011-01-01

    Proceedings of: Across Spaces11 Workshop in conjunction with the EC-TEL2011, Palermo, Italy, September 21, 2011 In this paper we show how Augmented Reality (AR) technology restricted to the use of mobiles or PCs, can be used to develop learning activities with the minimun level of orchestation required by meaningful learning sequences. We use Popcode as programming language to deploy orchestrated learning activities specified with an AR framework. Publicado

  9. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie

    2014-01-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…

  10. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie

    2014-01-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…

  11. Polygalasaponin F induces long-term potentiation in adult rat hippocampus via NMDA receptor activation

    Institute of Scientific and Technical Information of China (English)

    Feng SUN; Jian-dong SUN; Ning HAN; Chuang-jun LI; Yu-he YUAN; Dong-ming ZHANG; Nai-hong CHEN

    2012-01-01

    Aim:To investigate the effect and underlying mechanisms of polygalasaponin F (PGSF),a triterpenoid saponin isolated from Polygala japonica,on long-term potentiation (LTP)in hippocampus dentate gyrus (DG)of anesthetized rats.Methods:Population spike (PS)of hippocampal DG was recorded in anesthetized male Wistar rats.PGSF,the NMDAR inhibitor MK801 and the CaMKll inhibitor KN93 were intracerebroventricularly administered.Western blotting analysis was used to examine the phosphorylation expressions of NMDA receptor subunit 2B (NR2B),Ca2+/calmodulin-dependent kinase Ⅱ (CaMKII),extracellular signalregulated kinase (ERK),and cAMP response element-binding protein (CREB).Results:Intracerebroventricular administration of PGSF (1 and 10 μmol/L)produced long-lasting increase of PS amplitude in hippocampal DG in a dose-dependent manner.Pre-injection of MK801 (100 μmol/L)or KN93 (100 μmol/L)completely blocked PGSFinduced LTP.Furthermore,the phosphorylation of NR2B,CaMKII,ERK,and CREB in hippocampus was significantly increased 5-60min after LTP induction.The up-regulation of p-CaMKII expression could be completely abolished by pre-injection of MK801.The upregulation of p-ERK and p-CREB expressions could be partially blocked by pre-injection of KN93.Conclusion:PGSF could induce LTP in hippocampal DG in anesthetized rats via NMDAR activation mediated by CaMKII,ERK and CREB signaling pathway.

  12. Glutamatergic transmission in hydra: NMDA/D-serine affects the electrical activity of the body and tentacles of Hydra vulgaris (Cnidaria, Hydrozoa).

    Science.gov (United States)

    Kay, J C; Kass-Simon, G

    2009-04-01

    Previous electrophysiological studies on the early-evolved metazoan Hydra vulgaris provided evidence that glutamate, acting through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, affects hydra's pacemaker systems; immunocytochemical studies showed that N-methyl-d-aspartate (NMDA) receptors were present in hydra tentacles; behavioral studies demonstrated that NMDA/d-serine affected mouth opening induced by reduced glutathione, and with AMPA/kainate, discharge of nematocysts. In this study, extracellular recordings were made from the tentacle and peduncle of hydra during bath application of NMDA and d-serine (both at 1 x 10(-5) mol l(-1) to 1 x 10(-9) mol l(-1)) in the presence of 1 x 10(-7) mol l(-1) AMPA or kainate. NMDA/d-serine produced a significant increase in tentacle activity, increasing the rate of tentacle pacemaker pulses (TPs) at 1 x 10(-7) mol l(-1), and small, behaviorally uncorrelated tentacle pulses (SUTPs) at 1 x 10(-5) mol l(-1). The NMDA antagonist, d-2-amino-5-phosphonopentanoic acid (D-AP5), counteracted the effects. NMDA/d-serine (1 x 10(-7) mol l(-1)) also caused a potentially significant (trend) decrease in the rate of small, behaviorally uncorrelated electrical body pulses (SUBPs) and rhythmic potentials (RPs). The effect was counteracted by D-AP5. The ectodermal contraction burst (CB) pacemaker system was unaffected by NMDA/d-serine. Our results indicate that glutamate, acting on NMDA/AMPA-kainate receptors, may cause opposing effects on the coordinating systems of tentacle and body-exciting the tentacle effectors and potentially causing an inhibition in the body column.

  13. The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation.

    Directory of Open Access Journals (Sweden)

    David M Santucci

    2008-10-01

    Full Text Available N-Methyl-D-aspartic acid (NMDA receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future

  14. Antidepressant-like activity of magnesium in the chronic mild stress model in rats: alterations in the NMDA receptor subunits.

    Science.gov (United States)

    Pochwat, Bartłomiej; Szewczyk, Bernadeta; Sowa-Kucma, Magdalena; Siwek, Agata; Doboszewska, Urszula; Piekoszewski, Wojciech; Gruca, Piotr; Papp, Mariusz; Nowak, Gabriel

    2014-03-01

    Recent data suggests that the glutamatergic system is involved in the pathophysiology and treatment of major depressive disorder (MDD) and that the N-methyl-D-aspartate (NMDA) receptor is a potential target for antidepressant drugs. The magnesium ion blocks the ion channel of the NMDA receptor and prevents its excessive activation. Some preclinical and clinical evidence suggests also that magnesium may be useful in the treatment of depression. The present study investigated the effect of magnesium treatment (10, 15 and 20 mg/kg, given as magnesium hydroaspartate) in the chronic mild stress (CMS) model of depression in rats. Moreover, the effect of CMS and magnesium (with an effective dose) on the level of the proteins related to the glutamatergic system (GluN1, GluN2A, GluN2B and PSD-95) in the hippocampus, prefrontal cortex (PFC) and amygdala were examined. A significant reduction in the sucrose intake induced by CMS was increased by magnesium treatment at a dose of 15 mg/kg, beginning from the third week of administration. Magnesium did not affect this behavioural parameter in the control animals. CMS significantly increased the level of the GluN1 subunit in the amygdala (by 174%) and GluN2A in the hippocampus (by 191%), both of which were significantly attenuated by magnesium treatment. Moreover, magnesium treatment in CMS animals increased the level of GluN2B (by 116%) and PSD-95 (by 150%) in the PFC. The present results for the first time demonstrate the antidepressant-like activity of magnesium in the animal model of anhedonia (CMS), thus indicating the possible involvement of the NMDA/glutamatergic receptors in this activity.

  15. Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning.

    Science.gov (United States)

    Smith-Roe, S L; Kelley, A E

    2000-10-15

    The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.

  16. Improved Chemical Structure-Activity Modeling Through Data Augmentation.

    Science.gov (United States)

    Cortes-Ciriano, Isidro; Bender, Andreas

    2015-12-28

    Extending the original training data with simulated unobserved data points has proven powerful to increase both the generalization ability of predictive models and their robustness against changes in the structure of data (e.g., systematic drifts in the response variable) in diverse areas such as the analysis of spectroscopic data or the detection of conserved domains in protein sequences. In this contribution, we explore the effect of data augmentation in the predictive power of QSAR models, quantified by the RMSE values on the test set. We collected 8 diverse data sets from the literature and ChEMBL version 19 reporting compound activity as pIC50 values. The original training data were replicated (i.e., augmented) N times (N ∈ 0, 1, 2, 4, 6, 8, 10), and these replications were perturbed with Gaussian noise (μ = 0, σ = σnoise) on either (i) the pIC50 values, (ii) the compound descriptors, (iii) both the compound descriptors and the pIC50 values, or (iv) none of them. The effect of data augmentation was evaluated across three different algorithms (RF, GBM, and SVM radial) and two descriptor types (Morgan fingerprints and physicochemical-property-based descriptors). The influence of all factor levels was analyzed with a balanced fixed-effect full-factorial experiment. Overall, data augmentation constantly led to increased predictive power on the test set by 10-15%. Injecting noise on (i) compound descriptors or on (ii) both compound descriptors and pIC50 values led to the highest drop of RMSEtest values (from 0.67-0.72 to 0.60-0.63 pIC50 units). The maximum increase in predictive power provided by data augmentation is reached when the training data is replicated one time. Therefore, extending the original training data with one perturbed repetition thereof represents a reasonable trade-off between the increased performance of the models and the computational cost of data augmentation, namely increase of (i) model complexity due to the need for optimizing

  17. Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model.

    Science.gov (United States)

    Sershen, Henry; Hashim, Audrey; Dunlop, David S; Suckow, Raymond F; Cooper, Tom B; Javitt, Daniel C

    2016-02-01

    Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol(®)) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor NaB (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO

  18. Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

    Science.gov (United States)

    Sershen, Henry; Hashim, Audrey; Dunlop, David S.; Suckow, Raymond F.; Cooper, Tom B.; Javitt, Daniel C.

    2016-01-01

    Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level

  19. Astrocytic glutamate uptake is slow and does not limit neuronal NMDA receptor activation in the neonatal neocortex.

    Science.gov (United States)

    Hanson, Elizabeth; Armbruster, Moritz; Cantu, David; Andresen, Lauren; Taylor, Amaro; Danbolt, Niels Christian; Dulla, Chris G

    2015-10-01

    Glutamate uptake by astrocytes controls the time course of glutamate in the extracellular space and affects neurotransmission, synaptogenesis, and circuit development. Astrocytic glutamate uptake has been shown to undergo post-natal maturation in the hippocampus, but has been largely unexplored in other brain regions. Notably, glutamate uptake has never been examined in the developing neocortex. In these studies, we investigated the development of astrocytic glutamate transport, intrinsic membrane properties, and control of neuronal NMDA receptor activation in the developing neocortex. Using astrocytic and neuronal electrophysiology, immunofluorescence, and Western blot analysis we show that: (1) glutamate uptake in the neonatal neocortex is slow relative to neonatal hippocampus; (2) astrocytes in the neonatal neocortex undergo a significant maturation of intrinsic membrane properties; (3) slow glutamate uptake is accompanied by lower expression of both GLT-1 and GLAST; (4) glutamate uptake is less dependent on GLT-1 in neonatal neocortex than in neonatal hippocampus; and (5) the slow glutamate uptake we report in the neonatal neocortex corresponds to minimal astrocytic control of neuronal NMDA receptor activation. Taken together, our results clearly show fundamental differences between astrocytic maturation in the developing neocortex and hippocampus, and corresponding changes in how astrocytes control glutamate signaling.

  20. MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism.

    Directory of Open Access Journals (Sweden)

    Laura P Bernard

    Full Text Available The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs, are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer's disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA, through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse.

  1. Augmented reality to enhance an active telepresence system

    Science.gov (United States)

    Wheeler, Alison; Pretlove, John R. G.; Parker, Graham A.

    1996-12-01

    Tasks carried out remotely via a telerobotic system are typically complex, occur in hazardous environments and require fine control of the robot's movements. Telepresence systems provide the teleoperator with a feeling of being physically present at the remote site. Stereoscopic video has been successfully applied to telepresence vision systems to increase the operator's perception of depth in the remote scene and this sense of presence can be further enhanced using computer generated stereo graphics to augment the visual information presented to the operator. The Mechatronic Systems and Robotics Research Group have over seven years developed a number of high performance active stereo vision systems culminating in the latest, a four degree-of-freedom stereohead. This carries two miniature color cameras and is controlled in real time by the motion of the operator's head, who views the stereoscopic video images on an immersive head mounted display or stereo monitor. The stereohead is mounted on a mobile robot, the movement of which is controlled by a joystick interface. This paper describes the active telepresence system and the development of a prototype augmented reality (AR) application to enhance the operator's sense of presence at the remote site. The initial enhancements are a virtual map and compass to aid navigation in degraded visual conditions and a virtual cursor that provides a means for the operator to interact with the remote environment. The results of preliminary experiments using the initial enhancements are presented.

  2. A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans.

    Science.gov (United States)

    Cacciaglia, Raffaele; Nees, Frauke; Pohlack, Sebastian T; Ruttorf, Michaela; Winkelmann, Tobias; Witt, Stephanie H; Nieratschker, Vanessa; Rietschel, Marcella; Flor, Herta

    2013-09-01

    People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning.

  3. Abdomen and spinal cord segmentation with augmented active shape models.

    Science.gov (United States)

    Xu, Zhoubing; Conrad, Benjamin N; Baucom, Rebeccah B; Smith, Seth A; Poulose, Benjamin K; Landman, Bennett A

    2016-07-01

    Active shape models (ASMs) have been widely used for extracting human anatomies in medical images given their capability for shape regularization of topology preservation. However, sensitivity to model initialization and local correspondence search often undermines their performances, especially around highly variable contexts in computed-tomography (CT) and magnetic resonance (MR) images. In this study, we propose an augmented ASM (AASM) by integrating the multiatlas label fusion (MALF) and level set (LS) techniques into the traditional ASM framework. Using AASM, landmark updates are optimized globally via a region-based LS evolution applied on the probability map generated from MALF. This augmentation effectively extends the searching range of correspondent landmarks while reducing sensitivity to the image contexts and improves the segmentation robustness. We propose the AASM framework as a two-dimensional segmentation technique targeting structures with one axis of regularity. We apply AASM approach to abdomen CT and spinal cord (SC) MR segmentation challenges. On 20 CT scans, the AASM segmentation of the whole abdominal wall enables the subcutaneous/visceral fat measurement, with high correlation to the measurement derived from manual segmentation. On 28 3T MR scans, AASM yields better performances than other state-of-the-art approaches in segmenting white/gray matter in SC.

  4. Behavioural and neuronal activation after microinjections of AMPA and NMDA into the perifornical lateral hypothalamus in rats.

    Science.gov (United States)

    Li, Frederick W; Deurveilher, Samuel; Semba, Kazue

    2011-10-31

    The perifornical lateral hypothalamic area (PeFLH), which houses orexin/hypocretin (OX) neurons, is thought to play an important role in arousal, feeding, and locomotor activity. The present study examined behavioural effects of activating PeFLH neurons with microinjections of ionotropic glutamate receptor agonists. Three separate unilateral microinjections of either (1) AMPA (1 and 2mM in 0.1 μL artificial cerebrospinal fluid, ACSF) and ACSF, or (2) NMDA (1 and 10mM in 0.1 μL ACSF), and ACSF were made into the PeFLH of adult male rats. Following each injection, the rats were placed into an open field for behavioural scoring for 45 min. Rats were perfused after the third injection for immunohistochemistry for c-Fos and OX to assess the level of activation of OX neurons. Behavioural analyses showed that, as compared to ACSF conditions, AMPA injections produced a dose-dependent increase in locomotion and rearing that persisted throughout the 45 min recording period, and an increase in drinking. Injection of NMDA at 10mM, but not 1mM, induced a transient increase in locomotion and an increase in feeding. Histological analyses showed that while both agonists increased the number of neurons immunoreactive for c-Fos in the PeFLH, only AMPA increased the number of neurons immunoreactive for both c-Fos and OX. There were positive correlations between the number of c-Fos/OX-immunoreactive neurons and the amounts of locomotion, rearing, and drinking. These results support the role of ionotropic glutamate receptors on OX and other neurons in the PeFLH in the regulation of locomotor and ingestive behaviours.

  5. Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for histone deacetylase 4.

    Science.gov (United States)

    Chen, Yelin; Wang, Yuanyuan; Modrusan, Zora; Sheng, Morgan; Kaminker, Joshua S

    2014-11-12

    Neuronal gene expression is modulated by activity via calcium-permeable receptors such as NMDA receptors (NMDARs). While gene expression changes downstream of evoked NMDAR activity have been well studied, much less is known about gene expression changes that occur under conditions of basal neuronal activity. In mouse dissociated hippocampal neuronal cultures, we found that a broad NMDAR antagonist, AP5, induced robust gene expression changes under basal activity, but subtype-specific antagonists did not. While some of the gene expression changes are also known to be downstream of stimulated NMDAR activity, others appear specific to basal NMDAR activity. The genes altered by AP5 treatment of basal cultures were enriched for pathways related to class IIa histone deacetylases (HDACs), apoptosis, and synapse-related signaling. Specifically, AP5 altered the expression of all three class IIa HDACs that are highly expressed in the brain, HDAC4, HDAC5, and HDAC9, and also induced nuclear accumulation of HDAC4. HDAC4 knockdown abolished a subset of the gene expression changes induced by AP5, and led to neuronal death under long-term tetrodotoxin or AP5 treatment in rat hippocampal organotypic slice cultures. These data suggest that basal, but not evoked, NMDAR activity regulates gene expression in part through HDAC4, and, that HDAC4 has neuroprotective functions under conditions of low NMDAR activity.

  6. Activated CaMKII Couples GluN2B and Casein Kinase 2 to Control Synaptic NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Antonio Sanz-Clemente

    2013-03-01

    Full Text Available Synaptic activity triggers a profound reorganization of the molecular composition of excitatory synapses. For example, NMDA receptors are removed from synapses in an activity- and calcium-dependent manner, via casein kinase 2 (CK2 phosphorylation of the PDZ ligand of the GluN2B subunit (S1480. However, how synaptic activity drives this process remains unclear because CK2 is a constitutively active kinase, which is not directly regulated by calcium. We show here that activated CaMKII couples GluN2B and CK2 to form a trimolecular complex and increases CK2-mediated phosphorylation of GluN2B S1480. In addition, a GluN2B mutant, which contains an insert to mimic the GluN2A sequence and cannot bind to CaMKII, displays reduced S1480 phosphorylation and increased surface expression. We find that although disrupting GluN2B/CaMKII binding reduces synapse number, it increases synaptic-GluN2B content. Therefore, the GluN2B/CaMKII association controls synapse density and PSD composition in an activity-dependent manner, including recruitment of CK2 for the removal of GluN2B from synapses.

  7. Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential.

    Science.gov (United States)

    Alam, Badrul; Majumder, Rajib; Akter, Shahina; Lee, Sang-Han

    2015-02-01

    The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (PPiper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential.

  8. Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress

    OpenAIRE

    Duncan, Gary E.; Inada, Ken; Farrington, Joseph S.; Koller, Beverly H.; Moy, Sheryl S.

    2009-01-01

    Mice with reduced expression of the NR1 subunit of the NMDA receptor (NR1 hypomorphic mice) display altered behavioral phenotypes that may relate to behavioral characteristics of schizophrenia. Altered phenotypes in the NR1 hypomorphs include marked deficits in species-typical behavioral interactions in tests of social aggression and social affiliation. To gain insight into neuroanatomical circuits disrupted by reduced NMDA receptor function, the present work compared regional brain activatio...

  9. Retinal cell death induced by TRPV1 activation involves NMDA signaling and upregulation of nitric oxide synthases.

    Science.gov (United States)

    Leonelli, Mauro; Martins, Daniel O; Britto, Luiz R G

    2013-04-01

    The activation of the transient receptor potential vanilloid type 1 channel (TRPV1) has been correlated with oxidative and nitrosative stress and cell death in the nervous system. Our previous results indicate that TRPV1 activation in the adult retina can lead to constitutive and inducible nitric oxide synthase-dependent protein nitration and apoptosis. In this report, we have investigated the potential effects of TRPV1 channel activation on nitric oxide synthase (NOS) expression and function, and the putative participation of ionotropic glutamate receptors in retinal TRPV1-induced protein nitration, lipid peroxidation, and DNA fragmentation. Intravitreal injections of the classical TRPV1 agonist capsaicin up-regulated the protein expression of the inducible and endothelial NOS isoforms. Using 4,5-diaminofluorescein diacetate for nitric oxide (NO) imaging, we found that capsaicin also increased the production of NO in retinal blood vessels. Processes and perikarya of TRPV1-expressing neurons in the inner nuclear layer of the retina were found in the vicinity of nNOS-positive neurons, but those two proteins did not colocalize. Retinal explants exposed to capsaicin presented high protein nitration, lipid peroxidation, and cell death, which were observed in the inner nuclear and plexiform layers and in ganglion cells. This effect was partially blocked by AP-5, a NMDA glutamate receptor antagonist, but not by CNQX, an AMPA/kainate receptor antagonist. These data support a potential role for TRPV1 channels in physiopathological retinal processes mediated by NO, which at least in part involve glutamate release.

  10. GDNF selectively induces microglial activation and neuronal survival in CA1/CA3 hippocampal regions exposed to NMDA insult through Ret/ERK signalling.

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    Francesca Boscia

    Full Text Available The glial cell line-derived neurotrophic factor (GDNF is a potent survival factor for several neuronal populations in different brain regions, including the hippocampus. However, no information is available on the: (1 hippocampal subregions involved in the GDNF-neuroprotective actions upon excitotoxicity, (2 identity of GDNF-responsive hippocampal cells, (3 transduction pathways involved in the GDNF-mediated neuroprotection in the hippocampus. We addressed these questions in organotypic hippocampal slices exposed to GDNF in presence of N-methyl-D-aspartate (NMDA by immunoblotting, immunohistochemistry, and confocal analysis. In hippocampal slices GDNF acts through the activation of the tyrosine kinase receptor, Ret, without involving the NCAM-mediated pathway. Both Ret and ERK phosphorylation mainly occurred in the CA3 region where the two activated proteins co-localized. GDNF protected in a greater extent CA3 rather than CA1 following NMDA exposure. This neuroprotective effect targeted preferentially neurons, as assessed by NeuN staining. GDNF neuroprotection was associated with a significant increase of Ret phosphorylation in both CA3 and CA1. Interestingly, confocal images revealed that upon NMDA exposure, Ret activation occurred in microglial cells in the CA3 and CA1 following GDNF exposure. Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF-induced Ret activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotection involves a GDNF modulation of microglial cell activity.

  11. Fingolimod modulates microglial activation to augment markers of remyelination

    Directory of Open Access Journals (Sweden)

    Baker David

    2011-07-01

    Full Text Available Abstract Introduction Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells. Methods In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate, spheroid cell culture system. The lack of immune system components allowed elucidation of the direct effects of fingolimod on CNS cell types in an organotypic situation. Results Following demyelination, fingolimod significantly augmented expression of myelin basic protein in the remyelination phase. This increase was not associated with changes in neurofilament levels, indicating de novo myelin protein expression not associated with axonal branching. Myelin wrapping was confirmed morphologically using confocal and electron microscopy. Increased remyelination was associated with down-regulation of microglial ferritin, tumor necrosis factor alpha and interleukin 1 during demyelination when fingolimod was present. In addition, nitric oxide metabolites and apoptotic effectors caspase 3 and caspase 7 were reduced during demyelination in the presence of fingolimod. The sphingosine-1-phosphate receptor 1 and 5 agonist BAF312 also increased myelin basic protein levels, whereas the sphingosine-1-phosphate receptor 1 agonist AUY954 failed to replicate this effect on remyelination. Conclusions The results presented indicate that modulation of S1P receptors can ameliorate pathological effectors associated with microglial activation leading to a subsequent increase in protein and morphological markers of remyelination. In addition, sphingosine-1-phosphate

  12. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production.

    Science.gov (United States)

    Bordji, Karim; Becerril-Ortega, Javier; Nicole, Olivier; Buisson, Alain

    2010-11-24

    Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of Aβ. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal Aβ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release, representing a causal risk factor for developing AD.

  13. Effects of ifenprodil on the antidepressant-like activity of NMDA ligands in the forced swim test in mice.

    Science.gov (United States)

    Poleszak, Ewa; Wośko, Sylwia; Serefko, Anna; Szopa, Aleksandra; Wlaź, Aleksandra; Szewczyk, Bernadeta; Nowak, Gabriel; Wlaź, Piotr

    2013-10-01

    Multiple pre-clinical and clinical studies clearly displayed implication of the NMDA receptors in development of depressive disorders since a variety of NMDA receptor antagonists exhibit an antidepressant-like effect. The main aim of our study was to assess the influence of ifenprodil - an allosteric modulator selectively binding at the NR2B subunit on the performance in the forced swim test in mice of various NMDA receptor ligands interacting with distinct components of the NMDA receptor complex. Ifenprodil at a dose of 10mg/kg enhanced the antidepressant-like effect of CGP 37849 (a competitive NMDA receptor antagonist, 0.312mg/kg), L-701,324 (an antagonist at glycine site, 1mg/kg), MK-801 (a non-competitive antagonist, 0.05mg/kg) and d-cycloserine (a partial agonist of a glycine site, 2.5mg/kg) but it did not shorten the immobility time of animals which concurrently received an inorganic modulator of the NMDA receptor complex, such as Zn(2+) (2.5mg/kg) or Mg(2+) (10mg/kg). On the other hand, the antidepressant-like effect of ifenprodil (20mg/kg) was reversed by N-methyl-d-aspartic acid (an agonist at the glutamate site, 75mg/kg) or d-serine (an agonist at the glycine site, 100nmol/mouse). In conclusion, the antidepressant-like potential of ifenprodil given concomitantly with NMDA ligands was either reinforced (in the case of both partial agonist and antagonists, except for magnesium and zinc) or diminished (in the case of conventional full agonists).

  14. Synthesis and binding characteristics of N-(1-naphthyl)-N'-(3-[{sup 125}I]-iodophenyl)-N'-methylguanidine ([{sup 125}I]-CNS 1261): a potential SPECT agent for imaging NMDA receptor activation

    Energy Technology Data Exchange (ETDEWEB)

    Owens, Jonathan E-mail: j.owens@clinmed.gla.ac.uk; Tebbutt, Andrew A.; McGregor, Ailsa L.; Kodama, K.; Magar, Sharad S.; Perlman, Michael E.; Robins, David J.; Durant, Graham J.; McCulloch, James

    2000-06-01

    N-(1-Naphthyl)-N'-(3-[{sup 125}I]-iodophenyl)-N'-methylguanidine ([{sup 125}I]-CNS 1261) was synthesized as a potential radioligand to image N-methyl-D-aspartate (NMDA) receptor activation. [{sup 125}I]-CNS 1261 was prepared by radioiodination of N-(1-naphthyl)-N'-(3-tributylstannylphenyl)-N'-methylguanidine using Na{sup 125}I and peracetic acid. [{sup 125}I]-CNS 1261 uptake in vivo reflected NMDA receptor distribution in normal rat brain, whereas in ischemic rat brain, uptake was markedly increased in areas of NMDA receptor activation. Radiolabeled CNS 1261 appears to be a good candidate for further development as a single photon emission computed tomography tracer in the investigation of NMDA receptor activation in cerebral ischemia.

  15. Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons

    Directory of Open Access Journals (Sweden)

    Manfred eOswald

    2015-04-01

    Full Text Available Pauses in the tonic firing of striatal cholinergic interneurons (CINs emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarisation (AHP underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD of postsynaptic potentials (PSP in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg2+-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg2+-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.

  16. Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach.

    Science.gov (United States)

    Anan, Kosuke; Masui, Moriyasu; Hara, Shinichiro; Ohara, Miho; Kume, Masaharu; Yamamoto, Shoichi; Shinohara, Shunji; Tsuji, Hiroki; Shimada, Shinji; Yagi, Shigenori; Hasebe, Nobuyoshi; Kai, Hiroyuki

    2017-09-01

    NR2B subunit containing N-methyl-d-aspartate (NMDA) receptor is an attractive target for chronic pain due to its involvement in disease states and its limited distribution in the central nervous system. Cyclohexanol-based leads 6a and 6c were identified as potent NR2B-selective NMDA antagonists utilizing a scaffold hopping approach. Further optimization of this series through replacement of the amide in the leads with an isoxazole and efforts to optimize the pharmacokinetic profiles led to the discovery of orally available brain penetrants 7k and 7l, which demonstrated analgesic activity in the mouse formalin test at early and late phases. Copyright © 2017. Published by Elsevier Ltd.

  17. Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

    Science.gov (United States)

    Strick, Christine A; Li, Cheryl; Scott, Liam; Harvey, Brian; Hajós, Mihály; Steyn, Stefanus J; Piotrowski, Mary A; James, Larry C; Downs, James T; Rago, Brian; Becker, Stacey L; El-Kattan, Ayman; Xu, Youfen; Ganong, Alan H; Tingley, F David; Ramirez, Andres D; Seymour, Patricia A; Guanowsky, Victor; Majchrzak, Mark J; Fox, Carol B; Schmidt, Christopher J; Duplantier, Allen J

    2011-01-01

    Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Effect of brain-derived neurotrophic factor on activity-regulated cytoskeleton-associated protein gene expression in primary frontal cortical neurons. Comparison with NMDA and AMPA

    DEFF Research Database (Denmark)

    El-Sayed, Mona; Hofman-Bang, Jacob; Mikkelsen, Jens D

    2011-01-01

    The effect of brain-derived neurotrophic factor (BDNF) on activity-regulated cytoskeleton-associated protein (Arc) mRNA levels in primary neuronal cultures of rat frontal cortex was characterized pharmacologically and compared to the effect on expression of c-fos, bdnf, neuritin, cox-2 as examples...... of other immediate early genes. BDNF induced a very strong increase (around 100 fold) in Arc mRNA and the maximal effect seen at 25 ng/ml. The effect was dose-dependent with EC50 around 1.6 ng/ml. The time profile revealed a significant effect after 25 min. BDNF also increased levels of c-Fos, neuritin...... and BDNF mRNA, but not COX-2 mRNA. The pharmacological profile of NMDA and AMPA-induced arc gene expression in frontal cortical neurons was compared to BDNF. NMDA and AMPA increased Arc mRNA but their maximal effect did not exceed 20-fold. The effect of AMPA was completely blocked by the NMDA receptor...

  19. Aspirin Augments IgE-Mediated Histamine Release from Human Peripheral Basophils via Syk Kinase Activation

    Directory of Open Access Journals (Sweden)

    Hiroaki Matsuo

    2013-01-01

    Conclusions: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.

  20. Opposing action of conantokin-G on synaptically and extrasynaptically-activated NMDA receptors.

    Science.gov (United States)

    Balsara, Rashna; Li, Neill; Weber-Adrian, Danielle; Huang, Louxiu; Castellino, Francis J

    2012-06-01

    Synaptic and extrasynaptic activation of the N-methyl-D-aspartate receptor (NMDAR) has distinct consequences on cell signaling and neuronal survival. Since conantokin (con)-G antagonism is NR2B-selective, which is the key subunit involved in extrasynaptic activation of the receptor, its ability to specifically elicit distinct signaling outcomes in neurons with synaptically or extrasynaptically-activated NMDARs was evaluated. Inhibition of Ca(2+) influx through extrasynaptic NMDAR ion channels was neuroprotective, as it effectively enhanced levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), activated cAMP response element binding protein (CREB), enhanced mitochondrial viability, and attenuated the actin disorganization observed by extrasynaptic activation of NMDARs. Conversely, the pro-signaling pathways stimulated by synaptically-induced Ca(2+) influx were abolished by con-G. Furthermore, subunit non-selective con-T was unable to successfully redress the impairments in neurons caused by extrasynaptically-activated NMDARs, thus indicating that NR2B-specific antagonists are beneficial for neuron survival. Neurons ablated for the NR2B subunit showed weak synaptic Ca(2+) influx, reduced sensitivity to MK-801 blockage, and diminished extrasynaptic current compared to WT and NR2A(-/-) neurons. This indicates that the NR2B subunit is an integral component of both synaptic and extrasynaptic NMDAR channels. Altogether, these data suggest that con-G specifically targets the NR2B subunit in the synaptic and extrasynaptic locations, resulting in the opposing action of con-G on differentially activated pools of NMDARs.

  1. NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity.

    Science.gov (United States)

    Baron, A; Montagne, A; Cassé, F; Launay, S; Maubert, E; Ali, C; Vivien, D

    2010-05-01

    Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(*), 3R(*))-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.

  2. Positive feedback of NR2B-containing NMDA receptor activity is the initial step toward visual imprinting: a model for juvenile learning.

    Science.gov (United States)

    Nakamori, Tomoharu; Sato, Katsushige; Kinoshita, Masae; Kanamatsu, Tomoyuki; Sakagami, Hiroyuki; Tanaka, Kohichi; Ohki-Hamazaki, Hiroko

    2015-01-01

    Imprinting in chicks is a good model for elucidating the processes underlying neural plasticity changes during juvenile learning. We recently reported that neural activation of a telencephalic region, the core region of the hyperpallium densocellulare (HDCo), was critical for success of visual imprinting, and that N-Methyl-D-aspartic (NMDA) receptors containing the NR2B subunit (NR2B/NR1) in this region were essential for imprinting. Using electrophysiological and multiple-site optical imaging techniques with acute brain slices, we found that long-term potentiation (LTP) and enhancement of NR2B/NR1 currents in HDCo neurons were induced in imprinted chicks. Enhancement of NR2B/NR1 currents as well as an increase in surface NR2B expression occurred even following a brief training that was too weak to induce LTP or imprinting behavior. This means that NR2B/NR1 activation is the initial step of learning, well before the activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors which induces LTP. We also showed that knockdown of NR2B/NR1 inhibited imprinting, and inversely, increasing the surface NR2B expression by treatment with a casein kinase 2 inhibitor successfully reduced training time required for imprinting. These results suggest that imprinting stimuli activate post-synaptic NR2B/NR1 in HDCo cells, increase NR2B/NR1 signaling through up-regulation of its expression, and induce LTP and memory acquisition. The study investigated the neural mechanism underlying juvenile learning. In the initial stage of chick imprinting, NMDA receptors containing the NMDA receptor subunit 2B (NR2B) are activated, surface expression of NR2B/NR1 (NMDA receptor subunit 1) is up-regulated, and consequently long-term potentiation is induced in the telencephalic neurons. We suggest that the positive feedback in the NR2B/NR1 activation is a unique process of juvenile learning, exhibiting rapid memory acquisition. © 2014 International Society for Neurochemistry.

  3. Nicotinic α7 receptor activation selectively potentiates the function of NMDA receptors in glutamatergic terminals of the nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Stefania eZappettini

    2014-10-01

    Full Text Available We here provide functional and immunocytochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs and N-methyl-D-aspartic acid receptors (NMDARs in glutamatergic terminals of the nucleus accumbens (NAc. Immunocytochemical studies showed that a significant percentage of NAc terminals were glutamatergic and possessed GluN1 and α7-containing nAChR. A short-term pre-exposure of synaptosomes to nicotine (30 µM or choline (1 mM caused a significant potentiation of the 100 µM NMDA-evoked [3H]D-aspartate ([3H]D-Asp outflow, which was prevented by α-bungarotoxin (100 nM. The pre-exposure to nicotine (100 µM or choline (1 mM also enhanced the NMDA-induced cytosolic free calcium levels, as measured by FURA-2 fluorescence imaging in individual NAc terminals, an effect also prevented by α-bungarotoxin. Pre-exposure to the α4-nAChR agonists 5IA85380 (10 nM or RJR2429 (1 µM did not modify NMDA-evoked ([3H]D-Asp outflow and calcium transients. The NMDA-evoked ([3H]D-Asp overflow was partially antagonized by the NMDAR antagonists MK801, D-AP5, 5,7-DCKA and R(-CPP and unaffected by the GluN2B-NMDAR antagonists Ro256981 and ifenprodil. Notably, pre-treatment with choline increased GluN2A biotin-tagged proteins. In conclusion, our results show that the GluN2A-NMDA receptor function can be positively regulated in NAc terminals in response to a brief incubation with α7 but not α4 nAChRs agonists. This might be a general feature in different brain areas since a similar nAChR-mediated bolstering of NMDA-induced ([3H]D-Aspoverflow was also observed in hippocampal synaptosomes.

  4. N-methyl-D-aspartate increases acetylcholine release from rat striatum and cortex: its effect is augmented by choline

    Science.gov (United States)

    Ulus, I. H.; Buyukuysal, R. L.; Wurtman, R. J.

    1992-01-01

    We examined the effects of N-methyl-D-aspartate (NMDA), a glutamate agonist, and of glutamate itself, on acetylcholine (ACh) release from superfused rat striatal slices. In a Mg(++)-free medium, NMDA (32-1000 microM) as well as glutamate (1 mM) increased basal ACh release by 35 to 100% (all indicated differences, P less than .05), without altering tissue ACh or choline contents. This augmentation was blocked by Mg++ (1.2 mM) or by MK-801 (10 microM). Electrical stimulation (15 Hz, 75 mA) increased ACh release 9-fold (from 400 to 3660 pmol/mg of protein): this was enhanced (to 4850 pmol/mg of protein) by NMDA (100 microM). ACh levels in stimulated slices fell by 50 or 65% depending on the absence or presence of NMDA. The addition of choline (40 microM) increased ACh release both basally (570 pmol/mg of protein) and with electrical stimulation (6900 pmol/mg of protein). In stimulated slices choline acted synergistically with NMDA, raising ACh release to 10,520 pmol/mg of protein. The presence of choline also blocked the fall in tissue ACh. No treatment affected tissue phospholipid or protein levels. NMDA (32-320 microM) also augmented basal ACh release from cortical but not hippocampal slices. Choline efflux from striatal and cortical (but not hippocampal) slices decreased by 34 to 50% in Mg(++)-free medium. These data indicate that NMDA-like drugs may be useful, particularly in combination with choline, to enhance striatal and cortical cholinergic activity. ACh release from rat hippocampus apparently is not affected by NMDA receptors.

  5. An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes

    Science.gov (United States)

    Huang, Xiao-Ting; Li, Chen; Peng, Xiang-Ping; Guo, Jia; Yue, Shao-Jie; Liu, Wei; Zhao, Fei-Yan; Han, Jian-Zhong; Huang, Yan-Hong; Yang-Li, Y -L; Cheng, Qing-Mei; Zhou, Zhi-Guang; Chen, Chen; Feng, Dan-Dan; Luo, Zi-Qiang

    2017-01-01

    In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucose via activation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of β-cells under chronic high-glucose exposure. Long-term treatment of β-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated by GluN1 knockout. The NMDAR antagonist MK-801 or GluN1 knockout prevented high-glucose-induced dysfunction in β-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in β-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by hyperglycemia. PMID:28303894

  6. Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

    Institute of Scientific and Technical Information of China (English)

    ZHU Yong-ping; LONG Zai-hao; ZHENG Ming-lan; BINSACK Ralf

    2006-01-01

    Objective: To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. Methods: Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. Results: MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. Conclusion:Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

  7. Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor.

    Science.gov (United States)

    Sałat, Kinga; Siwek, Agata; Starowicz, Gabriela; Librowski, Tadeusz; Nowak, Gabriel; Drabik, Urszula; Gajdosz, Ryszard; Popik, Piotr

    2015-12-01

    Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 μM. The affinities of all three compounds were then assessed at NMDA receptors using [3H]MK-801 binding. The dose-response relationships of all 3 compounds in the forced swim test were also investigated in mice 30 min after IP administration. The effects of ketamine and norketamine (both 50 mg/kg) were then examined at 30 min, 3 days and 7 days post administration. Among the 80 potential targets examined, only NMDA receptors were affected with a magnitude of >50% by ketamine and norketamine at the concentration of 10 μM. The Ki values of ketamine, norketamine and dehydronorketamine at NMDA receptors were 0.119±0.01, 0.97±0.1 and 3.21±0.3 μM, respectively. Ketamine and norketamine reduced immobility with minimum effective doses (MEDs) of 10 and 50 mg/kg, respectively; dehydronorketamine did not affect immobility at doses of up to 50 mg/kg. Neither ketamine nor norketamine reduced immobility in the forced swim test 3 and 7 days following administration. Further, oral administration of ketamine (5-50 mg/kg) did not affect immobility. We demonstrate that ketamine and norketamine but not dehydronorketamine given acutely at subanesthetic doses reduced immobility in the forced swim test. These antidepressant-like effects appear attributable to NMDA receptor inhibition.

  8. Human-in-the-loop evaluation of RMS Active Damping Augmentation

    Science.gov (United States)

    Demeo, Martha E.; Gilbert, Michael G.; Scott, Michael A.; Lepanto, Janet A.; Bains, Elizabeth M.; Jensen, Mary C.

    1993-01-01

    Active Damping Augmentation is the insertion of Controls-Structures Integration Technology to benefit the on-orbit performance of the Space Shuttle Remote Manipulator System. The goal is to reduce the vibration decay time of the Remote Manipulator System following normal payload maneuvers and operations. Simulation of Active Damping Augmentation was conducted in the realtime human-in-the-loop Systems Engineering Simulator at the NASA Johnson Space Center. The objective of this study was to obtain a qualitative measure of operational performance improvement from astronaut operators and to obtain supporting quantitative performance data. Sensing of vibratory motions was simulated using a three-axis accelerometer mounted at the end of the lower boom of the Remote Manipulator System. The sensed motions were used in a feedback control law to generate commands to the joint servo mechanisms which reduced the unwanted oscillations. Active damping of the Remote Manipulator System with an attached 3990 lb. payload was successfully demonstrated. Six astronaut operators examined the performance of an Active Damping Augmentation control law following single-joint and coordinated six-joint translational and rotational maneuvers. Active Damping Augmentation disturbance rejection of Orbiter thruster firings was also evaluated. Significant reductions in the dynamic response of the 3990 lb. payload were observed. Astronaut operators recommended investigation of Active Damping Augmentation benefits to heavier payloads where oscillations are a bigger problem (e.g. Space Station Freedom assembly operators).

  9. Human-in-the-loop evaluation of RMS Active Damping Augmentation

    Science.gov (United States)

    Demeo, Martha E.; Gilbert, Michael G.; Scott, Michael A.; Lepanto, Janet A.; Bains, Elizabeth M.; Jensen, Mary C.

    1993-01-01

    Active Damping Augmentation is the insertion of Controls-Structures Integration Technology to benefit the on-orbit performance of the Space Shuttle Remote Manipulator System. The goal is to reduce the vibration decay time of the Remote Manipulator System following normal payload maneuvers and operations. Simulation of Active Damping Augmentation was conducted in the realtime human-in-the-loop Systems Engineering Simulator at the NASA Johnson Space Center. The objective of this study was to obtain a qualitative measure of operational performance improvement from astronaut operators and to obtain supporting quantitative performance data. Sensing of vibratory motions was simulated using a three-axis accelerometer mounted at the end of the lower boom of the Remote Manipulator System. The sensed motions were used in a feedback control law to generate commands to the joint servo mechanisms which reduced the unwanted oscillations. Active damping of the Remote Manipulator System with an attached 3990 lb. payload was successfully demonstrated. Six astronaut operators examined the performance of an Active Damping Augmentation control law following single-joint and coordinated six-joint translational and rotational maneuvers. Active Damping Augmentation disturbance rejection of Orbiter thruster firings was also evaluated. Significant reductions in the dynamic response of the 3990 lb. payload were observed. Astronaut operators recommended investigation of Active Damping Augmentation benefits to heavier payloads where oscillations are a bigger problem (e.g. Space Station Freedom assembly operators).

  10. UVA radiation augments cytotoxic activity of psoralens in melanoma cells.

    Science.gov (United States)

    Wrześniok, Dorota; Beberok, Artur; Rok, Jakub; Delijewski, Marcin; Hechmann, Anna; Oprzondek, Martyna; Rzepka, Zuzanna; Bacler-Żbikowska, Barbara; Buszman, Ewa

    2017-07-01

    Melanoma is an aggressive form of skin cancer. The aim of the study was to evaluate the influence of UVA radiation and psoralens: 5-methoxypsoralen (5-MOP) or 8-methoxypsoralen (8-MOP) on melanoma cells viability. The amelanotic C32 and melanotic COLO829 human melanoma cell lines were exposed to increasing concentrations of psoralens (0.1-100 μM) in the presence or absence of UVA radiation. Cell viability was evaluated by the WST-1 assay. We demonstrated that 8-MOP, in contrast to 5-MOP, has no cytotoxic effect on both melanoma cell lines. Simultaneous exposure of cells to 8-MOP and UVA radiation caused significant cytotoxic response in C32 cells where the EC50 value was estimated to be 131.0 μM (UVA dose: 1.3 J/cm(2)) and 105.3 μM (UVA dose: 2.6 J/cm(2)). The cytotoxicity of 5-MOP on both C32 and COLO829 cells was significantly augmented by UVA radiation - the EC50 was estimated to be 22.7 or 7.9 μM (UVA dose: 1.3 J/cm(2)) and 24.2 or 7.0 μM (UVA dose: 2.6 J/cm(2)), respectively. The demonstrated high cytotoxic response after simultaneous exposure of melanoma cells to psoralens and UVA radiation in vitro suggests the usefulness of PUVA therapy to treat melanoma in vivo.

  11. Immobilized-cell-augmented activated sludge process for treating wastewater containing hazardous compounds.

    Science.gov (United States)

    Jittawattanarat, Rungrod; Kostarelos, Konstantinos; Khan, Eakalak

    2007-05-01

    A novel bioaugmentation scheme called immobilized-cell-augmented activated sludge (ICAAS) was developed. Offline enricher reactors were used to maintain immobilized acclimated cells applied to augment completely mixed activated sludge (CMAS) treating a pentachlorophenol (PCP) pulse loading. Cellulose triacetate (CA) and powder activated carbon (PAC) combined with CA (PAC + CA) were the two media types used for entrapping the PCP-degrading culture. With ICAAS at 5% by volume augmentation, PCP removal of 73.1 and 75.1% via biodegradation, volatilization, and adsorption onto suspended cells, entrapped cells, and media was achieved for the systems with CA and PAC + CA media, respectively, while PCP removal in a control CMAS, which had a comparable level of combined PCP adsorption onto suspended cells and volatilization as the ICAAS, was 48.7%. Results further showed that the immobilized cells retained their PCP-degrading ability when they were fed with the inducer (PCP) once every 20 days.

  12. Frontopolar activity and connectivity support dynamic conscious augmentation of creative state.

    Science.gov (United States)

    Green, Adam E; Cohen, Michael S; Raab, Hillary A; Yedibalian, Christopher G; Gray, Jeremy R

    2015-03-01

    No ability is more valued in the modern innovation-fueled economy than thinking creatively on demand, and the "thinking cap" capacity to augment state creativity (i.e., to try and succeed at thinking more creatively) is of broad importance for education and a rich mental life. Although brain-based creativity research has focused on static individual differences in trait creativity, less is known about changes in creative state within an individual. How does the brain augment state creativity when creative thinking is required? Can augmented creative state be consciously engaged and disengaged dynamically across time? Using a novel "thin slice" creativity paradigm in 55 fMRI participants performing verb-generation, we successfully cued large, conscious, short-duration increases in state creativity, indexed quantitatively by a measure of semantic distance derived via latent semantic analysis. A region of left frontopolar cortex, previously associated with creative integration of semantic information, exhibited increased activity and functional connectivity to anterior cingulate gyrus and right frontopolar cortex during cued augmentation of state creativity. Individual differences in the extent of increased activity in this region predicted individual differences in the extent to which participants were able to successfully augment state creative performance after accounting for trait creativity and intelligence.

  13. Accelerometer signal-based human activity recognition using augmented autoregressive model coefficients and artificial neural nets.

    Science.gov (United States)

    Khan, A M; Lee, Y K; Kim, T S

    2008-01-01

    Automatic recognition of human activities is one of the important and challenging research areas in proactive and ubiquitous computing. In this work, we present some preliminary results of recognizing human activities using augmented features extracted from the activity signals measured using a single triaxial accelerometer sensor and artificial neural nets. The features include autoregressive (AR) modeling coefficients of activity signals, signal magnitude areas (SMA), and title angles (TA). We have recognized four human activities using AR coefficients (ARC) only, ARC with SMA, and ARC with SMA and TA. With the last augmented features, we have achieved the recognition rate above 99% for all four activities including lying, standing, walking, and running. With our proposed technique, real time recognition of some human activities is possible.

  14. Massively augmented hippocampal dentate granule cell activation accompanies epilepsy development

    Science.gov (United States)

    Dengler, Christopher G.; Yue, Cuiyong; Takano, Hajime; Coulter, Douglas A.

    2017-01-01

    In a mouse model of temporal lobe epilepsy, multicellular calcium imaging revealed that disease emergence was accompanied by massive amplification in the normally sparse, afferent stimulation-induced activation of hippocampal dentate granule cells. Patch recordings demonstrated reductions in local inhibitory function within the dentate gyrus at time points where sparse activation was compromised. Mimicking changes in inhibitory synaptic function and transmembrane chloride regulation was sufficient to elicit the dentate gyrus circuit collapse evident during epilepsy development. Pharmacological blockade of outward chloride transport had no effect during epilepsy development, and significantly increased granule cell activation in both control and chronically epileptic animals. This apparent occlusion effect implicates reduction in chloride extrusion as a mechanism contributing to granule cell hyperactivation specifically during early epilepsy development. Glutamine plays a significant role in local synthesis of GABA in synapses. In epileptic mice, sparse granule cell activation could be restored by glutamine application, implicating compromised GABA synthesis. Glutamine had no effect on granule cell activation earlier, during epilepsy development. We conclude that compromised feedforward inhibition within the local circuit generates the massive dentate gyrus circuit hyperactivation evident in animals during and following epilepsy development. However, the mechanisms underlying this disinhibition diverge significantly as epilepsy progresses. PMID:28218241

  15. TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

    OpenAIRE

    West, A. Phillip; Brodsky, Igor E.; Rahner, Christoph; Woo, Dong Kyun; Erdjument-Bromage, Hediye; Tempst, Paul; Walsh, Matthew C; Choi, Yongwon; Shadel, Gerald S.; Ghosh, Sankar

    2011-01-01

    Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria, and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase (Phox) machinery 1 . However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to macrophage bactericidal activity, although the mechanisms linking innate immune signaling to mitochondria for mROS generation remain unclear 2-4 . Here we demonstrate t...

  16. NMDA receptors and memory encoding.

    Science.gov (United States)

    Morris, Richard G M

    2013-11-01

    It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can

  17. Satellite Dynamic Damping via Active Force Control Augmentation

    Science.gov (United States)

    Varatharajoo, Renuganth

    2012-07-01

    An approach that incorporates the Active Force Control (AFC) technique into a conventional Proportional-Derivative (PD) controller is proposed for a satellite active dynamic damping towards a full attitude control. The AFC method has been established to facilitate a robust motion control of dynamical systems in the presence of disturbances, parametric uncertainties and changes that are commonly prevalent in the real-world environment. The usefulness of the method can be extended by introducing intelligent mechanisms to approximate the mass or inertia matrix of the dynamic system to trigger the compensation effect of the controller. AFC is a technique that relies on the appropriate estimation of the inertial or mass parameters of the dynamic system and the measurements of the acceleration and force signals induced by the system if practical implementation is ever considered. In AFC, it is shown that the system subjected to a number of disturbances remains stable and robust via the compensating action of the control strategy. We demonstrate that it is possible to design a spacecraft attitude feedback controller that will ensure the system dynamics set point remains unchanged even in the presence of the disturbances provided that the actual disturbances can be modeled effectively. In order to further facilitate this analysis, a combined energy and attitude control system (CEACS) is proposed as a model satellite attitude control actuator. All the governing equations are established and the proposed satellite attitude control architecture is made amenable to numerical treatments. The results show that the PD-AFC attitude damping performances are superiorly better than that of the solely PD type. It is also shown that the tunings of the AFC system gains are crucial to ensure a better attitude damping performance and this process is mandatory for AFC systems. Finally, the results demonstrate an important satellite dynamic damping enhancement capability using the AFC

  18. Propofol enhances facial stimulation-evoked responses in the cerebellar granule cell layer via NMDA receptor activation in mice in vivo.

    Science.gov (United States)

    Jin, Wen-Zhe; Liu, Heng; Wan, Peng; Chu, Chun-Ping; Qiu, De-Lai

    2016-10-05

    We recently reported that propofol depressed facial stimulation-evoked gamma-aminobutyric acid (GABA) transmission at cerebellar molecular layer interneuron-Purkinje cell (PC) synapses in mice in vivo, but facilitated excitatory parallel fiber inputs onto PCs. Here, we examine the effects of propofol on cerebellar granule cell layer (GCL) responses to facial stimulation in urethane-anesthetized mice, using electrophysiological and pharmacological methods. Cerebellar surface perfusion of propofol (50-1000μM) facilitated field potentials evoked in the cerebellar GCL by air-puff stimulation of the ipsilateral whisker pad, shown by increases in the half-width and area under the curve (AUC) of the stimulus onset response (Ron). Propofol also significantly increased the amplitude of the stimulus offset response (Roff) and Roff/Ron ratio. The propofol-induced increase in Ron AUC was dose-dependent, with a 50% effective concentration (EC50) of 242.4µM. Application of the GABAA receptor antagonist gabazine (20μM) significantly increased the amplitude, half-width, rise tau and AUC of Ron, but these parameters were further increased by additional application of propofol (300µM). Notably, application of the N-methyl-d-aspartate (NMDA) receptor blocker D-APV (250µM) significantly attenuated the half-width and AUC of Ron and the amplitude of Roff, without significantly changing the amplitude of Ron. These results indicate that propofol enhanced facial stimulation-evoked responses in the cerebellar GCL via NMDA receptor activation, which resulted in the facilitation of excitatory parallel fiber inputs onto cerebellar PCs in mice in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Effect of dimebon on NMDA-activated current in mice medium spiny neuron%Dimebon对小鼠中型多棘神经元NMDA激活电流的影响

    Institute of Scientific and Technical Information of China (English)

    许晓利; 李琴; 宋露; Ilya Bezprozvanny

    2015-01-01

    目的:探讨药物Dimebon在阿尔茨海默氏病(AD)和亨廷顿氏病(HD)的药理作用。方法采用膜片钳技术在培养的小鼠纹状体中型多棘神经元(medium spiny striatal neurons,MSN)上观察不同浓度的Dimebon对NMDA (N-methyl-D-aspartic acid)受体激活电流的影响。结果高浓度的Dimebon抑制NMDA激活电流,而低浓度的Dimebon增强NMDA激活电流,从而下调NMDA受体。结论 Dimebon对NMDA受体激活电流的影响有双重作用,依Dimebon浓度的不同而不同,为临床用药提供依据。%Objective Dimebon is an antihistamine compound which has been proposed to treat neurodegenerative disorders, but the mechanism remain elusive. To explore Dimebon effection on Alzheimer's disease and Huntington's disease. Method Membrane currents were measured by using whole cell patch clamp techniques. the influence ofdifferent concentration of Dimebon on NMDA-activated currents in primary Medium Spiny Striatal Neuronal cultures (MSN) from wild type (WT) mice were studied. Results 1~50 μmol/L Dimebon inhibited NMDA activated currents, but 0.1~0.5μmol/L increased NMDA activated currents. Conclusion Dimebon has dual function on NMDA receptors.

  20. Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections.

    Science.gov (United States)

    Stoop, Ron; Conquet, François; Zuber, Benoit; Voronin, Leon L; Pralong, Etienne

    2003-07-02

    The aim of this study was to describe the induction and expression mechanisms of a persistent bursting activity in a horizontal slice preparation of the rat limbic system that includes the ventral part of the hippocampus and the entorhinal cortex. Disinhibition of this preparation by bicuculline led to interictal-like bursts in the CA3 region that triggered synchronous activity in the entorhinal cortex. Washout of bicuculline after a 1 hr application resulted in a maintained production of hippocampal bursts that continued to spread to the entorhinal cortex. Separation of CA3 from the entorhinal cortex caused the activity in the latter to become asynchronous with CA3 activity in the presence of bicuculline and disappear after washout; however, in CA3, neither the induction of bursting nor its persistence were affected. Associated with the CA3 persistent bursting, a strengthening of recurrent collateral excitatory input to CA3 pyramidal cells and a decreased input to CA3 interneurons was found. Both the induction of the persistent bursting and the changes in synaptic strength were prevented by antagonists of metabotropic glutamate 5 (mGlu5) or NMDA receptors or protein synthesis inhibitors and did not occur in slices from mGlu5 receptor knock-out mice. The above findings suggest potential synaptic mechanisms by which the hippocampus switches to a persistent interictal bursting mode that may support a spread of interictal-like bursting to surrounding temporal lobe regions.

  1. Activity of the principal cells of the olfactory bulb promotes a structural dynamic on the distal dendrites of immature adult-born granule cells via activation of NMDA receptors.

    Science.gov (United States)

    Breton-Provencher, Vincent; Coté, Daniel; Saghatelyan, Armen

    2014-01-29

    The adult olfactory bulb is continuously supplied with neuronal precursors that differentiate into granule and periglomerular cells. Little is known about the structural dynamic of adult-born granule cells (GCs) at their different maturational stages, the mechanisms controlling the integration of new neurons into the pre-existing neuronal circuitry, or the role of principal cell activity in these processes. We used two-photon time-lapse imaging to reveal a high level of filopodia formation and retraction on the distal dendrites of adult-born GCs at their early maturational stages. This dynamic decreased as the adult-born interneurons matured. Filopodia formation/retraction on the dendrites of adult-born GCs at the early maturational stages depended on the activation of NMDA receptors (NMDARs). The stimulation of mitral cells using a pattern that mimics activity of these principal neurons to odor presentation promotes the NMDAR-dependent filopodia dynamic of adult-born GCs during their early but not late maturational stages. Moreover, NMDA iontophoresis was sufficient to induce the formation of new filopodia on the distal dendrites of immature adult-born GCs. The maturation of adult-born interneurons was accompanied by a progressive hyperpolarization of the membrane potential and an increased Mg(2+) block of NMDARs. Decreasing the extracellular Mg(2+) concentration led to filopodia formation on the dendrites of mature adult-born GCs following NMDA iontophoresis. Our findings reveal an increased structural dynamic of adult-born GCs during the early stages of their integration into the mouse bulbar circuitry and highlight a critical period during which the principal cells' activity influences filopodia formation/retraction on the dendrites of interneurons.

  2. Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

    Directory of Open Access Journals (Sweden)

    Stefanie A.G. Black

    2014-08-01

    Full Text Available Although it is well established that misfolding of the cellular prion protein (PrPC into the beta-sheet-rich, aggregated scrapie conformation (PrPSc causes a variety of transmissible spongiform encephalopathies (TSEs, the physiological roles of PrPC are still incompletely understood. There is accumulating evidence describing the roles of PrPC in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrPC that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrPC play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrPSc-induced neuronal death. Moreover, in mice lacking PrPC, infarct size is increased after focal cerebral ischemia, and absence of PrPC increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrPC was found to be a receptor for oligomeric beta-amyloid (Abeta peptides, suggesting a role for PrPC in Alzheimer’s disease. Our recent findings suggest that Abeta peptides enhance NMDA receptor current by perturbing the normal copper- and PrPC-dependent regulation of these receptors. Here, we review evidence highlighting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrPC-mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrPC-mediated regulation and identifying PrPC binding site(s on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for Alzheimer’s disease and other neurodegenerative disorders involving dysfunction of PrPC.

  3. Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?

    Science.gov (United States)

    Rodier, Marion; Prigent-Tessier, Anne; Béjot, Yannick; Jacquin, Agnès; Mossiat, Claude; Marie, Christine; Garnier, Philippe

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA)/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA) receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (r)t-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg) administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v.) while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p.) in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling.

  4. Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?

    Directory of Open Access Journals (Sweden)

    Marion Rodier

    Full Text Available Brain-derived neurotrophic factor (BDNF through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (rt-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v. while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p. in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling.

  5. Imaging the PCP site of the NMDA ion channel

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Rikki N. E-mail: rnw7@columbia.edu

    2003-11-01

    The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenousr substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and 'open' state, but not when it is in the inactive or 'closed' state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed.

  6. The Anticonvulsant Activity of a Flavonoid-Rich Extract from Orange Juice Involves both NMDA and GABA-Benzodiazepine Receptor Complexes

    Directory of Open Access Journals (Sweden)

    Rita Citraro

    2016-09-01

    Full Text Available The usage of dietary supplements and other natural products to treat neurological diseases has been growing over time, and accumulating evidence suggests that flavonoids possess anticonvulsant properties. The aim of this study was to examine the effects of a flavonoid-rich extract from orange juice (OJe in some rodent models of epilepsy and to explore its possible mechanism of action. The genetically audiogenic seizures (AGS-susceptible DBA/2 mouse, the pentylenetetrazole (PTZ-induced seizures in ICR-CD1 mice and the WAG/Rij rat as a genetic model of absence epilepsy with comorbidity of depression were used. Our results demonstrate that OJe was able to exert anticonvulsant effects on AGS-sensible DBA/2 mice and to inhibit PTZ-induced tonic seizures, increasing their latency. Conversely, it did not have anti-absence effects on WAG/Rij rats. Our experimental findings suggest that the anti-convulsant effects of OJe are likely mediated by both an inhibition of NMDA receptors at the glycine-binding site and an agonistic activity on benzodiazepine-binding site at GABAA receptors. This study provides evidences for the antiepileptic activity of OJe, and its results could be used as scientific basis for further researches aimed to develop novel complementary therapy for the treatment of epilepsy in a context of a multitarget pharmacological strategy.

  7. Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

    Science.gov (United States)

    Moreau, J. L.; Pieri, L.; Prud'hon, B.

    1989-01-01

    1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061

  8. Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.

    Science.gov (United States)

    de Winter, Josine Marieke; Buck, Danielle; Hidalgo, Carlos; Jasper, Jeffrey R; Malik, Fady I; Clarke, Nigel F; Stienen, Ger J M; Lawlor, Michael W; Beggs, Alan H; Ottenheijm, Coen A C; Granzier, Henk

    2013-06-01

    Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations. Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed. Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation-without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle. Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.

  9. Augmentation and Maximization of Per-Capita Call Active Space Through Chorusing in Anuran Amphibians

    Science.gov (United States)

    Fox, James Henderson

    It is poorly understood why anuran males form choruses. Although various reasons have been proposed, empirical support is lacking. This study proposed, developed, and evaluated the chorus active space (CAS) augmentation theory, which states that anuran choruses are formed and organized so as to augment and maximize per-capita CAS beyond that which could be achieved by an isolated male. This study involved three phases. First, computer models of hypothetical choruses indicated that CAS, as defined, is necessarily augmented for chorusing males. These models provided the necessary information from which optimal interindividual distances (IIDs), corresponding to maximal CASs, could be estimated differentially for linear and planar chorus configurations. The second phase examined Acris crepitans and Hyla cinerea choruses for optimal intermale spacing. A. crepitans, which utilizes mixed chorus geometries (either linear or planar, depending on available resources), cannot optimize IID within any observed pond-type breeding site; however, observed spacing would be optimal along a stream bank, where chorusing often occurs, for a chorus population of 61, approximately the minimum value at which CAS characteristics are stabile. H. cinerea males, which form only planar choruses, space orders of magnitude closer than optimal. Suboptimal spacing in this species is understandable, considering the would-be size of an optimally spaced chorus. In the final phase of this study, a database of CAS-related data was compiled mostly from published sources and was examined for variable relationships predicted on the basis of CAS augmentation theory. The findings suggest that very few planar geometry species may maximize CAS; whereas, a much larger number of mixed geometry species, perhaps as well as linear geometry species, may maximize CAS. These findings loosely agree with the field study findings and suggest that CAS augmentation theory applies to at least a subset of anuran species and

  10. Holographic Quantitative Structure-Activity Relationships of Tryptamine Derivatives at NMDA, 5HT1A and 5HT2A Receptors

    Directory of Open Access Journals (Sweden)

    Peter Wolschann

    2013-07-01

    Full Text Available Tryptamine derivatives (Ts were found to inhibit the binding of [3H]MK-801, [3H]ketanserin and [3H]8-OH-DPAT to rat brain membranes. [3H]MK-801 labels the NMDA (N-methyl-D-aspartate receptor, a ionotropic glutamate receptor which controls synaptic plasticity and memory function in the brain, whereas [3H]ketanserin and [3H]8-OH-DPAT label 5HT2A and 5HT1A receptors, respectively. The inhibitory potencies of 64 Ts (as given by IC50 values were correlated with their structural properties by using the Holographic QSAR procedure (HQSAR. This method uses structural fragments and connectivities as descriptors which were encoded in a hologram thus avoiding the usual problems with conformation and alignment of the structures. Four correlation equations with high predictive ability and appropriate statistical test values could be established. The results are visualized by generation of maps reflecting the contribution of individual structural parts to the biological activities.

  11. Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

    Science.gov (United States)

    Khodr, Christina E; Chen, Lihua; Dave, Sonya; Al-Harthi, Lena; Hu, Xiu-Ti

    2016-10-01

    Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K(+) influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca(2+) influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca(2+) potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca(2+) influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca(2+) dysregulation in the mPFC.

  12. Neuroprotective activity of parawixin 10, a compound isolated from Parawixia bistriata spider venom (Araneidae: Araneae in rats undergoing intrahippocampal NMDA microinjection

    Directory of Open Access Journals (Sweden)

    Helene Aparecida Fachim

    2015-01-01

    Full Text Available Background: Parawixia bistriata is a semi colonial spider found mainly in southeastern of Brazil. Parawixin 10 (Pwx 10 a compound isolated from this spider venom has been demonstrated to act as neuroprotective in models of injury regulating the glutamatergic neurotransmission through glutamate transporters. Objectives: The aim of this work was to evaluate the neuroprotective effect of Pwx 10 in a rat model of excitotoxic brain injury by N methyl D aspartate (NMDA injection. Material and Methods: Male Wistar rats have been used, submitted to stereotaxic surgery for saline or NMDA microinjection into dorsal hippocampus. Two groups of animals were treated with Pwx 10. These treated groups received a daily injection of the Pwx 10 (2.5 mg/μL in the right lateral ventricle into rats pretreated with NMDA, always at the same time, each one starting the treatment 1 h or 24 h. Nissl staining was performed for evaluating the extension and efficacy of the NMDA injury and the neuroprotective effect of Pwx 10. Results: The treatment with Pwx 10 showed neuroprotective effect, being most pronounced when the compound was administrated from 1 h after NMDA in all hippocampal subfields analyzed (CA1, CA3 and hilus. Conclusion: These results indicated that Pwx 10 may be a good template to develop therapeutic drugs for treating neurodegenerative diseases, reinforcing the importance of continuing studies on its effects in the central nervous system.

  13. Characterisation of the Redox Sensitive NMDA Receptor

    KAUST Repository

    Alzahrani, Ohood

    2016-05-01

    Glucose entry into the brain and its subsequent metabolism to L-lactate, regulated by astrocytes, plays a major role in synaptic plasticity and memory formation. A recent study has shown that L-lactate produced by the brain upon stimulation of glycolysis, and glycogen-derived L-lactate from astrocytes and its transport into neurons, is crucial for memory formation. A recent study revealed the molecular mechanisms that underlie the role of L-lactate in neuronal plasticity and long-term memory formation. L-lactate was shown to induce a cascade of molecular events via modulation of redox-sensitive N-Methyl-D-aspartate (NMDA) receptor activity that was mimicked by nicotinamide adenine dinucleotide hydride (NADH) co-enzyme. This indicated that changes in cellular redox state, following L-lactate transport inside the cells and its subsequent metabolism, production of NADH, and favouring a reduced state are the key effects of L-lactate. Therefore, we are investigating the role of L-lactate in modulating NMDA receptor function via redox modulatory sites. Accordingly, crucial redox-sensitive cysteine residues, Cys320 and Cys87, of the NR2A NMDA receptor subunit are mutated using site-directed mutation, transfected, and expressed in HEK293 cells. This cellular system will then be used to characterise and monitor its activity upon Llactate stimulation, compared to the wild type. This will be achieved by calcium imaging, using fluorescent microscopy. Our data shows that L-lactate potentiated NMDA receptor activity and increased intracellular calcium influx in NR1/NR2A wild type compared to the control condition (WT NR1/NR2A perfused with (1μM) glutamate and (1μM) glycine agonist only), showing faster response initiation and slower decay rate of the calcium signal to the baseline. Additionally, stimulating with L-lactate associated with greater numbers of cells having high fluorescent intensity (peak amplitude) compared to the control. Furthermore, L-lactate rescued the

  14. NMDA受体的活化调节原代皮层神经元的Wnt/β-catenin信号通路%NMDA Receptor Activation Regulates Wnt/β-catenin Signaling Pathway in Primary Cortical Neurons

    Institute of Scientific and Technical Information of China (English)

    彭彦茜; 万仙子; 李屹晨; 李莎莎; 张薇; Tang Shaojun; 钟翎

    2012-01-01

    Wnt signaling has a key role in regulation of synaptic formation and function in the brain. Gluta-mate, which is the mainly excitatory transmitter, binds the glutamic acid receptor to regulate the activity of many signaling pathways. To determine the effect of NMDA receptor activation on Wnt/p-catenin signaling, primary cortical C57 mouse neurons were treated with 10 umol/L MSG and 50 umol/L NMDA and the components of Wnt/ p-catenin signaling were analyzed by Western blot or immunofluorescent experiments. We found that NMDA receptor activation not only increased the p-Ser9-GSK-3p to inhibit its activity but also caused an increase of intracellu-lar P-catenin and induced its translocation into nuclei, thereby up-regulated the downstream gene expression. These results suggest that NMDA receptors activation up-regulates Wnt/p-catenin signaling in primary cortical cultured neurons.%经典的Wnt/β-catenin信号通路在中枢神经系统突触形成和功能中发挥重要的调节作用.作为兴奋性神经递质的谷氨酸,与其受体结合,参与许多信号调节活动.为了探讨NMDA受体活化对Wnt/βcatenin信号通路的作用,该文利用18d的C57小鼠胚胎培养皮层神经元(离体10 d),用10 μmol/L谷氨酸钠(monosodium glutamate,MSG)和50 μmol/L N-甲基-D-天冬氨酸(NMDA)处理细胞,通过蛋白免疫印迹技术或者细胞免疫荧光染色分析Wnt/β-catenin信号通路关键成员.结果发现,NMDA受体的活化能使GSK-3β的Ser9位磷酸化水平增加,活性被抑制,胞浆内β-catenin蛋白降解减少,入核增加,激活下游基因表达.这些结果提示,NMDA受体激活能够上调Wnt/β-catenin信号通路.

  15. Open Augmented Reality Standards: Current Activities in Standards- Development Organizations%Open Augmented Reality Standards: Current Activities in Standards- Development Organizations

    Institute of Scientific and Technical Information of China (English)

    Christine Perey

    2012-01-01

    Augmented reality (AR) has emerged from research laboratories and is now being accepted in other domains as an attractive way of visualizing information. Before AR can be used in the mass market, there are a number of obstacles that need to be overcome. Several of these can be overcome by adopting open standards. A global grassroots community seeking open, interoperable AR content and experiences began to take shape in early 2010. This community is working collaboratively to reduce the barriers to the flow of data from content provider to AR end user. Standards development organizations and industry groups that provide open interfaces for AR meet regularly to provide updates, identify complementary work, and seek harmonization. The community also identifies deployer and implementer needs, communicates requirements, and discusses emerging challenges that could be resolved with standards. In this article, we describe current activities in international standards-development organizations. We summarize the AR standards gap analysis and shed light on special considerations for using standards in mobile AR.

  16. Active glass-type human augmented cognition system considering attention and intention

    Science.gov (United States)

    Kim, Bumhwi; Ojha, Amitash; Lee, Minho

    2015-10-01

    Human cognition is the result of an interaction of several complex cognitive processes with limited capabilities. Therefore, the primary objective of human cognitive augmentation is to assist and expand these limited human cognitive capabilities independently or together. In this study, we propose a glass-type human augmented cognition system, which attempts to actively assist human memory functions by providing relevant, necessary and intended information by constantly assessing intention of the user. To achieve this, we exploit selective attention and intention processes. Although the system can be used in various real-life scenarios, we test the performance of the system in a person identity scenario. To detect the intended face, the system analyses the gaze points and change in pupil size to determine the intention of the user. An assessment of the gaze points and change in pupil size together indicates that the user intends to know the identity and information about the person in question. Then, the system retrieves several clues through speech recognition system and retrieves relevant information about the face, which is finally displayed through head-mounted display. We present the performance of several components of the system. Our results show that the active and relevant assistance based on users' intention significantly helps the enhancement of memory functions.

  17. N-Methyl-D-aspartic Acid (NMDA in the nervous system of the amphioxus Branchiostoma lanceolatum

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    Garcia-Fernàndez Jordi

    2007-12-01

    Full Text Available Abstract Background NMDA (N-methyl-D-aspartic acid is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone in the hypothalamus, and of LH (Luteinizing Hormone and PRL (Prolactin in the pituitary gland. Results In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 ± 0.37 nmol/g tissue in the nerve cord and 10.52 ± 1.41 nmol/g tissue in the cephalic vesicle. As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp by a NMDA synthase (also called D-aspartate methyl transferase. Conclusion Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.

  18. Dietary omega-3 deficiency reduces BDNF content and activation NMDA receptor and Fyn in dorsal hippocampus: implications on persistence of long-term memory in rats.

    Science.gov (United States)

    Bach, Simone Azevedo; de Siqueira, Letícia V; Müller, Alexandre P; Oses, Jean P; Quatrim, Andreia; Emanuelli, Tatiana; Vinadé, Lúcia; Souza, Diogo O; Moreira, Júlia D

    2014-07-01

    Omega-3 (n-3) fatty acids are important for adequate brain function and cognition. The aim of the present study was to evaluate how n-3 fatty acids influence the persistence of long-term memory (LTM) in an aversive memory task and to explore the putative mechanism involved. Female rats received isocaloric diets that included n-3 (n-3 group) or not (D group). The adult litters were subjected to an inhibitory avoidance task (0.7 mA, 1.0 seconds foot shock) to elicit persistent LTM. Twelve hours after the training session, the fatty acid profile and the brain derived neurotrophic factor (BDNF) content of the dorsal hippocampus were assessed. In addition, we measured the activation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor and the SRC family protein Fyn. Despite pronounced learning in both groups, the persistence of LTM was abolished in the D group 7 days after the training session. We also observed that the D group presented reductions in hippocampal DHA (22:6 n-3) and BDNF content. Twelve hours after the training session, the D group showed decreased NR2B and Fyn phosphorylation in the dorsal hippocampus, with no change in the total content of these proteins. Further, there was a decrease in the interaction of Fyn with NR2B in the D group, as observed by co-immunoprecipitation. Taken together, these data suggest that n-3 fatty acids influence the persistence of LTM by maintaining adequate levels of DHA and BDNF as well as by influencing the activation of NR2B and Fyn during the period of memory formation.

  19. Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice

    Directory of Open Access Journals (Sweden)

    Atul eMaheshwari

    2013-09-01

    Full Text Available Paradoxical seizure exacerbation by antiepileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV+ fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV+ cortical interneurons in stargazer show a near two-fold decrease in the dendrite:soma GluA4 expression ratio compared to wild type littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg2+ induced network discharges in wild type but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy.

  20. Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels

    OpenAIRE

    Mulholland, Patrick J.; Carpenter-Hyland, Ezekiel P.; Hearing, Matthew C.; Becker, Howard C.; Woodward, John J.; Chandler, L. Judson

    2008-01-01

    Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests Kv2.1 channel modulation is linked to glutamatergic neurotransmission. Since NMDA-type glutamate receptors are critical regulators of synaptic plasticity, we investigated NMDA receptor modulation of Kv2.1 channels in rodent hippocampus and cortex. Bath application of NMDA potently unclustered and dephosphorylated Kv2.1 and produced a ...

  1. Perlecan domain 1 recombinant proteoglycan augments BMP-2 activity and osteogenesis

    Directory of Open Access Journals (Sweden)

    DeCarlo Arthur A

    2012-09-01

    Full Text Available Abstract Background Many growth factors, such as bone morphogenetic protein (BMP-2, have been shown to interact with polymers of sulfated disacharrides known as heparan sulfate (HS glycosaminoglycans (GAGs, which are found on matrix and cell-surface proteoglycans throughout the body. HS GAGs, and some more highly sulfated forms of chondroitin sulfate (CS, regulate cell function by serving as co-factors, or co-receptors, in GF interactions with their receptors, and HS or CS GAGs have been shown to be necessary for inducing signaling and GF activity, even in the osteogenic lineage. Unlike recombinant proteins, however, HS and CS GAGs are quite heterogenous due, in large part, to post-translational addition, then removal, of sulfate groups to various positions along the GAG polymer. We have, therefore, investigated whether it would be feasible to deliver a DNA pro-drug to generate a soluble HS/CS proteoglycan in situ that would augment the activity of growth-factors, including BMP-2, in vivo. Results Utilizing a purified recombinant human perlecan domain 1 (rhPln.D1 expressed from HEK 293 cells with HS and CS GAGs, tight binding and dose-enhancement of rhBMP-2 activity was demonstrated in vitro. In vitro, the expressed rhPln.D1 was characterized by modification with sulfated HS and CS GAGs. Dose-enhancement of rhBMP-2 by a pln.D1 expression plasmid delivered together as a lyophilized single-phase on a particulate tricalcium phosphate scaffold for 6 or more weeks generated up to 9 fold more bone volume de novo on the maxillary ridge in a rat model than in control sites without the pln.D1 plasmid. Using a significantly lower BMP-2 dose, this combination provided more than 5 times as much maxillary ridge augmentation and greater density than rhBMP-2 delivered on a collagen sponge (InFuse™. Conclusions A recombinant HS/CS PG interacted strongly and functionally with BMP-2 in binding and cell-based assays, and, in vivo, the pln.247 expression plasmid

  2. Effect of Error Augmentation on Brain Activation and Motor Learning of a Complex Locomotor Task

    Directory of Open Access Journals (Sweden)

    Laura Marchal-Crespo

    2017-09-01

    Full Text Available Up to date, the functional gains obtained after robot-aided gait rehabilitation training are limited. Error augmenting strategies have a great potential to enhance motor learning of simple motor tasks. However, little is known about the effect of these error modulating strategies on complex tasks, such as relearning to walk after a neurologic accident. Additionally, neuroimaging evaluation of brain regions involved in learning processes could provide valuable information on behavioral outcomes. We investigated the effect of robotic training strategies that augment errors—error amplification and random force disturbance—and training without perturbations on brain activation and motor learning of a complex locomotor task. Thirty-four healthy subjects performed the experiment with a robotic stepper (MARCOS in a 1.5 T MR scanner. The task consisted in tracking a Lissajous figure presented on a display by coordinating the legs in a gait-like movement pattern. Behavioral results showed that training without perturbations enhanced motor learning in initially less skilled subjects, while error amplification benefited better-skilled subjects. Training with error amplification, however, hampered transfer of learning. Randomly disturbing forces induced learning and promoted transfer in all subjects, probably because the unexpected forces increased subjects' attention. Functional MRI revealed main effects of training strategy and skill level during training. A main effect of training strategy was seen in brain regions typically associated with motor control and learning, such as, the basal ganglia, cerebellum, intraparietal sulcus, and angular gyrus. Especially, random disturbance and no perturbation lead to stronger brain activation in similar brain regions than error amplification. Skill-level related effects were observed in the IPS, in parts of the superior parietal lobe (SPL, i.e., precuneus, and temporal cortex. These neuroimaging findings

  3. The role of striatal NMDA receptors in drug addiction.

    Science.gov (United States)

    Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian

    2009-01-01

    The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.

  4. [Beta]-Adrenergic Receptor Activation Rescues Theta Frequency Stimulation-Induced LTP Deficits in Mice Expressing C-Terminally Truncated NMDA Receptor GluN2A Subunits

    Science.gov (United States)

    Moody, Teena D.; Watabe, Ayako M.; Indersmitten, Tim; Komiyama, Noboru H.; Grant, Seth G. N.; O'Dell, Thomas J.

    2011-01-01

    Through protein interactions mediated by their cytoplasmic C termini the GluN2A and GluN2B subunits of NMDA receptors (NMDARs) have a key role in the formation of NMDAR signaling complexes at excitatory synapses. Although these signaling complexes are thought to have a crucial role in NMDAR-dependent forms of synaptic plasticity such as long-term…

  5. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity.

    Science.gov (United States)

    Carroll, Reed C; Zukin, R Suzanne

    2002-11-01

    Dynamic regulation of synaptic efficacy is thought to play a crucial role in formation of neuronal connections and in experience-dependent modification of neural circuitry. The molecular and cellular mechanisms by which synaptic changes are triggered and expressed are the focus of intense interest. This articles reviews recent evidence that NMDA receptors undergo dynamically regulated targeting and trafficking, and that the physical transport of NMDA receptors in and out of the synaptic membrane contributes to several forms of long-lasting synaptic plasticity. The identification of targeting and internalization sequences in NMDA-receptor subunits has begun the unraveling of some mechanisms that underlie activity-dependent redistribution of NMDA receptors. Given that NMDA receptors are widely expressed throughout the CNS, regulation of NMDA-receptor trafficking provides a potentially important way to modulate efficacy of synaptic transmission.

  6. NMDA receptor activation upstream of methyl farnesoate signaling for short day-induced male offspring production in the water flea, Daphnia pulex.

    Science.gov (United States)

    Toyota, Kenji; Miyakawa, Hitoshi; Yamaguchi, Katsushi; Shigenobu, Shuji; Ogino, Yukiko; Tatarazako, Norihisa; Miyagawa, Shinichi; Iguchi, Taisen

    2015-03-14

    The cladoceran crustacean Daphnia pulex produces female offspring by parthenogenesis under favorable conditions, but in response to various unfavorable external stimuli, it produces male offspring (environmental sex determination: ESD). We recently established an innovative system for ESD studies using D. pulex WTN6 strain, in which the sex of the offspring can be controlled simply by changes in the photoperiod: the long-day and short-day conditions can induce female and male offspring, respectively. Taking advantage of this system, we demonstrated that de novo methyl farnesoate (MF) synthesis is necessary for male offspring production. These results indicate the key role of innate MF signaling as a conductor between external environmental stimuli and the endogenous male developmental pathway. Despite these findings, the molecular mechanisms underlying up- and downstream signaling of MF have not yet been well elucidated in D. pulex. To elucidate up- and downstream events of MF signaling during sex determination processes, we compared the transcriptomes of daphnids reared under the long-day (female) condition with short-day (male) and MF-treated (male) conditions. We found that genes involved in ionotropic glutamate receptors, known to mediate the vast majority of excitatory neurotransmitting processes in various organisms, were significantly activated in daphnids by the short-day condition but not by MF treatment. Administration of specific agonists and antagonists, especially for the N-methyl-D-aspartic acid (NMDA) receptor, strongly increased or decreased, respectively, the proportion of male-producing mothers. Moreover, we also identified genes responsible for male production (e.g., protein kinase C pathway-related genes). Such genes were generally shared between the short-day reared and MF-treated daphnids. We identified several candidate genes regulating ESD which strongly suggests that these genes may be essential factors for male offspring production as an

  7. Berberine augments ATP-induced inflammasome activation in macrophages by enhancing AMPK signaling

    Science.gov (United States)

    Xu, Li-Hui; Liang, Yi-Dan; Wei, Hong-Xia; Hu, Bo; Pan, Hao; Zha, Qing-Bing; Ouyang, Dong-Yun; He, Xian-Hui

    2017-01-01

    The isoquinoline alkaloid berberine possesses many pharmacological activities including antibacterial infection. Although the direct bactericidal effect of berberine has been documented, its influence on the antibacterial functions of macrophages is largely unknown. As inflammasome activation in macrophages is important for the defense against bacterial infection, we aimed to investigate the influence of berberine on inflammasome activation in murine macrophages. Our results showed that berberine significantly increased ATP-induced inflammasome activation as reflected by enhanced pyroptosis as well as increased release of caspase-1p10 and mature interleukin-1β (IL-1β) in macrophages. Such effects of berberine could be suppressed by AMP-activated protein kinase (AMPK) inhibitor compound C or by knockdown of AMPKα expression, indicating the involvement of AMPK signaling in this process. In line with increased IL-1β release, the ability of macrophages to kill engulfed bacteria was also intensified by berberine. This was corroborated by the in vivo finding that the peritoneal live bacterial load was decreased by berberine treatment. Moreover, berberine administration significantly improved survival of bacterial infected mice, concomitant with increased IL-1β levels and elevated neutrophil recruitment in the peritoneal cavity. Collectively, these data suggested that berberine could enhance bacterial killing by augmenting inflammasome activation in macrophages through AMPK signaling. PMID:27980220

  8. Can FES-augmented active cycling training improve locomotion in post-acute elderly stroke patients?

    Directory of Open Access Journals (Sweden)

    Elisabetta Peri

    2016-06-01

    Full Text Available Recent studies advocated the use of active cycling coupled with functional electrical stimulation to induce neuroplasticity and enhance functional improvements in stroke adult patients. The aim of this work was to evaluate whether the benefits induced by such a treatment are superior to standard physiotherapy. A single-blinded randomized controlled trial has been performed on post-acute elderly stroke patients. Patients underwent FES-augmented cycling training combined with voluntary pedaling or standard physiotherapy. The intervention consisted of fifteen 30-minutes sessions carried out within 3 weeks. Patients were evaluated before and after training, through functional scales, gait analysis and a voluntary pedaling test. Results were compared with an age-matched healthy group. Sixteen patients completed the training. After treatment, a general improvement of all clinical scales was obtained for both groups. Only the mechanical efficiency highlighted a group effect in favor of the experimental group. Although a group effect was not found for any other cycling or gait parameters, the experimental group showed a higher percentage of change with respect to the control group (e.g. the gait velocity was improved of 35.4% and 25.4% respectively, and its variation over time was higher than minimal clinical difference for the experimental group only. This trend suggests that differences in terms of motor recovery between the two groups may be achieved increasing the training dose. In conclusion, this study, although preliminary, showed that FES-augmented active cycling training seems to be effective in improving cycling and walking ability in post-acute elderly stroke patients. A higher sample size is required to confirm results.

  9. Spinal NMDA receptor activation constrains inactivity-induced phrenic motor facilitation in Charles River Sprague-Dawley rats

    Science.gov (United States)

    Streeter, K. A.

    2014-01-01

    Reduced spinal synaptic inputs to phrenic motor neurons elicit a unique form of spinal plasticity known as inactivity-induced phrenic motor facilitation (iPMF). iPMF requires tumor necrosis factor-α (TNF-α) and atypical protein kinase C (aPKC) activity within spinal segments containing the phrenic motor nucleus to stabilize early, transient increases in phrenic burst amplitude into long-lasting iPMF. Here we tested the hypothesis that spinal N-methyl-d-aspartate receptor (NMDAR) activation constrains long-lasting iPMF in some rat substrains. Phrenic motor output was recorded in anesthetized, ventilated Harlan (HSD) and Charles River (CRSD) Sprague-Dawley rats exposed to a 30-min central neural apnea. HSD rats expressed a robust, long-lasting (>60 min) increase in phrenic burst amplitude (i.e., long-lasting iPMF) when respiratory neural activity was restored. By contrast, CRSD rats expressed an attenuated, transient (∼15 min) iPMF. Spinal NMDAR inhibition with DL-2-amino-5-phosphonopentanoic acid (APV) before neural apnea or shortly (4 min) prior to the resumption of respiratory neural activity revealed long-lasting iPMF in CRSD rats that was phenotypically similar to that in HSD rats. By contrast, APV did not alter iPMF expression in HSD rats. Spinal TNF-α or aPKC inhibition impaired long-lasting iPMF enabled by NMDAR inhibition in CRSD rats, suggesting that similar mechanisms give rise to long-lasting iPMF in CRSD rats with NMDAR inhibition as those giving rise to long-lasting iPMF in HSD rats. These results suggest that NMDAR activation can impose constraints on TNF-α-induced aPKC activation after neural apnea, impairing stabilization of transient iPMF into long-lasting iPMF. These data may have important implications for understanding differential responses to reduced respiratory neural activity in a heterogeneous human population. PMID:25103979

  10. Concept of an immersive assistance system with augmented reality for the support of manual activities in radioactive production environments; Konzept eines immersiven Assistenzsystems mit Augmented Reality zur Unterstuetzung manueller Aktivitaeten in radioaktiven Produktionsumgebungen

    Energy Technology Data Exchange (ETDEWEB)

    Eursch, Andreas A.

    2010-06-29

    The thesis on an immersive assistance system concept with augmented reality for the support of manual activities in radioactive production environments covers the following topics: analysis of the situation: production and use of radioactive materials, problem analysis of the work in the production facilities, necessity of manual activities, automation, prediction in hot cells; status of research and development; assistance system concept, immersive camera system; augmented reality support in hot cells; economic evaluation and generalization.

  11. An Augmented Reality Approach to Integrate Practical Activities in E-Learning Systems

    Directory of Open Access Journals (Sweden)

    EL KABTANE Hamada

    2016-02-01

    Full Text Available In the past, the term E-learning was mentioned to any learning method that used electronic machine for the distribution. With the evolution and the apparition of the internet, the term e learning has been evolved and referred to the online courses. There are a lot of platform which serves to distribute and manage the learning content. In some domain learners need to use some equipment and useful product for purpose completing the image built in the theoretical part by the practical activity part. However, most of those platforms suffer from a lack in tools that offer practical activities for learners. Using videos, virtual laboratories or distance control of real equipment as solutions to solve this lack were proposed but still limited. The mixed reality as new technology promised to create a virtual environment where the learner is an actor and can interact with the virtual objects. This article present an approach for developing integrated E-learning systems, helping to carry out the practical work by establishing a virtual laboratory that all tools and products can be manipulated by learners and teachers like in real practical activity, based on an augmented reality system.

  12. Individual and combined manipulation of muscarinic, NMDA, and benzodiazepine receptor activity in the water maze task: implications for a rat model of Alzheimer dementia.

    Science.gov (United States)

    Cain, D P; Ighanian, K; Boon, F

    2000-06-15

    Recent evidence indicates that Alzheimer disease typically involves different degrees of impairment in a variety of neurotransmitter systems, behaviors, and cognitive abilities in different patients. To investigate the relations between neurotransmitter system, behavioral, and cognitive impairments in an animal model of Alzheimer disease we studied spatial learning in a Morris water maze in male Long-Evans rats given neurochemical agents that targeted muscarinic cholinergic, NMDA, or benzodiazepine systems. Naive rats given a single agent or a combination of agents were severely impaired in place responding and had behavioral strategy impairments. Rats made familiar with the required water maze behavioral strategies by non-spatial pretraining performed as well as controls if given a single agent. Non-spatially pretrained rats with manipulation of both muscarinic cholinergic and NMDA or muscarinic cholinergic and benzodiazepine systems had a specific place response impairment but no behavioral strategy impairments. The results suggest that impairment of both muscarinic cholinergic and NMDA, or muscarinic cholinergic and benzodiazepine systems may model some aspects of human Alzheimer disease (impairments in navigation in familiar environments), but not other aspects of this disorder (global dementia leading to general loss of adaptive behavior). Previous research suggests that impairment of both muscarinic cholinergic and serotonergic systems may provide a better model of global dementia. The water maze testing and detailed behavioral analysis techniques used here appear to provide a means of investigating the contributions of various combinations of neurotransmitter system impairments to an animal model of Alzheimer disease.

  13. Augmented Reality for Augmented Reality

    OpenAIRE

    Pankratz, Frieder

    2016-01-01

    A recurring challenge when setting up any augmented reality system is the correct calibration and registration of the involved devices. Augmented Reality for Augmented Reality (AR4AR) generates augmented reality guides by using the already existing knowledge about the AR system which stems from the setup of the AR system itself. As these guides involve plenty of 3D information, it is again best presented through means of Augmented Reality, thus the name AR4AR. Eine wiederkehrende Herausfor...

  14. An Augmented Reality-Based Mobile Learning System to Improve Students' Learning Achievements and Motivations in Natural Science Inquiry Activities

    Science.gov (United States)

    Chiang, Tosti H. C.; Yang, Stephen J. H.; Hwang, Gwo-Jen

    2014-01-01

    In this study, an augmented reality-based mobile learning system is proposed for conducting inquiry-based learning activities. An experiment has been conducted to examine the effectiveness of the proposed approach in terms of learning achievements and motivations. The subjects were 57 fourth graders from two classes taught by the same teacher in…

  15. An Augmented Reality-Based Mobile Learning System to Improve Students' Learning Achievements and Motivations in Natural Science Inquiry Activities

    Science.gov (United States)

    Chiang, Tosti H. C.; Yang, Stephen J. H.; Hwang, Gwo-Jen

    2014-01-01

    In this study, an augmented reality-based mobile learning system is proposed for conducting inquiry-based learning activities. An experiment has been conducted to examine the effectiveness of the proposed approach in terms of learning achievements and motivations. The subjects were 57 fourth graders from two classes taught by the same teacher in…

  16. Augmented vagal heart rate modulation in active hypoestrogenic pre-menopausal women with functional hypothalamic amenorrhoea.

    Science.gov (United States)

    O'Donnell, Emma; Goodman, Jack M; Morris, Beverly L; Floras, John S; Harvey, Paula J

    2015-11-01

    Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin-angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24 ± 1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n=11) or eumenorrhoeic cycles (ExOv; n=17) and sedentary with eumenorrhoeic cycles (SedOv; n=17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; -10, -20 and -40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms(2)) were determined and, owing to skewness, log10-transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower (P0.05). At each stage, HR correlated inversely (Ppost-menopausal women.

  17. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds.

    Science.gov (United States)

    Lagrue, Kathryn; Carisey, Alex; Morgan, David J; Chopra, Rajesh; Davis, Daniel M

    2015-07-02

    As multiple myeloma (MM) progresses, natural killer (NK)-cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for treatment of MM but its influence on NK-cell biology is unclear. Here, we report that lenalidomide lowers the threshold for NK-cell activation, causing a 66% decrease in the 50% effective concentration (EC50) for activation through CD16, and a 38% decrease in EC50 for NK group 2 member D (NKG2D)-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augments NK-cell responses, causing a twofold increase in the proportion of primary NK cells producing interferon-γ (IFN-γ), and a 20-fold increase in the amount of IFN-γ produced per cell. Importantly, lenalidomide did not trigger IFN-γ production in unstimulated NK cells. Thus, lenalidomide enhances the NK-cell arm of the immune response, without activating NK cells inappropriately. Of particular clinical importance, lenalidomide also allowed NK cells to be activated by lower doses of rituximab, an anti-CD20 monoclonal antibody (mAb) widely used to treat B-cell malignancies. This supports combined use of lenalidomide and rituximab in a clinical setting. Finally, superresolution microscopy revealed that lenalidomide increased the periodicity of cortical actin at immune synapses, resulting in an increase in the area of the actin mesh predicted to be penetrable to vesicles containing IFN-γ. NK cells from MM patients also responded to lenalidomide in this way. This indicates that nanometer-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds.

  18. NMDA receptors and the differential ischemic vulnerability of hippocampal neurons.

    Science.gov (United States)

    Gee, Christine E; Benquet, Pascal; Raineteau, Olivier; Rietschin, Lotty; Kirbach, Sebastian W; Gerber, Urs

    2006-05-01

    Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.

  19. Functional heterogeneity of NMDA receptors in rat substantia nigra pars compacta and reticulata neurones.

    Science.gov (United States)

    Suárez, F; Zhao, Q; Monaghan, D T; Jane, D E; Jones, S; Gibb, A J

    2010-08-01

    The nigra substantia nigra pars compacta (SNc) and substantia pars reticulata (SNr) form two major basal ganglia components with different functional roles. SNc dopaminergic (DA) neurones are vulnerable to cell death in Parkinson's disease, and NMDA receptor activation is a potential contributing mechanism. We have investigated the sensitivity of whole-cell and synaptic NMDA responses to intracellular ATP and GTP application in the SNc and SNr from rats on postnatal day (P) 7 and P28. Both NMDA current density (pA/pF) and desensitization to prolonged or repeated NMDA application were greater in the SNr than in the SNc. When ATP levels were not supplemented, responses to prolonged NMDA administration desensitized in P7 SNc DA neurones but not at P28. At P28, SNr neurones desensitized more than SNc neurones, with or without added ATP. Responses to brief NMDA applications and synaptic NMDA currents were not sensitive to inclusion of ATP in the pipette solution. To investigate these differences between the SNc and SNr, NR2 subunit-selective antagonists were tested. NMDA currents were inhibited by ifenprodil (10 microM) and UBP141 (4 microM), but not by Zn(2+) (100 nm), in both the SNr and SNc, suggesting that SNc and SNr neurones express similar receptor subunits; NR2B and NR2D, but not NR2A. The different NMDA response properties in the SNc and SNr may be caused by differences in receptor modulation and/or trafficking. The vulnerability of SNc DA neurones to cell death is not correlated with NMDA current density or receptor subtypes, but could in part be related to inadequate NMDA receptor desensitization.

  20. Inhibition of elongation factor-2 kinase augments the antitumor activity of Temozolomide against glioma.

    Directory of Open Access Journals (Sweden)

    Xiao-Yuan Liu

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM, the most common form of brain cancer with an average survival of less than 12 months, is a highly aggressive and fatal disease characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Temozolomide (TMZ is commonly used chemotherapy for treatment of primary and recurrent high-grade gliomas. Nevertheless, the therapeutic outcome of TMZ is often unsatisfactory. In this study, we sought to determine whether eEF-2 kinase affected the sensitivity of glioma cells to treatment with TMZ. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA interference approach, a small molecule inhibitor of eEF-2 kinase, and in vitro and in vivo glioma models, we observed that inhibition of eEF-2 kinase could enhance sensitivity of glioma cells to TMZ, and that this sensitizing effect was associated with blockade of autophagy and augmentation of apoptosis caused by TMZ. CONCLUSIONS/SIGNIFICANCE: These findings demonstrated that targeting eEF-2 kinase can enhance the anti-glioma activity of TMZ, and inhibitors of this kinase may be exploited as chemo-sensitizers for TMZ in treatment of malignant glioma.

  1. Augmented supraorbital skin sympathetic nerve activity responses to symptom trigger events in rosacea patients.

    Science.gov (United States)

    Metzler-Wilson, Kristen; Toma, Kumika; Sammons, Dawn L; Mann, Sarah; Jurovcik, Andrew J; Demidova, Olga; Wilson, Thad E

    2015-09-01

    Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm(-2)·min(-1), P rosacea and controls, respectively) stress was augmented in rosacea (both P rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component.

  2. Heavy Resistance Training and Supplementation With the Alleged Testosterone Booster Nmda has No Effect on Body Composition, Muscle Performance, and Serum Hormones Associated With the Hypothalamo-Pituitary-Gonadal Axis in Resistance-Trained Males.

    Science.gov (United States)

    Willoughby, Darryn S; Spillane, Mike; Schwarz, Neil

    2014-01-01

    The effects of 28 days of heavy resistance training while ingesting the alleged testosterone-boosting supplement, NMDA, were determined on body composition, muscle strength, serum cortisol, prolactin, and hormones associated with the hypothalamo-pituitary- gonadal (HPG) axis. Twenty resistance-trained males engaged in 28 days of resistance training 4 times/wk while orally ingesting daily either 1.78 g of placebo (PLAC) or NMDA. Data were analyzed with separate 2 x 2 ANOVA (p supplementation. No changes were noted for total body water and fat mass in response to resistance training (p > 0.05) or supplementation (p > 0.05). In regard to total body mass and fat-free mass, however, each was significantly increased in both groups in response to resistance training (p supplementation (p > 0.05). In both groups, lower-body muscle strength was significantly increased in response to resistance training (p supplementation had no effect (p > 0.05). All serum hormones (total and free testosterone, LH, GnRH, estradiol, cortisol, prolactin) were unaffected by resistance training (p > 0.05) or supplementation (p > 0.05). The gonadal hormones and cortisol and prolactin were unaffected by 28 days of NMDA supplementation and not associated with the observed increases in muscle strength and mass. At the dose provided, NMDA had no effect on HPG axis activity or ergogenic effects in skeletal muscle. Key PointsIn response to 28 days of heavy resistance training and NMDA supplementation, similar increases in muscle mass and strength in both groups occurred; however, the increases were not different between supplement groups.The supplementation of NMDA had no preferential effect on augmenting testosterone or decreasing estrogen, cortisol, and prolactin.While resistance training was effective in increasing muscle mass and strength, it was not preferentially due to NMDA supplementation.At the dose provided, NMDA supplementation for 28 days combined with resistance training does not

  3. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Wen-Zhu [Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Hainan 572013 (China); Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China); Miao, Yu-Liang [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Guo, Wen-Zhi [Department of Anesthesiology, Beijing Military General Hospital of Chinese People’s Liberation Army, Beijing 100700 (China); Wu, Wei, E-mail: wwzwgk@163.com [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); Li, Bao-Wei [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); An, Li-Na [Department of Anesthesiology, Armed Police General Hospital, Beijing 100039 (China); Fang, Wei-Wu [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Mi, Wei-Dong, E-mail: elite2005gg@163.com [Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China)

    2014-04-25

    Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

  4. Cytosolic phospholipase A(2) alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment.

    Science.gov (United States)

    Shen, Ying; Kishimoto, Koji; Linden, David J; Sapirstein, Adam

    2007-04-03

    The arachidonic acid-generating enzyme cytosolic phospholipase A(2) alpha (cPLA(2)alpha) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA(2)alpha toxicity have yet to be determined. Here, we used a model system exposing mouse hippocampal slices to NMDA as an excitotoxic injury, in combination with simultaneous patch-clamp recording and confocal Ca(2+) imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA(2)alpha null CA1 neurons. Bath application of NMDA evoked a slow inward current in voltage-clamped neurons (composed of both NMDA receptor-mediated and other conductances) that was smaller in cPLA(2)alpha null than in WT slices. This was not due to down-regulation of NMDA receptor function because NMDA receptor-mediated currents were equivalent in each genotype following brief photolysis of caged glutamate. Current-clamp recordings were made during and following NMDA exposure by eliciting a single action potential with a brief current injection. After NMDA exposure, WT CA1 neurons developed a spike-evoked plateau potential and an increased spike-evoked dendritic Ca(2+) transient. These effects were absent in CA1 neurons from cPLA(2)alpha null mice and WT neurons treated with a cPLA(2)alpha inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca(2+) enhancement in WT and cPLA(2)alpha null slices. NMDA application in WT and arachidonate applied to cPLA(2)alpha null cells occluded the effects of apamin/paxilline. These results indicate that cPLA(2)alpha activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.

  5. Asparagus racemosus ameliorates cisplatin induced toxicities and augments its antileishmanial activity by immunomodulation in vivo.

    Science.gov (United States)

    Sachdeva, Heena; Sehgal, Rakesh; Kaur, Sukhbir

    2014-02-01

    Current drugs for the treatment of visceral leishmaniasis are inadequate and their efficacies are also compromised due to suppression of immune function associated during the course of infection. To overcome this problem, efforts are needed to develop therapies with effective immunomodulatory agents where decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In this study we have evaluated a new therapeutic approach based on combination of Asparagus racemosus, an immunomodulatory drug, in combination with cisplatin against Leishmania donovani infected BALB/c mice. We demonstrate that A. racemosus (650 mg/kg b.wt./day for 15 days, orally) in combination with cisplatin (5 mg/kg b.wt./day for 5 days, intraperitoneally) enhanced the clearance of parasites as determined by Giemsa-stained liver impression smears. Besides having better killing activity, this combination group achieved increased production of disease resolving Th-1 response (IFN-gamma, IL-2), heightened DTH (delayed type hypersensitivity) response and augmented levels of IgG2a. Moreover, A. racemosus in combination with cisplatin not only provided enhanced protective immune response but also resulted in remarkable improved kidney and liver function tests as manifested by normal levels of SGOT, SGPT, alkaline phosphatase, creatinine and urea in blood plasma with normal histological observations as compared to only cisplatin treated L. donovani infected BALB/c mice. Through this study we have ascertained that A. racemosus in combination with cisplatin in L. donovani infected BALB/c mice boosted as well as restored both cellular and humoral immunity. Thus in view of severe immunosuppression in visceral leishmaniasis, a better and effective strategy for optimum efficacy of future antileishmanial drugs would direct not only killing of parasite by the drug, but also simultaneous generation of immunity against the disease. © 2013.

  6. Proteolytically modified human beta 2-microglobulin augments the specific cytotoxic activity in murine mixed lymphocyte culture

    DEFF Research Database (Denmark)

    Nissen, Mogens Holst; Claësson, M H

    1987-01-01

    (M-beta 2-m) bind to murine lymphocytes expressing H-2 class I antigens; M-beta 2-m, when added at day 0 and 1 of culture in nanomolar concentrations to a one-way murine allogeneic mixed lymphocyte culture (MLC) augments the generation of specific cytotoxic T lymphocytes; M-beta 2-m increases...... the endogenous production of interleukin 2 in the MLC culture; monoclonal antibody which reacts with both the native beta 2-m and M-beta 2-m molecule blocks the augmentation of cytotoxic T lymphocyte production induced by M-beta 2-m; murine as well as human MLC responder cells can proteolytically modify native...

  7. Advanced structure-activity relationships applied to Mentha spicata L. subsp. spicata essential oil compounds as AChE and NMDA ligands, in comparison with donepezil, galantamine and memantine - new approach in brain disorders pharmacology.

    Science.gov (United States)

    Avram, Speranta; Maria, Mernea; Bagci, Eyup; Hritcu, Lucian; Borcan, Livia-Cristina; Mihailescu, Dan

    2017-01-13

    Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D-aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy. We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil. We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine. The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 Å2, SA_Hmemantine= 358 Å2, SA_Hdonepezil= 655 Å2) or polar atoms (SA_P1,8-cineole= 4 Å2, SA_Pmemantine=10 Å2, SA_Pdonepezil=44.62 Å2). Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders.

  8. Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: Implications for affective pain

    Institute of Scientific and Technical Information of China (English)

    Hong Cao; Wen-Hua Ren; Mu-Ye Zhu; Zhi-Qi Zhao; Yu-Qiu Zhang

    2012-01-01

    Objective The rostral anterior cingulate cortex (rACC) is implicated in processing the emotional component of pain.N-methyl-D-aspartate receptors (NMDARs) are highly expressed in the rACC and mediate painrelated affect by activating a signaling pathway that involves cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and/or extracellular regulated kinase (ERK)/cAMP-response element-binding protein (CREB).The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB both in vitro and in vivo in rat rACC.Methods Immunohistochemistry and Western blot analysis were used to separately assess the expression of phospho-ERK (pERK) and phospho-CREB (pCREB) in vitro and in vivo.Double immunostaining was also used to determine the colocalization of pERK and pCREB.Results Both bath application of NMDA in brain slices in vitro and intraplantar injection of formalin into the rat hindpaw in vivo induced significant up-regulation of pERK and pCREB in the rACC,which was inhibited by the NMDAR antagonist DL-2-amino-5-phospho-novaleric acid.Selective blockade of the NMDAR GluN2B subunit and the glycinebinding site,or degradation of endogenous D-serine,a co-agonist for the glycine site,significantly decreased the upregulation of pERK and pCREB expression in the rACC.Further,the activated ERK predominantly colocalized with CREB.Conclusion Either the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats,and these might be fundamental molecular mechanisms underlying pain affect.

  9. Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus.

    Directory of Open Access Journals (Sweden)

    Daniela C Dieterich

    2008-02-01

    Full Text Available NMDA (N-methyl-D-aspartate receptors and calcium can exert multiple and very divergent effects within neuronal cells, thereby impacting opposing occurrences such as synaptic plasticity and neuronal degeneration. The neuronal Ca2+ sensor Caldendrin is a postsynaptic density component with high similarity to calmodulin. Jacob, a recently identified Caldendrin binding partner, is a novel protein abundantly expressed in limbic brain and cerebral cortex. Strictly depending upon activation of NMDA-type glutamate receptors, Jacob is recruited to neuronal nuclei, resulting in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree. Jacob's nuclear trafficking from distal dendrites crucially requires the classical Importin pathway. Caldendrin binds to Jacob's nuclear localization signal in a Ca2+-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-alpha to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca2+ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca2+ microdomains such as postsynaptic spines. Extrasynaptic NMDA receptors, as opposed to their synaptic counterparts, trigger the cAMP response element-binding protein (CREB shut-off pathway, and cell death. We found that nuclear knockdown of Jacob prevents CREB shut-off after extrasynaptic NMDA receptor activation, whereas its nuclear overexpression induces CREB shut-off without NMDA receptor stimulation. Importantly, nuclear knockdown of Jacob attenuates NMDA-induced loss of synaptic contacts, and neuronal degeneration. This defines a novel mechanism of synapse-to-nucleus communication via a synaptic Ca2+-sensor protein, which links the activity of NMDA receptors to nuclear signalling events involved in modelling synapto-dendritic input and NMDA receptor-induced cellular degeneration.

  10. [Anti-NMDA-receptor encephalitis].

    Science.gov (United States)

    Engen, Kristine; Agartz, Ingrid

    2016-06-01

    BACKGROUND In 2007 a clinical disease caused by autoantibodies directed against the N-methyl-D-aspartate (NMDA) receptor was described for the first time. Anti-NMDA-receptor encephalitis is a subacute, autoimmune neurological disorder with psychiatric manifestations. The disease is a form of limbic encephalitis and is often paraneoplastic. The condition is also treatable. In this review article we examine the development of the disease, clinical practice, diagnostics and treatment.MATERIAL AND METHOD The article is based on references retrieved from searches in PubMed, and a discretionary selection of articles from the authors' own literature archive.RESULTS The disease most frequently affects young women. It may initially be perceived as a psychiatric condition, as it usually presents in the form of delusions, hallucinations or mania. The diagnosis should be suspected in patients who later develop neurological symptoms such as various movement disorders, epileptic seizures and autonomic instability. Examination of serum or cerebrospinal fluid for NMDA receptor antibodies should be included in the assessment of patients with suspected encephalitis. MRI, EEG and assessment for tumours are important tools in diagnosing the condition and any underlying malignancy.INTERPRETATION If treatment is initiated early, the prognosis is good. Altogether 75 % of patients will fully recover or experience significant improvement. Apart from surgical resection of a possible tumour, the treatment consists of immunotherapy. Because of good possibilities for treatment, it is important that clinicians, particularly those in acute psychiatry, are aware of and alert to this condition.

  11. Augmented Reality

    DEFF Research Database (Denmark)

    Kjærgaard, Hanne Wacher; Kjeldsen, Lars Peter Bech; Rahn, Annette

    2015-01-01

    This chapter describes the use of iPad-facilitated application of augmented reality in the teaching of highly complex anatomical and physiological subjects in the training of nurses at undergraduate level. The general aim of the project is to investigate the potentials of this application in terms...... of augmented reality are discussed....

  12. Augmented Reality

    DEFF Research Database (Denmark)

    Kjærgaard, Hanne Wacher; Kjeldsen, Lars Peter Bech; Rahn, Annette

    2015-01-01

    This chapter describes the use of iPad-facilitated application of augmented reality in the teaching of highly complex anatomical and physiological subjects in the training of nurses at undergraduate level. The general aim of the project is to investigate the potentials of this application in terms...... of augmented reality are discussed....

  13. Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.

    Science.gov (United States)

    Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika; Rapoport, Stanley I; Andreazza, Ana C

    2016-05-01

    Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.

  14. Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII

    OpenAIRE

    Jin, Dao-Zhong; Xue, Bing; Mao, Li-Min; Wang, John Q

    2015-01-01

    Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA rece...

  15. Adult forebrain NMDA receptors gate social motivation and social memory.

    Science.gov (United States)

    Jacobs, Stephanie; Tsien, Joe Z

    2017-02-01

    Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals.

    Science.gov (United States)

    Chen, Wenling; Walwyn, Wendy; Ennes, Helena S; Kim, Hyeyoung; McRoberts, James A; Marvizón, Juan Carlos G

    2014-05-01

    NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75(NTR) ), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75(NTR) inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr(1472) phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  17. Scavenging ROS dramatically increase NMDA receptor whole-cell currents in painted turtle cortical neurons.

    Science.gov (United States)

    Dukoff, David James; Hogg, David William; Hawrysh, Peter John; Buck, Leslie Thomas

    2014-09-15

    Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca(2+) concentrations ([Ca(2+)]i) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or N-acetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca(2+)]i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca(2+) release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATP-sensitive potassium (mKATP) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. Fluorescent measurement of [Ca(2+)]i and ROS levels demonstrated that [Ca(2+)]i increases before ROS decreases. We conclude that decreases in ROS concentration are not linked to anoxia-mediated decreases in NMDA/AMPA receptor currents but are rather associated with an increase in NMDA receptor currents that is prevented during anoxia by mitochondrial Ca(2+) release.

  18. Current Evidence of Chinese Herbal Constituents with Effects on NMDA Receptor Blockade

    Directory of Open Access Journals (Sweden)

    David T. Yew

    2013-08-01

    Full Text Available NMDA receptor (NMDA-R is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified.

  19. Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons.

    Directory of Open Access Journals (Sweden)

    Fumiaki Fukushima

    Full Text Available Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA, suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.

  20. In search of augmentation at human SI: Somatosensory cortical responses to stimulus trains and their modulation by motor activity.

    Science.gov (United States)

    Huttunen, Juha

    2010-05-17

    In many animal preparations, repeated stimulation at ca. 10 Hz in thalamic nuclei leads to rapid changes in the cortical evoked responses, known as the augmenting response. The present study was undertaken to evaluate whether anything similar to the augmenting response can be observed in awake human subjects when a peripheral nerve is stimulated, and whether a possible human correlate of augmenting would be modified when the subject is engaged in an active motor task. Somatosensory-evoked magnetic fields (SEFs) were recorded in healthy human subjects in response to stimulus trains (15 pulses at 10 Hz) applied to the left median nerve. SEFs were recorded in a resting condition and during a finger-tapping task performed with the stimulated hand. In the resting condition, the most marked change in the SEF configuration was a reduction of the P35m deflection and a concurrent enhancement of the N45m deflection during the 1st few stimuli of the trains. Another conspicuous feature was a prolongation of the latencies of the N45m and P60m deflections toward the end of the train. In the motor task, the response modulation during the pulse trains was in general similar to the resting condition. The most notable difference was that the P35m amplitude was markedly reduced already for the 1st pulse of the train when compared with rest. Also, the latencies of N45m and P60m were not prolonged during the train. We discuss the possibility that the reduction of P35m and a concurrent increase of N45m during a pulse train constitute a human analogue to the augmenting response, and suggest that these changes may reflect a decrease of inhibitory postsynaptic potentials (IPSPs, P35m) and an increase of secondary excitatory postsynaptic potentials (N45m) during stimulus train presentation. The reduction of P35m during motor activity compared with rest already at the beginning of stimulus trains suggests that postsynaptic IPSPs in response to afferent stimulation are reduced during active

  1. Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals.

    Science.gov (United States)

    Hofstoetter, Ursula S; Krenn, Matthias; Danner, Simon M; Hofer, Christian; Kern, Helmut; McKay, William B; Mayr, Winfried; Minassian, Karen

    2015-10-01

    The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.

  2. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons

    DEFF Research Database (Denmark)

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L;

    2013-01-01

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling...

  3. Augmented reality

    National Research Council Canada - National Science Library

    Patrik Pucer

    2011-01-01

    .... In such a mixed reality, real and virtual objects coexist in the same environment. The reality, where users watch and use the real environment upgraded with virtual objects is called augmented reality...

  4. Breast Augmentation

    Science.gov (United States)

    ... surgery might even improve your body image and self-esteem. If you're looking for perfection, however, you ... www.mayoclinic.org/tests-procedures/breast-augmentation/basics/definition/prc-20021493 . Mayo Clinic Footer Legal Conditions and ...

  5. BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A

    Directory of Open Access Journals (Sweden)

    David Lau

    2015-08-01

    Full Text Available The health of neurons is critically dependent on the relative signaling intensities of survival-promoting synaptic and death-inducing extrasynaptic NMDA receptors. Here, we show that BDNF is a regulator of this balance and promotes neuroprotection by reducing toxic NMDA receptor signaling. BDNF acts by initiating synaptic NMDA-receptor/nuclear-calcium-driven adaptogenomics, leading to increased expression of inhibin β-A (inhba. Inhibin β-A (its homodimer is known as activin A in turn reduces neurotoxic extrasynaptic NMDA-receptor-mediated calcium influx, thereby shielding neurons against mitochondrial dysfunction, a major cause of excitotoxicity. Thus, BDNF induces acquired neuroprotection by enhancing synaptic activity and lowering extrasynaptic NMDA receptor death signaling through a nuclear calcium-inhibin β-A pathway. This process, which confers protection against ischemic brain damage in a mouse stroke model, may be compromised in Huntington’s disease, Alzheimer’s disease, or aging-related neurodegenerative conditions that are associated with reduced BDNF levels and/or enhanced extrasynaptic NMDA receptor signaling.

  6. Augmentative phalloplasty.

    Science.gov (United States)

    Panfilov, Dimitrije E

    2006-01-01

    Until 20 years ago, penis size (either nonerected or erected) was not mentioned, discussed, or defined even in serious books of human anatomy. The need of some men to enlarge and elongate their penile size is equivalent to the need of some women to ask for breast augmentation. The same method of transferring autologous fat into other parts of the body can be used in male patients for augmentative phalloplasty. The circumference of the penis increases 2 to 3 cm, and before of a heavier penis, the length increases 1 to 2 cm. If more lengthening is desired, subtotal dissection of the ligament fundiforme penis below the symphysis could be done, pull the corpus cavernosus out, and fix the tunica albuginea at the periost. At the root of the phallus, the skin can be elongated by V-Y-plasty, and the scrotal skin can be released by 1 or 2 Z-plasties. Combining both autologous fat transfer and ligament release allows for penis elongation of 3 to 5 cm. The authors have performed augentative phalloplasty on 88 patients since 1996. They have transplanted 40 to 68 ml of pure fat. Of the 88 patients, 57 underwent autologous fat transfer only, and 31 received additional ligament release. Penis length increased 1.5 to 4.8 cm (average, 2.42 cm), and circumference increased 1.4 to 4.0 cm (average, 2.65 cm). The initial penis lengths were 6.5 to 10.0 cm (average, 8.72 cm), and the circumference were 8.0 to 10.1 cm (average, 9.18 cm) not erected. This article details a simple operative procedure to enlarge the penis and simple postoperative bandages. Patients are advised to obstain from sexual activity for 5 weeks after the surgery. Two patients who disregarded this advice had an unsatisfactory result. In one patient too, much of the grafted fat had to be removed from the preputium. No other serious complications were observed.

  7. Memantine as an Augmentation Therapy for Anxiety Disorders

    Directory of Open Access Journals (Sweden)

    Thomas L. Schwartz

    2012-01-01

    Full Text Available Objective. Glutamate, an excitatory neurotransmitter in the central nervous system (CNS, may play a role in the development of anxiety. Memantine partially blocks N-methyl-D-aspartate (NMDA receptors' glutamate channels located in the CNS. This paper evaluates memantine as an augmentation therapy for treatment of anxiety. Methods. 15 consecutive partially responding anxious patients were treated with adjunctive memantine for 10 weeks. Memantine was dosed 5–20 mg/day. Result. Memantine augmentation resulted in clinically relevant reduction in anxiety symptoms when compared to baseline. Forty percent of patients achieved remission (HAM-A ≥ 7. Memantine improved sleep quality. Mean dose was 14 mg/d (range 5–20 mg/d. Typical adverse events included nausea and headache. Conclusion. The NMDA receptor antagonist memantine may be an effective augmentation therapy in patients with treatment-resistant anxiety.

  8. Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

    OpenAIRE

    Mazahir T Hasan; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

    2013-01-01

    The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, her...

  9. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats.

    Science.gov (United States)

    Ma, Yao-Ying; Guo, Chang-Yong; Yu, Peng; Lee, David Yue-Wei; Han, Ji-Sheng; Cui, Cai-Lian

    2006-08-01

    It has been reported that N-methyl-D-aspartate (NMDA) receptor is implicated in drug addiction and antagonists of the NMDA receptor complex can inhibit the development and expression of conditioned place preference (CPP) induced by several addictive drugs, implying that this class of compounds might be considered as candidate for the treatment of substance abuse. To explore this possibility, it is important to evaluate whether the inhibitory effect of NMDA receptor antagonists would be confined to behaviors produced by drugs of abuse only, but not by natural reinforcers. According to the quantitative changes of NMDA receptor subunits, including NR1, NR2A, and NR2B, induced by diverse types of reinforcers, we chose NR2B subunit as the target of research. Experimental results showed that (1) an augmented expression of NR2B subunit was revealed by Western blotting in the nucleus accumbens (NAc) and the hippocampus in rats with CPP induced by morphine, but not by natural rewards such as food, novel environment and social interaction. (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction. Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse.

  10. Augmented reality

    Directory of Open Access Journals (Sweden)

    Patrik Pucer

    2011-08-01

    Full Text Available Today we can obtain in a simple and rapid way most of the information that we need. Devices, such as personal computers and mobile phones, enable access to information in different formats (written, pictorial, audio or video whenever and wherever. Daily we use and encounter information that can be seen as virtual objects or objects that are part of the virtual world of computers. Everyone, at least once, wanted to bring these virtual objects from the virtual world of computers into real environments and thus mix virtual and real worlds. In such a mixed reality, real and virtual objects coexist in the same environment. The reality, where users watch and use the real environment upgraded with virtual objects is called augmented reality. In this article we describe the main properties of augmented reality. In addition to the basic properties that define a reality as augmented reality, we present the various building elements (possible hardware and software that provide an insight into such a reality and practical applications of augmented reality. The applications are divided into three groups depending on the information and functions that augmented reality offers, such as help, guide and simulator.

  11. Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS.

    Science.gov (United States)

    Hewett, S J; Csernansky, C A; Choi, D W

    1994-08-01

    Nitric oxide (NO) produced by the constitutive NO synthase (cNOS) in neurons has been implicated in mediating excitotoxic neuronal death. In our murine cortical cell culture system, NMDA neurotoxicity was not blocked by addition of the NOS inhibitors, NG-nitro-L-arginine or aminoguanidine. However, following activation of inducible NOS in astrocytes by interleukin-1 beta plus interferon-gamma, NMDA but not kainate neurotoxicity was markedly potentiated. This selective potentiation of NMDA neurotoxicity was blocked by NOS inhibition or antioxidants (superoxide dismutase/catalase or Tempol) and could be mimicked by NO generators (SIN-1 or SNAP) or the oxygen radical generator, pyragallol. These results raise the possibility that NO production by astrocytes may contribute to NMDA receptor-mediated neuronal death, perhaps through interaction with oxygen radicals.

  12. A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain

    Directory of Open Access Journals (Sweden)

    Yang Qi

    2009-12-01

    Full Text Available Abstract The midbrain periaqueductal grey (PAG is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp, one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

  13. Human augmenter of liver regeneration: molecular cloning, biological activity and roles in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    杨晓明; 谢玲; 邱兆华; 吴祖泽; 贺福初

    1997-01-01

    The complete amino acid sequence of human augmenter of liver regeneration (hALR) was reported by deduction from nucleotide sequence of its complementary DNA . The cDNA for hALR was isolated by screening a human fetal liver cDNA library and the sequencing of this insert revealed an open reading frame encoding a protein with 125aa and highly homologous (87% ) with rat ALR encoding sequence. The recombinant hALR expressed from its cDNA in transient expression experiments in cos-7 cells could stimulate DNA synthesis of HTC hepatoma cell in the dose-dependent and heat-resistant way. Northern blot analysis with rat ALR cDNA as probe confirmed that ALR mRNA was expressed in the normal rat liver at low level and that dramatically increased in the regenerating liver after partial hepatectomied rat. This size of hALR mRNA is 1.4 kb long and expressed in human fetal liver, kidney and testis. These findings indicated that liver itself may be the resource of ALR and suggested that ALR seems to be an im-portant parac

  14. Augmented Reality

    DEFF Research Database (Denmark)

    Nielsen, Birgitte Lund; Brandt, Harald; Radmer, Ole

    2017-01-01

    Artiklen præsenterer resultater fra pilotafprøvning i 7.-klasses fysik/kemi og biologi af to Augmented Reality (AR)-apps til naturfagsundervisning. Muligheder og udfordringer ved lærerens stilladsering af elevernes undersøgende samtale og modelleringskompetence er undersøgt med interview...

  15. Augmented Reality

    DEFF Research Database (Denmark)

    Kjærgaard, Hanne Wacher; Kjeldsen, Lars Peter Bech; Rahn, Annette

    2015-01-01

    This chapter describes the use of iPad-facilitated application of augmented reality in the teaching of highly complex anatomical and physiological subjects in the training of nurses at undergraduate level. The general aim of the project is to investigate the potentials of this application in term...

  16. Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine.

    Science.gov (United States)

    Motevasseli, Tahmineh; Rezayof, Ameneh; Zarrindast, Mohammad-Reza; Nayer-Nouri, Touraj

    2010-12-02

    The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1μg/mouse) with an ineffective dose of morphine (3mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2μg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.

  17. The opioid ketobemidone has a NMDA blocking effect

    DEFF Research Database (Denmark)

    Andersen, S; Dickenson, A H; Kohn, M;

    1996-01-01

    There are clinical observations that neurogenic pain can respond well to the opioid ketobemidone, in contrast to pethidine and morphine. This has led us to the hypothesis that the analgesic effect of ketobemidone in neurogenic pain may be due to both opioid as well as additional non-opioid effects......-fibre strength and their responses quantified. The wind-up of the neurones, due to N-methyl-D-aspartate (NMDA) receptor activation, leading to marked increases in C-fibre responses and an associated post-discharge was also measured. Ketobemidone, applied to the spinal cord, equivalent to an intrathecal injection...... with a Ki value of 26 microM. Therefore, ketobemidone appears to possess both mu opioid agonist as well as NMDA blocking effects....

  18. Effects of Augmented Exercise Therapy on Outcome of Gait and Gait-Related Activities in the First 6 Months After Stroke A Meta-Analysis

    NARCIS (Netherlands)

    Veerbeek, Janne M.; Koolstra, Muriel; Ket, Johannes C. F.; van Wegen, Erwin E. H.; Kwakkel, Gert

    2011-01-01

    Background and Purpose-The purpose of this study was to determine the effects of augmented exercise therapy on gait, gait-related activities, and (basic and extended) activities of daily living within the first 6 months poststroke. Methods-A systematic literature search in electronic databases from

  19. Interactive augmented reality using Scratch 2.0 to improve physical activities for children with developmental disabilities.

    Science.gov (United States)

    Lin, Chien-Yu; Chang, Yu-Ming

    2015-02-01

    This study uses a body motion interactive game developed in Scratch 2.0 to enhance the body strength of children with disabilities. Scratch 2.0, using an augmented-reality function on a program platform, creates real world and virtual reality displays at the same time. This study uses a webcam integration that tracks movements and allows participants to interact physically with the project, to enhance the motivation of children with developmental disabilities to perform physical activities. This study follows a single-case research using an ABAB structure, in which A is the baseline and B is the intervention. The experimental period was 2 months. The experimental results demonstrated that the scores for 3 children with developmental disabilities increased considerably during the intervention phrases. The developmental applications of these results are also discussed.

  20. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest...... that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  1. Human Neuroepithelial Cells Express NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Cappell B

    2003-11-01

    Full Text Available Abstract L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1 cerebral endothelial barrier and 2 cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR expression via immunohistochemistry and murine neuroepithelial cell line (V1 were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

  2. NMDA receptor and schizophrenia: a brief history.

    Science.gov (United States)

    Coyle, Joseph T

    2012-09-01

    Although glutamate was first hypothesized to be involved in the pathophysiology of schizophrenia in the 1980s, it was the demonstration that N-methyl-D-aspartate (NMDA) receptor antagonists, the dissociative anesthetics, could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects that placed the "NMDA receptor hypofunction hypothesis" on firm footing. Additional support came from the demonstration that a variety of agents that enhanced NMDA receptor function at the glycine modulatory site significantly reduced negative symptoms and variably improved cognition in patients with schizophrenia receiving antipsychotic drugs. Finally, persistent blockade of NMDA receptors recreates in experimental animals the critical pathologic features of schizophrenia including downregulation of parvalbumin-positive cortical GABAergic neurons, pyramidal neuron dendritic dysgenesis, and reduced spine density.

  3. Musical Peddy-Paper: A Collaborative Learning Activity Suported by Augmented Reality

    Science.gov (United States)

    Gomes, José Duarte Cardoso; Figueiredo, Mauro Jorge Guerreiro; Amante, Lúcia da Graça Cruz Domingues; Gomes, Cristina Maria Cardoso

    2014-01-01

    Gaming activities are an integral part of the human learning process, in particular for children. Game-based learning focuses on motivation and children's engagement towards learning. Educational game-based activities are becoming effective strategies to enhance the learning process. This paper presents an educational activity focusing to merge…

  4. Augmented Reality

    DEFF Research Database (Denmark)

    Arusoaie, Andrei; Cristei, Alexandru Ionuţ; Chircu, Cristian

    2011-01-01

    applications. In the first section the focus is set on the Augmented Reality basic concepts and the necessity of developing such a framework. The prototype that we present in the second part of this paper comes to demonstrate how our framework can be used to achieve our targeted application for Augmented......Virtual Reality is becoming more than a part of our everyday life, helping us to identify quickly the elements of the environment or to better entertain us. The purpose of this paper is to present an application framework that we are developing, in order to help others implement their own...... Reality. It also contains some future works to highlight the capabilities of the AR API. © 2010 IEEE....

  5. Membrane phospholipid augments cytochrome P4501a enzymatic activity by modulating structural conformation during detoxification of xenobiotics.

    Directory of Open Access Journals (Sweden)

    Manik C Ghosh

    Full Text Available Cytochrome P450 is a superfamily of membrane-bound hemoprotein that gets involved with the degradation of xenobiotics and internal metabolites. Accumulated body of evidence indicates that phospholipids play a crucial role in determining the enzymatic activity of cytochrome P450 in the microenvironment by modulating its structure during detoxification; however, the structure-function relationship of cytochrome P4501A, a family of enzymes responsible for degrading lipophilic aromatic hydrocarbons, is still not well defined. Inducibility of cytochrome P4501A in cultured catfish hepatocytes in response to carbofuran, a widely used pesticide around the world, was studied earlier in our laboratory. In this present investigation, we observed that treating catfish with carbofuran augmented total phospholipid in the liver. We examined the role of phospholipid on the of cytochrome P4501A-marker enzyme which is known as ethoxyresorufin-O-deethylase (EROD in the context of structure and function. We purified the carbofuran-induced cytochrome P4501A protein from catfish liver. Subsequently, we examined the enzymatic activity of purified P4501A protein in the presence of phospholipid, and studied how the structure of purified protein was influenced in the phospholipid environment. Membrane phospholipid appeared to accelerate the enzymatic activity of EROD by changing its structural conformation and thus controlling the detoxification of xenobiotics. Our study revealed the missing link of how the cytochrome P450 restores its enzymatic activity by changing its structural conformation in the phospholipid microenvironment.

  6. Role of AMPA and NMDA receptors and back-propagating action potentials in spike timing-dependent plasticity.

    Science.gov (United States)

    Fuenzalida, Marco; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington

    2010-01-01

    The cellular mechanisms that mediate spike timing-dependent plasticity (STDP) are largely unknown. We studied in vitro in CA1 pyramidal neurons the contribution of AMPA and N-methyl-d-aspartate (NMDA) components of Schaffer collateral (SC) excitatory postsynaptic potentials (EPSPs; EPSP(AMPA) and EPSP(NMDA)) and of the back-propagating action potential (BAP) to the long-term potentiation (LTP) induced by a STDP protocol that consisted in pairing an EPSP and a BAP. Transient blockade of EPSP(AMPA) with 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX) during the STDP protocol prevented LTP. Contrastingly LTP was induced under transient inhibition of EPSP(AMPA) by combining SC stimulation, an imposed EPSP(AMPA)-like depolarization, and BAP or by coupling the EPSP(NMDA) evoked under sustained depolarization (approximately -40 mV) and BAP. In Mg(2+)-free solution EPSP(NMDA) and BAP also produced LTP. Suppression of EPSP(NMDA) or BAP always prevented LTP. Thus activation of NMDA receptors and BAPs are needed but not sufficient because AMPA receptor activation is also obligatory for STDP. However, a transient depolarization of another origin that unblocks NMDA receptors and a BAP may also trigger LTP.

  7. Walky for embodied microblogging: sharing mundane activities through augmented everyday objects

    DEFF Research Database (Denmark)

    Nazzi, Elena; Sokoler, Tomas

    2011-01-01

    In this paper we present our ongoing exploration of a theoretical concept: Embodied Microblogging. Looking for a more situated way to communicate mundane activities in local communities, EM informs the design of digital technology to facilitate senior citizens in making their everyday activities ...

  8. Supplemental Immobilization of Hanford Low-Activity Waste: Cast Stone Augmented Formulation Matrix Tests

    Energy Technology Data Exchange (ETDEWEB)

    Cozzi, A. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Crawford, C. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Fox, K. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Hansen, E. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Roberts, K. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2015-07-20

    Matrix tests. A set of Cast Stone formulations were devised to augment the original screening test matrix and focus on the range of the test conditions. Fly ash and blast furnace slag were limited to either northwest or southeast and the salt solutions were narrowed to the Average and the SST Blend at the 7.8M Na concentration. To fill in the matrix, a mix ratio of 0.5 was added. In addition, two admixtures, Xypex Admix C-500 and Rheomac SF100 (silica fume), were added as an additional dry material binder in select compositions. As in the Screening Matrix, both fresh and cured properties were evaluated for the formulations. In this study, properties that were influenced by the W/DM ratio in the Screening Matrix; flow diameter, plastic viscosity, density, and compressive strength, showed consistent behavior with respect to W/DM. The leach index for highly soluble components, sodium and nitrate, were not influenced by changes in formulation or the admixtures. The leach index for both iodine and Tc-99 show an influence from the addition of the admixture, Xypex Admix C-500. Additional testing should be performed to further evaluate the influence of Xypex Admix C-500 on the leach index over a range of admixture concentrations, Cast Stone formulations, and curing and storage conditions.

  9. Antagonistas de los receptores glutamatérgicos NMDA en el tratamiento del dolor crónico NMDA glutamatergic receptor antagonists for the management of chronic pain

    Directory of Open Access Journals (Sweden)

    F. Neira

    2004-05-01

    receptores opioides mu, pero además es un antagonista no competitivo de los receptores NMDA. La utilización de la metadona permite mejorar el control del dolor al disminuir el desarrollo de tolerancia a los opioides. La memantina es un antagonista no competitivo de los receptores NMDA. Disminuye la facilitación intracortical y aumenta la inhibición intracortical. Experimentalmente ha demostrado características antinociceptivas en la fase secundaria a la inflamación inducida por la prueba de la formalina. Disminuye la hiperalgesia térmica y mecánica. Los antagonistas de los receptores NMDA, abren un nuevo horizonte en el tratamiento del dolor neuropático. Son fármacos que habitualmente requieren la asociación de otros analgésicos, normalmente actúan como coadyuvantes. Los resultados dispares de los diferentes antagonistas sobre una misma indicación, no hacen sino confirmar la complejidad de su mecanismo de acción, que no se limita a antagonizar los receptores NMDA, sino que va mucho más allá.NMDA receptors are associated to learning and memory processes, development and neural plasticity, as well as acute and chronic pain conditions. They are involved in the outset and maintenance of central sensitization associated to damage or inflammation of peripheral tissues. Glutamate is the main amino acid that stimulates the CNS, can be involved in nociceptive transmission processes at the spine level and is the main responsible for the fast synaptic transmission. The action of glutamate in the pain routes is mostly mediated by ionotropic receptors (AMPA, NMDA and kainic. The activation of NMDA receptors plays a major role in the excitatory neurotransmission and the synaptic plasticity of the CNS. Glutamate and its agonists (NMDA, AMPA or kainic acid are involved in the generation and maintenance of hyperalgesia conditions (exacerbated response to noxious stimulus and alodynia (decrease of pain threshold. The clinical effectiveness of NMDA receptor antagonists

  10. Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged and Older Adults with Mild Memory Complaints

    Directory of Open Access Journals (Sweden)

    Susan Y. Bookheimer

    2013-01-01

    Full Text Available Despite increasing emphasis on the potential of dietary antioxidants in preventing memory loss and on diet as a precursor of neurological health, rigorous studies investigating the cognitive effects of foods and their components are rare. Recent animal studies have reported memory and other cognitive benefits of polyphenols, found abundantly in pomegranate juice. We performed a preliminary, placebo-controlled randomized trial of pomegranate juice in older subjects with age-associated memory complaints using memory testing and functional brain activation (fMRI as outcome measures. Thirty-two subjects (28 completers were randomly assigned to drink 8 ounces of either pomegranate juice or a flavor-matched placebo drink for 4 weeks. Subjects received memory testing, fMRI scans during cognitive tasks, and blood draws for peripheral biomarkers before and after the intervention. Investigators and subjects were all blind to group membership. After 4 weeks, only the pomegranate group showed a significant improvement in the Buschke selective reminding test of verbal memory and a significant increase in plasma trolox-equivalent antioxidant capacity (TEAC and urolithin A-glucuronide. Furthermore, compared to the placebo group, the pomegranate group had increased fMRI activity during verbal and visual memory tasks. While preliminary, these results suggest a role for pomegranate juice in augmenting memory function through task-related increases in functional brain activity.

  11. Platelets augment respiratory burst in neutrophils activated by selected species of gram-positive or gram-negative bacteria.

    Directory of Open Access Journals (Sweden)

    Kamila Pytel

    2008-12-01

    Full Text Available Neutrophils and platelets circulate in blood system and play important physiological roles as part of immunological system. Neutrophils are the first line of host defense against various intruders, and platelets are satellite cells cooperating with other components of defense system. Recent studies report about the cooperation among these types of cells. We analyzed the effect of platelets on oxygen burst in neutrophils triggered by Staphylococcus aureus and Escherichia coli bacteria in vitro. The effect of platelets on oxygen burst in neutrophils was measured by luminol enhanced chemiluminescence. Opsonized and non-opsonized bacteria were used as activators. Activation of neutrophils with live non-opsonized and opsonized bacteria in the presence of platelets increased the oxygen burst as compared to the same system without platelets. The gram-positive bacteria (Staphylococcus aureus were causing higher activation than gram-negative bacteria (Escherichia coli. This work demonstrate that platelets potentate the response of neutrophils augmenting their respiratory burst in vitro when triggered by bacteria.

  12. Pomegranate juice augments memory and FMRI activity in middle-aged and older adults with mild memory complaints.

    Science.gov (United States)

    Bookheimer, Susan Y; Renner, Brian A; Ekstrom, Arne; Li, Zhaoping; Henning, Susanne M; Brown, Jesse A; Jones, Mike; Moody, Teena; Small, Gary W

    2013-01-01

    Despite increasing emphasis on the potential of dietary antioxidants in preventing memory loss and on diet as a precursor of neurological health, rigorous studies investigating the cognitive effects of foods and their components are rare. Recent animal studies have reported memory and other cognitive benefits of polyphenols, found abundantly in pomegranate juice. We performed a preliminary, placebo-controlled randomized trial of pomegranate juice in older subjects with age-associated memory complaints using memory testing and functional brain activation (fMRI) as outcome measures. Thirty-two subjects (28 completers) were randomly assigned to drink 8 ounces of either pomegranate juice or a flavor-matched placebo drink for 4 weeks. Subjects received memory testing, fMRI scans during cognitive tasks, and blood draws for peripheral biomarkers before and after the intervention. Investigators and subjects were all blind to group membership. After 4 weeks, only the pomegranate group showed a significant improvement in the Buschke selective reminding test of verbal memory and a significant increase in plasma trolox-equivalent antioxidant capacity (TEAC) and urolithin A-glucuronide. Furthermore, compared to the placebo group, the pomegranate group had increased fMRI activity during verbal and visual memory tasks. While preliminary, these results suggest a role for pomegranate juice in augmenting memory function through task-related increases in functional brain activity.

  13. An Augmented Reality-Based Mobile Learning System to Improve Students' Learning Achievements and Motivations in Natural Science Inquiry Activities

    Science.gov (United States)

    Chiang, Tosti H. C.; Yang, Stephen J. H.; Hwang, Gwo-Jen

    2014-01-01

    In this study, an augmented reality-based mobile learning system is proposed for conducting inquiry-based learning activities. An experiment has been conducted to examine the effectiveness of the proposed approach in terms of learning achievements and motivations. The subjects were 57 fourth graders from two classes taught by the same teacher in…

  14. Walky for embodied microblogging: sharing mundane activities through augmented everyday objects

    DEFF Research Database (Denmark)

    Nazzi, Elena; Sokoler, Tomas

    2011-01-01

    In this paper we present our ongoing exploration of a theoretical concept: Embodied Microblogging. Looking for a more situated way to communicate mundane activities in local communities, EM informs the design of digital technology to facilitate senior citizens in making their everyday activities...... design research community looking at social well being in Aging in place suggesting EM as informing theoretical concept for designing digital technology for social interaction....

  15. NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801.

    Science.gov (United States)

    Roshanravan, Hila; Kim, Eun Young; Dryer, Stuart E

    2016-10-01

    N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney, and the abundance of these receptors and some of their endogenous agonists are increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca(2+) influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. We observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared with controls. A similar increase in NMDA subunits, especially NR1, NR2A, and NR2C, was observed in glomeruli and tubules of Akita mice. Sustained continuous treatment with the strong NMDA receptor antagonist dizocilpine (MK-801) for 28 days starting at 8 weeks of age reduced 24-h albumin excretion and mesangial matrix expansion and improved glomerular ultrastructure in Akita mice. MK-801 did not alleviate reduced Akita mouse body weight and had no effect on kidney histology or ultrastructure in DBA/2J controls. The structurally dissimilar NMDA antagonist memantine also reduced diabetic nephropathy, although it was less effective than MK-801. Inhibition of NMDA receptors may represent a valid therapeutic approach to reduce renal complications of diabetes, and it is possible to develop well-tolerated agents with minimal central nervous system effects. Two such agents, memantine and dextromethorphan, are already in widespread clinical use.

  16. Manganese inhibits NMDA receptor channel function: implications to psychiatric and cognitive effects.

    Science.gov (United States)

    Guilarte, Tomás R; Chen, Ming-Kai

    2007-11-01

    Humans exposed to excess levels of manganese (Mn(2+)) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn(2+) produces such effects. We now report that Mn(2+) is a potent inhibitor of [(3)H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [(3)H]-MK-801 to the NMDA receptor channel by Mn(2+) was activity-dependent since Mn(2+) was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (K(i)=35.9+/-3.1 microM) than in their absence (K(i)=157.1+/-6.5 microM). We also show that Mn(2+) is a NMDA receptor channel blocker since its inhibition of [(3)H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn(2+) significantly increased the affinity constant (K(d)) with no significant effect on the maximal number of [(3)H]-MK-801 binding sites (B(max)). Under stimulating conditions, Mn(2+) was equipotent in inhibiting [(3)H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn(2+) was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn(2+) exposure in non-human primates increases Cu(2+), but not zinc or iron concentrations in the basal ganglia [Guilarte TR, Chen M-K, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 2006a;202:381-90]. Therefore, we also tested the inhibitory effects of Cu(2+) on [(3)H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu(2+) in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn(2

  17. Real-time RMS active damping augmentation: Heavy and very light payload evaluations

    Science.gov (United States)

    Demeo, Martha E.; Gilbert, Michael G.; Lepanto, Janet A.; Flueckiger, Karl W.; Bains, Elizabeth M.; Jensen, Mary C.

    1994-01-01

    Controls-Structures Integration Technology has been applied to the Space Shuttle Remote Manipulator System (RMS) to improve on-orbit performance. The objective was to actively damp undesired oscillatory motions of the RMS following routine payload maneuvering and Shuttle attitude control thruster firings. Simulation of active damping was conducted in the real-time, man-in-the-loop Systems Engineering Simulator at NASA's Johnson Space Center. The simulator was used to obtain qualitative and quantitative data on active damping performance from astronaut operators. Using a simulated three-axis accelerometer mounted on the RMS, 'sensed' vibration motions were used to generate joint motor commands that reduced the unwanted oscillations. Active damping of the RMS with heavy and light attached payloads was demonstrated in this study. Five astronaut operators examined the performance of active damping following operator commanded RMS maneuvers and Shuttle thruster firings. Noticeable improvements in the damping response of the RMS with the heavy, Hubble Space Telescope payload and the very light, astronaut in Manipulator Foot Restraint payload were observed. The potential of active damping to aid in precisely maneuvering payloads was deemed significant.

  18. Resveratrol-induced augmentation of telomerase activity delays senescence of endothelial progenitor cells

    Institute of Scientific and Technical Information of China (English)

    WANG Xiao-bin; ZHU Li; HUANG Jun; YIN Yi-gang; KONG Xiang-qing; RONG Qi-fei; SHI Ai-wu; CAO Ke-jiang

    2011-01-01

    Background Previous studies have shown that resveratrol increases endothelial progenitor cell (EPC) numbers and functional activity.Increased EPC numbers and activity are associated with the inhibition of EPC senescence.In this study,we investigated the effect of resveratrol on the senescence of EPCs,leading to potentiation of cellular function.Methods EPCs were isolated from human peripheral blood and identified immunocytochemically.EPCs were incubated with resveratrol (1,10,and 50 μmol/L) or control for specified times.After in vitro cultivation,acidic β-galactosidase staining revealed the extent of senescence in the cells.To gain further insight into the underlying mechanism of the effect of resveratrol,we measured telomerase activity using a polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA) technique.Furthermore,we measured the expression of human telomerase reverse transcriptase (hTERT) and the phosphorylation of Akt by immunoblotting.Results Resveratrol dose-dependently inhibited the onset of EPC senescence in culture.Resveratrol also significantly increased telomerase activity.Interestingly,quantitative real-time PCR analysis demonstrated that resveratrol dose-dependently increased the expression of the catalytic subunit,hTERT,an effect that was significantly inhibited by pharmacological phosphatidylinositol 3-kinase (PI3-K) blockers (wortmannin).The expression of hTERT is regulated by the PI3-K/Akt pathway; therefore,we examined the effect of resveratrol on Akt activity in EPCs.Immunoblotting analysis revealed that resveratrol led to dose-dependent phosphorylation and activation of Akt in EPCs.Conclusion Resveratrol delayed EPCs senescence in vitro,which may be dependent on telomerase activation.

  19. Nontrivial augmentations in mixing performance through integrated active and passive mixing in serpentine microchannels

    Science.gov (United States)

    Biswas, Sujay K.; Das, Tamal; Chakraborty, Suman

    2012-03-01

    Achievement of efficient mixing in microfluidic systems appears to be a highly challenging proposition, as attributable to typical low Reynolds number hydrodynamics over small scales. To circumvent these constraints, numerous strategies, either relying upon a modulation in the microchannel geometry or involving active flow perturbations have been proposed in the literature. However, while the geometric or passive means suffer from a lack of dynamic control on the mixing process, the active methods can be unfavorably energy expensive. Here we show that the problem of controllability and energy efficiency can be optimized to a large extent by combining the active and passive strategies within an integrated microfluidic platform, in the form of serpentine microchannel geometry with embedded electrodes. We demonstrate, both theoretically and experimentally, that in specific operating regimes, the mixing effectiveness (expressed in terms of a quantifiable index) of the designed system can be nontrivially higher than the algebraic sum of effectivenesses realized from pure active and passive mixing configurations, leading to a nonlinear amplification in the separation efficiency. Results of our experiments may be used a generic design principle for optimized mixing performance of lab-on-a-chip microdevices, with a judicious combination of the active and passive mixing paradigms.

  20. Achieving a predictable 24-hour return to normal activities after breast augmentation: part I. Refining practices by using motion and time study principles.

    Science.gov (United States)

    Tebbetts, John B

    2002-01-01

    The purpose of this study was to develop techniques to predictably return patients receiving inframammary and axillary, subpectoral breast augmentation to full normal activities within 24 hours of their primary breast augmentation. This 5-year study applies motion and time study principles to refine practices in augmentation mammaplasty to reduce perioperative morbidity and shorten patient recovery. Retrospective data for operative times, medications administered, recovery times, times to discharge, and time to return to normal activities were collected from patient chart reviews and patient contacts from 1982 to 1984 (group 1, n = 16, axillary partial retropectoral augmentations) and 1990 (group 2, n = 16, inframammary partial retropectoral augmentations). Videotapes from operative procedures of groups 1 and 2 were analyzed with macromotion and micromotion study principles, and tables of events were formulated for all operating room personnel, detailing every step of each function they performed. The events tables were then refined into detailed scripts by using motion and time study principles. Scripts were used for surgeon and personnel training and for reference during operative procedures. Extensive changes in all aspects of patient care, including patient education, preparation, operative planning, implant selection, anesthesia techniques, surgical techniques, instrumentation, and postoperative care derived from data and videotape studies of patients in groups 1 and 2 were then applied to a third group of patients (group 3), collecting prospective data over a 3-year period (1998 to 2000). Group 3 (n = 627) data included timed events, medications, and time to return to normal activities. Patients in group 3 had substantially shorter anesthesia, operation, and postanesthesia care unit times and time to discharge and time to return to normal activities compared with groups 1 and 2. Of the patients in group 3, 96 percent were able to return to normal activities

  1. Vagus Nerve Activity Augments Intestinal Macrophage Phagocytosis via Nicotinic Acetylcholine Receptor alpha 4 beta 2

    NARCIS (Netherlands)

    van der Zanden, Esmerij P.; Snoek, Susanne A.; Heinsbroek, Sigrid E.; Stanisor, Oana I.; Verseijden, Caroline; Boeckxstaens, Guy E.; Peppelenbosch, Maikel P.; Greaves, David R.; Gordon, Siamon; de Jonge, Wouter J.

    2009-01-01

    BACKGROUND & AIMS: The vagus nerve negatively regulates macrophage cytokine production via the release of acetylcholine (ACh) and activation of nicotinic acetylcholine receptors (nAChR). In various models of intestinal inflammation, vagus nerve efferent stimulation ameliorates disease. Given the act

  2. Indomethacin augments lymphokine-activated killer cell generation by patients with malignant mesothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Manning, L.S.; Bowman, R.V.; Davis, M.R.; Musk, A.W.; Robinson, B.W. (Queen Elizabeth II Medical Centre, Nedlands (Australia))

    1989-10-01

    Human malignant mesothelioma (MM) cells are resistant to natural killer (NK) cell lysis but susceptible to lysis by lymphokine-activated killer (LAK) cells from control individuals. The present study was performed to determine the capacity of patients with MM (n = 22) and individuals occupationally exposed to asbestos (the major population at risk of developing this disease, n = 52) to generate LAK cells capable of effectively lysing human mesothelioma cells. Compared to controls (n = 20), both patient groups demonstrated significantly depressed LAK cell activity against mesothelioma tumor cell targets (55 +/- 3% lysis by controls vs 34 +/- 3% lysis by patients with MM, P less than 0.005; and 45 +/- 3% lysis by asbestos-exposed individuals, P less than 0.025). Addition of 10 micrograms/ml indomethacin during LAK cell generation restored normal LAK cell activity for patients with MM (52 +/- 6% lysis of cultured human MM cells, P = NS compared to controls), suggesting that the defective cytolytic cell function observed in some patients with MM is a result of prostaglandin-induced immunosuppression. The ability of indomethacin to restore suppressed LAK cell activity in patients with MM suggests that the concomitant use of this agent in ex vivo LAK cell generation and in patients undergoing interleukin/LAK cell therapy may be beneficial.

  3. Dectin-2 Recognizes Mannosylated O-antigens of Human Opportunistic Pathogens and Augments Lipopolysaccharide Activation of Myeloid Cells*

    Science.gov (United States)

    Wittmann, Alexandra; Lamprinaki, Dimitra; Bowles, Kristian M.; Katzenellenbogen, Ewa; Knirel, Yuriy A.; Whitfield, Chris; Nishimura, Takashi; Matsumoto, Naoki; Yamamoto, Kazuo; Iwakura, Yoichiro; Saijo, Shinobu; Kawasaki, Norihito

    2016-01-01

    LPS consists of a relatively conserved region of lipid A and core oligosaccharide and a highly variable region of O-antigen polysaccharide. Whereas lipid A is known to bind to the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, the role of the O-antigen remains unclear. Here we report a novel molecular interaction between dendritic cell-associated C-type lectin-2 (Dectin-2) and mannosylated O-antigen found in a human opportunistic pathogen, Hafnia alvei PCM 1223, which has a repeating unit of [-Man-α1,3-Man-α1,2-Man-α1,2-Man-α1,2-Man-α1,3-]. H. alvei LPS induced higher levels of TNFα and IL-10 from mouse bone marrow-derived dendritic cells (BM-DCs), when compared with Salmonella enterica O66 LPS, which has a repeat of [-Gal-α1,6-Gal-α1,4-[Glc-β1,3]GalNAc-α1,3-GalNAc-β1,3-]. In a cell-based reporter assay, Dectin-2 was shown to recognize H. alvei LPS. This binding was inhibited by mannosidase treatment of H. alvei LPS and by mutations in the carbohydrate-binding domain of Dectin-2, demonstrating that H. alvei LPS is a novel glycan ligand of Dectin-2. The enhanced cytokine production by H. alvei LPS was Dectin-2-dependent, because Dectin-2 knock-out BM-DCs failed to do so. This receptor cross-talk between Dectin-2 and TLR4 involved events including spleen tyrosine kinase (Syk) activation and receptor juxtaposition. Furthermore, another mannosylated LPS from Escherichia coli O9a also bound to Dectin-2 and augmented TLR4 activation of BM-DCs. Taken together, these data indicate that mannosylated O-antigens from several Gram-negative bacteria augment TLR4 responses through interaction with Dectin-2. PMID:27358401

  4. Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer

    Directory of Open Access Journals (Sweden)

    Srivastava MK

    2012-10-01

    Full Text Available Minu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–31Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USAAbstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs. MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with

  5. Augmentation of the in vitro activity of azlocillin against Bacteroides fragilis by clavulanic acid.

    Science.gov (United States)

    Bansal, M B; Chuah, S K; Thadepalli, H

    1984-01-01

    Azlocillin was active against 90% of 154 strains of Bacteroides fragilis at a concentration of 64 micrograms/ml. Twenty-eight strains of B. fragilis with an azlocillin MIC of greater than or equal to 8 micrograms/ml were retested with a combination of azlocillin plus clavulanic acid. Of these strains, 71% showed a 4- to 32-fold decrease in the MIC of azlocillin plus clavulanic acid. PMID:6517552

  6. Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

    Energy Technology Data Exchange (ETDEWEB)

    Matthew, E.; Parfitt, A.G.; Sugden, D.; Engelhardt, D.L.; Zimmerman, E.A.; Klein, D.C.

    1984-02-01

    Studies of (/sup 3/H)diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot (Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture). Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects of diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the (/sup 3/H)diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT.

  7. Intracellular calcium elevation during plateau potentials mediated by extrasynaptic NMDA receptor activation in rat hippocampal CA1 pyramidal neurons is primarily due to calcium entry through voltage-gated calcium channels.

    Science.gov (United States)

    Oda, Yoshiaki; Kodama, Satoshi; Tsuchiya, Sadahiro; Inoue, Masashi; Miyakawa, Hiroyoshi

    2014-05-01

    We reported previously that plateau potentials mediated by extrasynaptic N-methyl-d-aspartate receptors (NMDARs) can be induced either by synaptic stimulation in the presence of glutamate transporter antagonist or by iontophoresis of NMDA in rat hippocampal CA1 pyramidal neurons. To examine whether the plateau potentials are accompanied by an elevation of intracellular Ca2+ and to determine the source of Ca2+ elevation, we performed Ca2+ imaging during the plateau potential. Neurons were loaded with Ca2+ indicator fluo-4, and the plateau potentials were generated either synaptically in the presence of glutamate transporter antagonist or by iontophoretically applying NMDA. We have found that a transient elevation in intracellular Ca2+ accompanies the plateau potential. The synaptically induced plateau potential and the Ca2+ elevation were blocked by 5,7-dichlorokynurenic acid (5,7-dCK), an antagonist for the glycine-binding sites of NMDAR. A mixture of Cd2+ and tetrodotoxin did not block NMDA-induced plateau potentials, but completely abolished the accompanying Ca2+ elevation in both the presence and absence of Mg2+ ions in the bathing solution. The NMDA-induced plateau potential was blocked by further adding 5,7-dCK. Our results show that the NMDAR-mediated plateau potential is accompanied by elevation of intracellular Ca2+ that is primarily caused by the influx of Ca2+ through voltage-gated Ca2+ channels. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  8. Anti-NMDA Receptor Encephalitis in a Pregnant Woman

    OpenAIRE

    Kim, JiYoung; Park, Seung Ha; Jung, Yu Ri; Park, Soon Won; Jung, Dae Soo

    2015-01-01

    Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is one of the most common types of autoimmune synaptic encephalitis. Anti-NMDA receptor encephalitis commonly occurs in young women with ovarian teratoma. It has variable clinical manifestations and treatment responses. Sometimes it is misdiagnosed as a psychiatric disorder or viral encephalitis. To the best of our knowledge, anti-NMDA receptor encephalitis is a rare condition in pregnant women. We report a case of anti-NMDA receptor ence...

  9. Leptin into the rostral ventral lateral medulla (RVLM augments renal sympathetic nerve activity and blood pressure

    Directory of Open Access Journals (Sweden)

    Maria J Barnes

    2014-08-01

    Full Text Available Leptin is a hormone released from adipose tissue. While this hormone normally acts to reduce feeding behavior and increase energy expenditure, in obesity, resistance to these effects occurs even though the hormone is released in large amounts. Although leptin no longer works to suppress feeding in the obese, leptin retains its potent effects on other autonomic functions such as blood pressure regulation. Leptin has been associated with hypertension and increased sympathetic autonomic activity. Therefore, leptin is emerging as a major contributor to the hypertensive state observed in obesity. Sympathetic control of blood pressure is maintained principally by autonomic reflex control circuits in the caudal brainstem. The rostral ventral-lateral medulla (RVLM is the primary regulator of the sympathetic nervous system, sending excitatory fibers to sympathetic preganglionic neurons to regulate sympathetic control over resistance vessels and blood pressure. Previous studies from our laboratory have shown that neurons in the ventral lateral medulla express leptin receptors (ObRb. Our present study using pseudo-rabies multi-synaptic retrograde tract tracing and immunohistochemical methods revealed that neurons within the RVLM that send sympathetic projections to the kidney express leptin receptors. Acute microinjection of leptin (1 and 3µg; 40nL into the RVLM evoked a significant increase in Mean Arterial Pressure (MAP and renal sympathetic nerve activity (RSNA. When the 3µg dose of leptin was preceded with a leptin antagonist, (SLAN-4; 1ng, it attenuated the cardiovascular response of leptin. Taken together, these data suggest that leptin’s actions within the RVLM may influence blood pressure and renal sympathetic nerve activity.

  10. The effects of GABAA and NMDA receptors in the shell-accumbens on spatial memory of METH-treated rats.

    Science.gov (United States)

    Heysieattalab, Soomaayeh; Naghdi, Nasser; Zarrindast, Mohammad-Reza; Haghparast, Abbas; Mehr, Shahram Ejtemaei; Khoshbouei, Habibeh

    2016-03-01

    Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment and deficits in hippocampal plasticity. Striatal dopamine system is one of the main targets of METH. The dopamine neurons in the striatum directly or indirectly regulate the GABA and glutamatergic signaling in this region and thus their outputs. This is consistent with previous reports showing modification of neuronal activity in the striatum modulates the expression of hippocampal LTP and hippocampal-dependent memory tasks such as Morris water maze (MWM). Therefore, reversing or preventing METH-induced synaptic modifications via pharmacological manipulations of the shell-nucleus accumbens (shell-NAc) may introduce a viable therapeutic target to attenuate the METH-induced memory deficits. This study is designed to investigate the role of intra-shell NAc manipulation of GABAA and NMDA receptors and their interaction with METH on memory performance in MWM task. Pharmacological manipulations were performed in rats received METH or saline. We found systemic saline plus intra-shell NAc infusions of muscimol dose-dependently impaired performance, while bicuculline had no effect. Surprisingly, the intra-NAc infusions of 0.005μg/rat muscimol that has no effect on memory performance (ineffective dose) prevented METH-induced memory impairment. In the contrary, the intra-NAc infusions of bicuculline (0.2μg/rat) increased METH-induced memory impairment. However, pre-training intra-NAc infusions of D-AP5 dose-dependently impaired performance, while NMDA had no effect in rats received systemic saline (control group). The intra-NAc infusions with an ineffective dose of NMDA (0.1μg/rat) increased METH-induced memory impairment. Furthermore, intra-NAc infusions of D-AP5 with an ineffective dose (0.1μg/rat) prevented METH-induced memory impairment. Our result is consistent with the interpretation that METH-mediated learning deficit

  11. Augmented expression of urokinase plasminogen activator and extracellular matrix proteins associates with multiple myeloma progression.

    Science.gov (United States)

    Khan, Rehan; Gupta, Nidhi; Kumar, Raman; Sharma, Manoj; Kumar, Lalit; Sharma, Alpana

    2014-06-01

    Multiple myeloma (MM) represents a B cell malignancy, characterized by a monoclonal proliferation of malignant plasma cells. Interactions between tumor cells and extracellular matrix (ECM) are of importance for tumor invasion and metastasis. Protein levels of urokinase plasminogen activator (uPA) and fibulin 1, nidogen and laminin in plasma and serum respectively and mRNA levels of these molecules in peripheral blood mononuclear cells were determined in 80 subjects by using ELISA and quantitative PCR and data was analyzed with severity of disease. Pearson correlation was determined to observe interrelationship between different molecules. A statistical significant increase for ECM proteins (laminin, nidogen and fibulin 1) and uPA at circulatory level as well as at mRNA level was observed compared to healthy controls. The levels of these molecules in serum might be utilized as a marker of active disease. Significant positive correlation of all ECM proteins with uPA was found and data also correlates with severity of disease. Strong association found between ECM proteins and uPA in this study supports that there might be interplay between these molecules which can be targeted. This study on these molecules may help to gain insight into processes of growth, spread, and clinical behavior of MM.

  12. Whole abdominal wall segmentation using augmented active shape models (AASM) with multi-atlas label fusion and level set

    Science.gov (United States)

    Xu, Zhoubing; Baucom, Rebeccah B.; Abramson, Richard G.; Poulose, Benjamin K.; Landman, Bennett A.

    2016-03-01

    The abdominal wall is an important structure differentiating subcutaneous and visceral compartments and intimately involved with maintaining abdominal structure. Segmentation of the whole abdominal wall on routinely acquired computed tomography (CT) scans remains challenging due to variations and complexities of the wall and surrounding tissues. In this study, we propose a slice-wise augmented active shape model (AASM) approach to robustly segment both the outer and inner surfaces of the abdominal wall. Multi-atlas label fusion (MALF) and level set (LS) techniques are integrated into the traditional ASM framework. The AASM approach globally optimizes the landmark updates in the presence of complicated underlying local anatomical contexts. The proposed approach was validated on 184 axial slices of 20 CT scans. The Hausdorff distance against the manual segmentation was significantly reduced using proposed approach compared to that using ASM, MALF, and LS individually. Our segmentation of the whole abdominal wall enables the subcutaneous and visceral fat measurement, with high correlation to the measurement derived from manual segmentation. This study presents the first generic algorithm that combines ASM, MALF, and LS, and demonstrates practical application for automatically capturing visceral and subcutaneous fat volumes.

  13. Site-specific insertion of selenium into the redox-active disulfide of the flavoprotein augmenter of liver regeneration.

    Science.gov (United States)

    Schaefer-Ramadan, Stephanie; Thorpe, Colin; Rozovsky, Sharon

    2014-04-15

    Augmenter of liver regeneration (sfALR) is a small disulfide-bridged homodimeric flavoprotein with sulfhydryl oxidase activity. Here, we investigate the catalytic and spectroscopic consequences of selectively replacing C145 by a selenocysteine to complement earlier studies in which random substitution of ∼90% of the 6 cysteine residues per sfALR monomer was achieved growing Escherichia coli on selenite. A selenocysteine insertion sequence (SECIS) element was installed within the gene for human sfALR. SecALR2 showed a spectrum comparable to that of wild-type sfALR. The catalytic efficiency of SecALR2 towards dithiothreitol was 6.8-fold lower than a corresponding construct in which position 145 was returned to a cysteine residue while retaining the additional mutations introduced with the SECIS element. This all-cysteine control enzyme formed a mixed disulfide between C142 and β-mercaptoethanol releasing C145 to form a thiolate-flavin charge transfer absorbance band at ∼530nm. In contrast, SecALR2 showed a prominent long-wavelength absorbance at 585 nm consistent with the expectation that a selenolate would be a better charge-transfer donor to the isoalloxazine ring. These data show the robustness of the ALR protein fold towards the multiple mutations required to insert the SECIS element and provide the first example of a selenolate to flavin charge-transfer complex. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Augmentation of anti-tumor activity by immunization with Mycobacterium tuberculosis (Tbc and tuberculin-coupled tumor cells.

    Directory of Open Access Journals (Sweden)

    Yada,Yoshihiko

    1985-04-01

    Full Text Available The anti-tumor effect of immunization with heat-killed Mycobacterium tuberculosis (Tbc and Tuberculin (PPD-coupled syngeneic tumor cells was examined in vivo. Three tumor cell lines were employed. Immunization of Tbc-primed BALB/c mice with PPD-coupled syngeneic Meth-A tumor cells displayed a potent anti-tumor effect on viable Meth-A cells inoculated subcutaneously. Neither PPD-coupled LLC (Lewis Lung Carcinoma cells nor sonicated PPD-coupled Meth-A cells were capable of immunizing these mice. PPD-coupled syngeneic whole tumor cells were indispensable for induction of this tumor-specific resistance. Immunization of Tbc-primed C3H/He mice with PPD-coupled syngeneic MH134 tumor cells did not elicit anti-tumor activity against MH134, but additional pretreatment of mice with cyclophosphamide brought on an anti-tumor effect. Antimetastatic reactivity was investigated in C57BL/6 mice bearing LLC, with a reduction in metastases noted. This antimetastatic effect was observed even when the mice were immunized with PPD-coupled LLC cells three days after removal of the initial tumor. Immunization with Tbc and PPD-coupled Meth-A cells together with intraperitoneal administration of murine or rat interleukin 2 (IL 2 further augmented anti-Meth-A resistance. Murine IL 2 further inhibited tumor growth during the early stage, while rat IL 2 showed an anti-tumor effect throughout the course of tumor growth.

  15. Endothelial IL-33 Expression Is Augmented by Adenoviral Activation of the DNA Damage Machinery.

    Science.gov (United States)

    Stav-Noraas, Tor Espen; Edelmann, Reidunn J; Poulsen, Lars La Cour; Sundnes, Olav; Phung, Danh; Küchler, Axel M; Müller, Fredrik; Kamen, Amine A; Haraldsen, Guttorm; Kaarbø, Mari; Hol, Johanna

    2017-04-15

    IL-33, required for viral clearance by cytotoxic T cells, is generally expressed in vascular endothelial cells in healthy human tissues. We discovered that endothelial IL-33 expression was stimulated as a response to adenoviral transduction. This response was dependent on MRE11, a sensor of DNA damage that can also be activated by adenoviral DNA, and on IRF1, a transcriptional regulator of cellular responses to viral invasion and DNA damage. Accordingly, we observed that endothelial cells responded to adenoviral DNA by phosphorylation of ATM and CHK2 and that depletion or inhibition of MRE11, but not depletion of ATM, abrogated IL-33 stimulation. In conclusion, we show that adenoviral transduction stimulates IL-33 expression in endothelial cells in a manner that is dependent on the DNA-binding protein MRE11 and the antiviral factor IRF1 but not on downstream DNA damage response signaling. Copyright © 2017 by The American Association of Immunologists, Inc.

  16. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN-mediated [correction of INF] natural killer activity.

    Science.gov (United States)

    Yamamoto, S; Yamamoto, T; Kataoka, T; Kuramoto, E; Yano, O; Tokunaga, T

    1992-06-15

    Thirty-mer single-stranded oligonucleotides, with a sequence chosen from the known cDNA encoding the 64-kDa protein named Ag A or the MPB-70 protein of Mycobacterium bovis BCG and the human cellular proteins such as complement component 1 inhibitor and Ig rearranged lambda-chain, were used to dissect the capability to induce IFN and to augment NK cell activity of mouse spleen cells by coincubation in vitro. Three with the hexamer palindromic sequence as GACGTC were active, whereas two kinds of oligonucleotides with no palindrome were inactive. The oligonucleotides containing at least one of the different palindromic sequences showed no activity. When a portion of the sequence of the inactive oligonucleotides was substituted with either palindromic sequence of GACGTC, AGCGCT, or AACGTT, the oligonucleotide acquired the ability to augment NK activity. In contrast, the oligonucleotides substituted with another palindromic sequence such as ACCGGT was without effect. Furthermore, exchange of two neighboring mononucleotides within, but not outside, the active palindromic sequence destroyed the ability of the oligonucleotides to augment NK cell activity. Stimulation of spleen cells with the substituted oligonucleotide, A4a-AAC, induced production of significant amounts of IFN-alpha/beta and small amounts of IFN-gamma. Augmentation of NK activity of the cells by the oligonucleotide was ascribed to IFN-alpha/beta production. These results strongly suggest that the presence of the unique palindromic sequences, such as GACGTC, AGCGCT, and AACGTT, but not ACCGGT, is essential for the immunostimulatory activity of oligonucleotides.

  17. Adaptation to short photoperiods augments circadian food anticipatory activity in Siberian hamsters.

    Science.gov (United States)

    Bradley, Sean P; Prendergast, Brian J

    2014-06-01

    This article is part of a Special Issue "Energy Balance". Both the light-dark cycle and the timing of food intake can entrain circadian rhythms. Entrainment to food is mediated by a food entrainable circadian oscillator (FEO) that is formally and mechanistically separable from the hypothalamic light-entrainable oscillator. This experiment examined whether seasonal changes in day length affect the function of the FEO in male Siberian hamsters (Phodopus sungorus). Hamsters housed in long (LD; 15 h light/day) or short (SD; 9h light/day) photoperiods were subjected to a timed-feeding schedule for 10 days, during which food was available only during a 5h interval of the light phase. Running wheel activity occurring within a 3h window immediately prior to actual or anticipated food delivery was operationally-defined as food anticipatory activity (FAA). After the timed-feeding interval, hamsters were fed ad libitum, and FAA was assessed 2 and 7 days later via probe trials of total food deprivation. During timed-feeding, all hamsters exhibited increases FAA, but FAA emerged more rapidly in SD; in probe trials, FAA was greater in magnitude and persistence in SD. Gonadectomy in LD did not induce the SD-like FAA phenotype, indicating that withdrawal of gonadal hormones is not sufficient to mediate the effects of photoperiod on FAA. Entrainment of the circadian system to light markedly affects the functional output of the FEO via gonadal hormone-independent mechanisms. Rapid emergence and persistent expression of FAA in SD may reflect a seasonal adaptation that directs behavior toward sources of nutrition with high temporal precision at times of year when food is scarce.

  18. Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections.

    OpenAIRE

    Stoop, Ron; Conquet, François; Zuber, Benoît; Voronin, Leon L.; Pralong, Etienne

    2003-01-01

    The aim of this study was to describe the induction and expression mechanisms of a persistent bursting activity in a horizontal slice preparation of the rat limbic system that includes the ventral part of the hippocampus and the entorhinal cortex. Disinhibition of this preparation by bicuculline led to interictal-like bursts in the CA3 region that triggered synchronous activity in the entorhinal cortex. Washout of bicuculline after a 1 hr application resulted in a maintained production of hip...

  19. Augmentation by interleukin-18 of MHC-nonrestricted killer activity of human peripheral blood mononuclear cells in response to interleukin-12.

    Science.gov (United States)

    Singh, S M; Yanagawa, H; Hanibuchi, M; Miki, T; Okamura, H; Sone, S

    2000-01-01

    Interleukin (IL)-18 is a novel cytokine with pleiotropic functions. In the present study, we examined the induction of the killer activity of peripheral blood mononuclear cells (MNC) against lung cancer cell lines upon treatment with IL-18 in combination with IL-12. Cytotoxic activity was measured by standard (51)Cr release assay. IL-18 (100 ng/ml) was found to significantly augment IL-12-induced killer activity in a MHC-nonrestricted manner against allogeneic NK-resistant Daudi cells and lung cancer cell lines: SBC-3, RERF-LC-AI and A549. IL-18 could augment IL-12-induced killer activity both at the optimal as well as suboptimal doses of the latter. However, IL-18 was found to have little effect on the killer activity of MNC induced by optimal or suboptimal dose of IL-2 or IL-15. Treatment of MNC with IL-18 in combination with IL-12 for a period of more than 4 days was observed to optimally induce the killer activity. As for induction of IFN-gamma production by MNC, IL-18 augmented that induced by IL-2 and IL-15, as well as that induced by IL-12. These results show the potential of IL-18 in combination with IL-12 for clinical application in treatment of cancer.

  20. Inflammation and activity augment brain-derived neurotrophic factor peripheral release.

    Science.gov (United States)

    Qiao, L Y; Shen, S; Liu, M; Xia, C; Kay, J C; Zhang, Q L

    2016-03-24

    Brain-derived neurotrophic factor (BDNF) release to nerve terminals in the central nervous system is crucial in synaptic transmission and neuronal plasticity. However, BDNF release peripherally from primary afferent neurons has not been investigated. In the present study, we show that BDNF is synthesized by primary afferent neurons located in the dorsal root ganglia (DRG) in rat, and releases to spinal nerve terminals in response to depolarization or visceral inflammation. In two-compartmented culture that separates DRG neuronal cell bodies and spinal nerve terminals, application of 50mM K(+) to either the nerve terminal or the cell body evokes BDNF release to the terminal compartment. Inflammatory stimulation of the visceral organ (e.g. the urinary bladder) also facilitates an increase in spontaneous BDNF release from the primary afferent neurons to the axonal terminals. In the inflamed viscera, we show that BDNF immunoreactivity is increased in nerve fibers that are immuno-positive to the neuronal marker PGP9.5. Both BDNF and pro-BDNF levels are increased, however, pro-BDNF immunoreactivity is not expressed in PGP9.5-positive nerve-fiber-like structures. Determination of receptor profiles in the inflamed bladder demonstrates that BDNF high affinity receptor TrkB and general receptor p75 expression levels are elevated, with an increased level of TrkB tyrosine phosphorylation/activity. These results suggest a possibility of pro-proliferative effect in the inflamed bladder. Consistently we show that the proliferation marker Ki67 expression levels are enhanced in the inflamed organ. Our results imply that in vivo BDNF release to the peripheral organ is an important event in neurogenic inflammatory state.

  1. Depressive behavior in the forced swim test can be induced by TRPV1 receptor activity and is dependent on NMDA receptors.

    Science.gov (United States)

    Abdelhamid, Ramy E; Kovács, Katalin J; Nunez, Myra G; Larson, Alice A

    2014-01-01

    Blocking, desensitizing, or knocking out transient receptor potential vanilloid type 1 (TRPV1) receptors decreases immobility in the forced swim test, a measure of depressive behavior. We questioned whether enhancing TRPV1 activity promotes immobility in a fashion that is prevented by antidepressants. To test this we activated heat-sensitive TRPV1 receptors in mice by water that is warmer than body temperature (41 °C) or a low dose of resiniferatoxin (RTX). Water at 41 °C elicited less immobility than cooler water (26 °C), indicating that thermoregulatory sites do not contribute to immobility. Although a desensitizing regimen of RTX (3-5 injections of 0.1 mg/kg s.c.) decreased immobility during swims at 26 °C, it did not during swims at 41 °C. In contrast, low dose of RTX (0.02 mg/kg s.c.) enhanced immobility, but only during swims at 41 °C. Thus, activation of TRPV1 receptors, endogenously or exogenously, enhances immobility and these sites are activated by cold rather than warmth. Two distinct types of antidepressants, amitriptyline (10mg/kg i.p.) and ketamine (50 mg/kg i.p.), each inhibited the increase in immobility induced by the low dose of RTX, verifying its mediation by TRPV1 sites. When desensitization was limited to central populations using intrathecal injections of RTX (0.25 μg/kg i.t.), immobility was attenuated at both temperatures and the increase in immobility produced by the low dose of RTX was inhibited. This demonstrates a role for central TRPV1 receptors in depressive behavior, activated by conditions (cold stress) distinct from those that activate TRPV1 receptors along thermosensory afferents (heat).

  2. Effects of Anti-NMDA Antibodies on Functional Recovery and Synaptic Rearrangement Following Hemicerebellectomy.

    Science.gov (United States)

    Laricchiuta, Daniela; Cavallucci, Virve; Cutuli, Debora; De Bartolo, Paola; Caporali, Paola; Foti, Francesca; Finke, Carsten; D'Amelio, Marcello; Manto, Mario; Petrosini, Laura

    2016-06-01

    The compensation that follows cerebellar lesions is based on synaptic modifications in many cortical and subcortical regions, although its cellular mechanisms are still unclear. Changes in glutamatergic receptor expression may represent the synaptic basis of the compensated state. We analyzed in rats the involvement of glutamatergic system of the cerebello-frontal network in the compensation following a right hemicerebellectomy. We evaluated motor performances, spatial competencies and molecular correlates in compensated hemicerebellectomized rats which in the frontal cortex contralateral to the hemicerebellectomy side received injections of anti-NMDA antibodies from patients affected by anti-NMDA encephalitis. In the compensated hemicerebellectomized rats, the frontal injections of anti-NMDA antibodies elicited a marked decompensation state characterized by slight worsening of the motor symptoms as well as severe impairment of spatial mnesic and procedural performances. Conversely, in the sham-operated group the frontal injections of anti-NMDA antibodies elicited slight motor and spatial impairment. The molecular analyses indicated that cerebellar compensatory processes were related to a relevant rearrangement of glutamatergic synapses (NMDA and AMPA receptors and other glutamatergic components) along the entire cortico-cerebellar network. The long-term maintenance of the rearranged glutamatergic activity plays a crucial role in the maintenance of recovered function.

  3. NMDA and AMPA receptors mediate intracellular calcium increase in rat cortical astrocytes

    Institute of Scientific and Technical Information of China (English)

    Bo HU; Sheng-gang SUN; E-tang TONG

    2004-01-01

    AIM: To study the effect of glutamate on the intracellular calcium signal of pure cultured rat astrocytes and the role of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in the procedure. METHODS: The fluorescence of calcium was measured by Fura-2/AM (F345/F380).RESULTS: L-Glutamate induced [Ca2+]i increase in most of the cells in concentration- and time-dependent manner.NMDA 50 mmol/L induced the fluorescence increase by almost three to four times, while the effect of AMPA 50mmol/L was just half of that of D-(-)-2-amino-5-phosphonopentanoic acid (D-AP-5; a selective antagonist of the NMDA receptor). 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selective antagonist of the AMPA receptor)abolished the effects of NMDA and AMPA, respectively. D-AP-5 and CNQX simultaneously or respectively attenuated the effect of L-glutamate at different degrees, but could not abolish it entirely. CONCLUSION: Glutamate modulated intracellular Ca2+ of pure cultured rat astrocytes through different pathways. The activation of NMDA and AMPA receptors took part in the complex mechanisms.

  4. Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin

    Science.gov (United States)

    Sachser, Ricardo Marcelo; Santana, Fabiana; Crestani, Ana Paula; Lunardi, Paula; Pedraza, Lizeth Katherine; Quillfeldt, Jorge Alberto; Hardt, Oliver; de Oliveira Alvares, Lucas

    2016-01-01

    In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca2+ channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca2+ influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time. PMID:26947131

  5. Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin.

    Science.gov (United States)

    Sachser, Ricardo Marcelo; Santana, Fabiana; Crestani, Ana Paula; Lunardi, Paula; Pedraza, Lizeth Katherine; Quillfeldt, Jorge Alberto; Hardt, Oliver; Alvares, Lucas de Oliveira

    2016-03-07

    In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca(2+) channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca(2+) influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time.

  6. ARLearn: augmented reality meets augmented virtuality

    NARCIS (Netherlands)

    Ternier, Stefaan; Klemke, Roland; Kalz, Marco; Van Ulzen, Patricia; Specht, Marcus

    2012-01-01

    Ternier, S., Klemke, R., Kalz, M., Van Ulzen, P., & Specht, M. (2012). ARLearn: augmented reality meets augmented virtuality [Special issue]. Journal of Universal Computer Science - Technology for learning across physical and virtual spaces, 18(15), 2143-2164.

  7. ARLearn: augmented reality meets augmented virtuality

    NARCIS (Netherlands)

    Ternier, Stefaan; Klemke, Roland; Kalz, Marco; Van Ulzen, Patricia; Specht, Marcus

    2012-01-01

    Ternier, S., Klemke, R., Kalz, M., Van Ulzen, P., & Specht, M. (2012). ARLearn: augmented reality meets augmented virtuality [Special issue]. Journal of Universal Computer Science - Technology for learning across physical and virtual spaces, 18(15), 2143-2164.

  8. Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers.

    Science.gov (United States)

    Mexal, S; Frank, M; Berger, R; Adams, C E; Ross, R G; Freedman, R; Leonard, S

    2005-10-03

    Nicotine is known to induce the release of multiple neurotransmitters, including glutamate and dopamine, through activation of nicotinic receptors. Gene expression in the N-methyl-d-aspartate postsynaptic density (NMDA-PSD), as well as other functional groups, was compared in postmortem hippocampus of schizophrenic and nonmentally ill smokers and nonsmokers utilizing a microarray and quantitative RT-PCR approach. The expression of 277 genes was significantly changed between all smokers and nonsmokers. Specific gene groups, most notably genes expressed in the NMDA-PSD, were prevalent among these transcripts. Analysis of the interaction between smoking and schizophrenia identified several genes in the NMDA-PSD that were differentially affected by smoking in patients. The present findings suggest that smoking may differentially modulate glutamatergic function in schizophrenic patients and control subjects. The biological mechanisms underlying chronic tobacco use are likely to differ substantially between these two groups.

  9. Mechanisms for Antagonistic Regulation of AMPA and NMDA-D1 Receptor Complexes at Postsynaptic Sites

    Science.gov (United States)

    Schumann, Johann; Scheler, Gabriele

    2004-01-01

    From the analysis of these pathways we conclude that postsynaptic processes that regulate synaptic transmission undergo significant cross-talk with respect to glutamatergic and neuromodulatory (dopamine) signals. The main hypothesis is that of a compensatory regulation, a competitive switch between the induction of increased AMPA conductance by CaMKII-dependent phosphorylation and reduced expression of PP2A, and increased D1 receptor sensitivity and expression by increased PKA, PP2A and decreased PP-1/calcineurin expression. Both types of plasticity are induced by NMDA receptor activation and increased internal calcium, they require different internal conditions to become expressed. Specifically we propose that AMPA regulation and D1 regulation are inversely coupled;The net result may be a bifurcation of synaptic state into predominantly AMPA or NMDA-D1 synapses. This could have functional consequences: stable connections for AMPA and conditional gating for NMDA-D1 synapses.

  10. Fast cortical oscillation after thalamic degeneration: pivotal role of NMDA receptor.

    Science.gov (United States)

    Kyuhou, Shin-ichi; Gemba, Hisae

    2007-04-27

    We examined electrophysiological and molecular changes of the thalamocortical system after thalamic degeneration in Purkinje cell degeneration (pcd) mice. In pcd mice, neurons in specific thalamic nuclei including the ventral medial geniculate nucleus began to degenerate around postnatal day 50, whereas the visual thalamic nucleus and nonspecific thalamic nuclei remained almost intact. In association with the morphological changes, auditory evoked potentials in the primary auditory cortex (AC) began to decrease gradually. Fast Fourier transform analysis of spontaneous cortical field potentials revealed that fast oscillation (FO) around 25 Hz occurred in the AC but not in the visual cortex. Quantitative mRNA analysis demonstrated that expression of the N-methyl-D-aspartate (NMDA) receptor was up-regulated in the AC but not in the visual cortex. Systemic administration of an NMDA antagonist abolished the FO in the AC. These results indicate that increased NMDA activity may cause the FO in the AC of pcd mice.

  11. Anti-NMDA Receptor Encephalitis and Vaccination

    Science.gov (United States)

    Wang, Hsiuying

    2017-01-01

    Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint. PMID:28106787

  12. Seizures and Anti-NMDA-Receptor Encephalitis

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2008-12-01

    Full Text Available The clinical and immunological features of 100 patients with encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor were analyzed in a study at the Children’s Hospital of Philadelphia, and University of Pennsylvania.

  13. Anti-NMDA Receptor Encephalitis and Vaccination

    Directory of Open Access Journals (Sweden)

    Hsiuying Wang

    2017-01-01

    Full Text Available Anti-N-methyl-d-aspartate (Anti-NMDA receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint.

  14. Anti-NMDA Receptor Encephalitis and Vaccination.

    Science.gov (United States)

    Wang, Hsiuying

    2017-01-18

    Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint.

  15. Alpha-synuclein promotes clathrin-mediated endocytosis of NMDA receptors in dopaminergic cells

    Institute of Scientific and Technical Information of China (English)

    Shun Yu; Furong Cheng; Xin Li; Yaohua Li; Tao Wang; Guangwei Liu; Andrius Baskys

    2012-01-01

    Loss of dopaminergic i a compensatory increase in nput to the striatum associated with Parkinson' s disease brings about glutamate release onto the dopaminergic cell bodies in the substantia nigra pars compacta (SNpc)[1] Glutamate over-activation of NMDA receptors on these cells can cause excitotoxicity and contribute to their further loss. NMDA receptor-mediated neuronal death is reduced by group I mGluR-mediated up-regulation of endocytosis protein RAB5B[2.3] Among proteins shown to interact with RAB5 proteins is a-synuclein

  16. Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes.

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    Iben Lundgaard

    2013-12-01

    Full Text Available Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.

  17. Bradykinin augments EGF-induced airway smooth muscle proliferation by activation of conventional protein kinase C isoenzymes

    NARCIS (Netherlands)

    Gosens, R; Bromhaar, MMG; Maarsingh, H; ten Damme, A; Meurs, H; Zaagsma, J; Nelemans, SA

    2006-01-01

    This study aims to investigate the effects of bradykinin, alone and in combination with growth factors on proliferation of cultured bovine tracheal smooth muscle cells. Bradykinin did not induce mitogenic responses by itself, but concentration-dependently augmented growth factor-induced [H-3]thymidi

  18. NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn

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    MacDermott Amy B

    2010-05-01

    Full Text Available Abstract Background NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter. Results Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations. Conclusions Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.

  19. Isolated NMDA receptor-mediated synaptic responses express both LTP and LTD.

    Science.gov (United States)

    Xie, X; Berger, T W; Barrionuevo, G

    1992-04-01

    1. The possibility of use-dependent, long-lasting modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission was examined by intracellular recordings from granule cells of the hippocampal dentate gyrus in vitro. In the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinaxaline-2,3-dione (CNQX, 10 microM) robust, long-term potentiation (LTP) of NMDA receptor-mediated synaptic potentials was induced by brief, high (50 Hz) and lower (10 Hz) frequency tetanic stimuli of glutamatergic afferents (60 +/- 6%, n = 8, P less than 0.001 and 43 +/- 12%, n = 3, P less than 0.05, respectively). 2. Hyperpolarization of granule cell membrane potential to -100 mV during 50-Hz tetanic stimuli reversibly blocked the induction of LTP (-6 +/- 2%, n = 6, P greater than 0.05) indicating that simultaneous activation of pre- and postsynaptic elements is a prerequisite for potentiation of NMDA receptor-mediated synaptic transmission. In contrast, hyperpolarization of the granule cell membrane potential to -100 mV during 10-Hz tetanic stimuli resulted in long-term depression (LTD) of NMDA receptor-mediated synaptic potentials (-34 +/- 8%, n = 8, P less than 0.01). 3. We also studied the role of [Ca2+]i in the induction of LTP and LTD of NMDA receptor-mediated synaptic responses. Before tetanization, [Ca2+]i was buffered by iontophoretic injections of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA). BAPTA completely blocked the induction of LTP (3 +/- 5%, n = 13) and partially blocked LTD (-14.8 +/- 6%, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Characterising seizures in anti-NMDA-receptor encephalitis with dynamic causal modelling.

    Science.gov (United States)

    Cooray, Gerald K; Sengupta, Biswa; Douglas, Pamela; Englund, Marita; Wickstrom, Ronny; Friston, Karl

    2015-09-01

    We characterised the pathophysiology of seizure onset in terms of slow fluctuations in synaptic efficacy using EEG in patients with anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis. EEG recordings were obtained from two female patients with anti-NMDA-R encephalitis with recurrent partial seizures (ages 19 and 31). Focal electrographic seizure activity was localised using an empirical Bayes beamformer. The spectral density of reconstructed source activity was then characterised with dynamic causal modelling (DCM). Eight models were compared for each patient, to evaluate the relative contribution of changes in intrinsic (excitatory and inhibitory) connectivity and endogenous afferent input. Bayesian model comparison established a role for changes in both excitatory and inhibitory connectivity during seizure activity (in addition to changes in the exogenous input). Seizures in both patients were associated with a sequence of changes in inhibitory and excitatory connectivity; a transient increase in inhibitory connectivity followed by a transient increase in excitatory connectivity and a final peak of excitatory-inhibitory balance at seizure offset. These systematic fluctuations in excitatory and inhibitory gain may be characteristic of (anti NMDA-R encephalitis) seizures. We present these results as a case study and replication to motivate analyses of larger patient cohorts, to see whether our findings generalise and further characterise the mechanisms of seizure activity in anti-NMDA-R encephalitis.

  1. NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress.

    Science.gov (United States)

    Zhu, Xinjian; Dong, Jingde; Shen, Kai; Bai, Ying; Zhang, Yuan; Lv, Xuan; Chao, Jie; Yao, Honghong

    2015-05-01

    The N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of several neurological diseases, including epilepsy. The present study investigated the effect of NMDA receptor NR2B subunits on pentylenetetrazole (PTZ)-kindling-induced pathological and biochemical events in mice. Our results showed that PTZ-kindling up-regulates the expression of NMDA receptor NR2B subunits in the hippocampus and that kindled mice were characterized by significant astrocytosis and neuron loss in the hippocampus. Oxidative stress, including excessive malondialdehyde (MDA) production and decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were detected in the hippocampus after the mice were fully kindled. Additionally, expression of brain-derived neurotrophic factor (BDNF) in the hippocampus was found to be up-regulated in PTZ-kindled mice. However, selectively blocking NMDA receptor NR2B subunits by ifenprodil significantly suppressed PTZ-kindling-induced hippocampal astrocytosis, oxidative stress and neuron loss. Furthermore, blocking NMDA receptor NR2B subunits also abolished PTZ-kindling-induced BDNF expression. These results indicate that NMDA receptor NR2B subunits contribute to epilepsy-associated pathological and biochemical events, including hippocampal astrocytosis, oxidative stress and neuron loss, and these events might be correlated with up-regulation of BDNF expression.

  2. The hippocampal NMDA receptors may be involved in acquisition, but not expression of ACPA-induced place preference.

    Science.gov (United States)

    Nasehi, Mohammad; Sharaf-Dolgari, Elmira; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2015-12-01

    Numerous studies have investigated the functional interactions between the endocannabinoid and glutamate systems in the hippocampus. The present study was made to test whether N-methyl-D-aspartate (NMDA) receptors of the CA1 region of the dorsal hippocampus (CA1) are implicated in ACPA (a selective cannabinoid CB1 receptor agonist)-induced place preference. Using a 3-day schedule of conditioning, it was found that intraperitoneal (i.p.) administration of ACPA (0.02mg/kg) caused a significant conditioned place preference (CPP) in male albino NMRI mice. Intra-CA1 microinjection of the NMDA or D-[1]-2-amino-7-Phosphonoheptanoic acid (D-AP7, NMDA receptor antagonist), failed to induce CPP or CPA (condition place aversion), while NMDA (0.5μg/mouse) potentiated the ACPA (0.01mg/kg)-induced CPP; and D-AP7 (a specific NMDA receptor antagonist; 0.5 and 1μg/mouse) reversed the ACPA (0.02mg/kg)-induced CPP. Moreover, microinjection of different doses of glutamatergic agents on the testing day did not alter the expression of ACPA-induced place preference. None of the treatments, with the exception of ACPA (0.04mg/kg), had an effect on locomotor activity. In conclusion, these observations provide evidence that glutamate NMDA receptors of the CA1 may be involved in the potentiation of ACPA rewarding properties in the acquisition, but not expression, of CPP in mice.

  3. Anti-Diabetic Activities of Jiaotaiwan in db/db Mice by Augmentation of AMPK Protein Activity and Upregulation of GLUT4 Expression

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    Na Hu

    2013-01-01

    Full Text Available Jiaotaiwan (JTW, which is composed of Coptis chinensis (CC and cinnamon (CIN, is one of the most well-known traditional Chinese medicines. In this study, we investigated the antidiabetic effects and mechanism of JTW in db/db mice. Results showed that JTW significantly decreased the level of fasting blood glucose and improved glucose and insulin tolerance better than CC or CIN alone. JTW also effectively protected the pancreatic islet shape, augmented the activation of AMP-activated protein kinase (AMPK in the liver, and increased the expression of glucose transporter 4 (GLUT4 protein in skeletal muscle and white fat. AMPK and GLUT4 contributed to glucose metabolism regulation and had an essential function in the development of diabetes mellitus (DM. Therefore, the mechanisms of JTW may be related to suppressing gluconeogenesis by activating AMPK in the liver and affecting glucose uptake in surrounding tissues through the upregulation of GLUT4 protein expression. These findings provided a new insight into the antidiabetic clinical applications of JTW and demonstrated the potential of JTW as a new drug candidate for DM treatment.

  4. Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1β.

    Science.gov (United States)

    Lee, Paul R; Johnson, Tory P; Gnanapavan, Sharmilee; Giovannoni, Gavin; Wang, Tongguang; Steiner, Joseph P; Medynets, Marie; Vaal, Mark J; Gartner, Valerie; Nath, Avindra

    2017-06-27

    The cause of neurodegeneration in progressive forms of multiple sclerosis is unknown. We investigated the impact of specific neuroinflammatory markers on human neurons to identify potential therapeutic targets for neuroprotection against chronic inflammation. Surface immunocytochemistry directly visualized protease-activated receptor-1 (PAR1) and interleukin-1 (IL-1) receptors on neurons in human postmortem cortex in patients with and without neuroinflammatory lesions. Viability of cultured neurons was determined after exposure to cerebrospinal fluid from patients with progressive multiple sclerosis or purified granzyme B and IL-1β. Inhibitors of PAR1 activation and of PAR1-associated second messenger signaling were used to elucidate a mechanism of neurotoxicity. Immunohistochemistry of human post-mortem brain tissue demonstrated cells expressing higher amounts of PAR1 near and within subcortical lesions in patients with multiple sclerosis compared to control tissue. Human cerebrospinal fluid samples containing granzyme B and IL-1β were toxic to human neuronal cultures. Granzyme B was neurotoxic through activation of PAR1 and subsequently the phospholipase Cβ-IP3 second messenger system. Inhibition of PAR1 or IP3 prevented granzyme B toxicity. IL-1β enhanced granzyme B-mediated neurotoxicity by increasing PAR1 expression. Neurons within the inflamed central nervous system are imperiled because they express more PAR1 and are exposed to a neurotoxic combination of both granzyme B and IL-1β. The effects of these inflammatory mediators may be a contributing factor in the progressive brain atrophy associated with neuroinflammatory diseases. Knowledge of how exposure to IL-1β and granzyme B act synergistically to cause neuronal death yields potential novel neuroprotective treatments for neuroinflammatory diseases.

  5. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

    Science.gov (United States)

    Levite, Mia

    2014-08-01

    Glutamate is the major excitatory neurotransmitter of the Central Nervous System (CNS), and it is crucially needed for numerous key neuronal functions. Yet, excess glutamate causes massive neuronal death and brain damage by excitotoxicity--detrimental over activation of glutamate receptors. Glutamate-mediated excitotoxicity is the main pathological process taking place in many types of acute and chronic CNS diseases and injuries. In recent years, it became clear that not only excess glutamate can cause massive brain damage, but that several types of anti-glutamate receptor antibodies, that are present in the serum and CSF of subpopulations of patients with a kaleidoscope of human neurological diseases, can undoubtedly do so too, by inducing several very potent pathological effects in the CNS. Collectively, the family of anti-glutamate receptor autoimmune antibodies seem to be the most widespread, potent, dangerous and interesting anti-brain autoimmune antibodies discovered up to now. This impression stems from taking together the presence of various types of anti-glutamate receptor antibodies in a kaleidoscope of human neurological and autoimmune diseases, their high levels in the CNS due to intrathecal production, their multiple pathological effects in the brain, and the unique and diverse mechanisms of action by which they can affect glutamate receptors, signaling and effects, and subsequently impair neuronal signaling and induce brain damage. The two main families of autoimmune anti-glutamate receptor antibodies that were already found in patients with neurological and/or autoimmune diseases, and that were already shown to be detrimental to the CNS, include the antibodies directed against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the antibodies directed against Metabotropic glutamate receptors: the anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of these anti

  6. High- and low-conductance NMDA receptors are present in layer 4 spiny stellate and layer 2/3 pyramidal neurons of mouse barrel cortex.

    Science.gov (United States)

    Scheppach, Christian

    2016-12-01

    N-Methyl-D-aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate in the mammalian brain and are important in synaptic function and plasticity, but are also found in extrasynaptic locations and influence neuronal excitability. There are different NMDA receptor subtypes which differ in their single-channel conductance. Recently, synaptic plasticity has been studied in the mouse barrel cortex, the primary sensory cortex for input from the animal's whiskers. Pharmacological data imply the presence of low-conductance NMDA receptors in spiny stellate neurons of cortical layer 4, but of high-conductance NMDA receptors in pyramidal neurons of layer 2/3. Here, to obtain complementary electrophysiological information on the functional NMDA receptors expressed in layer 4 and layer 2/3 neurons, single NMDA receptor currents were recorded with the patch-clamp method. Both cell types were found to contain high-conductance as well as low-conductance NMDA receptors. The results are consistent with the reported pharmacological data on synaptic plasticity, and with previous claims of a prominent role of low-conductance NMDA receptors in layer 4 spiny stellate neurons, including broad integration, amplification and distribution of excitation within the barrel in response to whisker stimulation, as well as modulation of excitability by ambient glutamate. However, layer 4 cells also expressed high-conductance NMDA receptors. The presence of low-conductance NMDA receptors in layer 2/3 pyramidal neurons suggests that some of these functions may be shared with layer 4 spiny stellate neurons.

  7. GABAB receptors modulate NMDA receptor calcium signals in dendritic spines.

    Science.gov (United States)

    Chalifoux, Jason R; Carter, Adam G

    2010-04-15

    Metabotropic GABA(B) receptors play a fundamental role in modulating the excitability of neurons and circuits throughout the brain. These receptors influence synaptic transmission by inhibiting presynaptic release or activating postsynaptic potassium channels. However, their ability to directly influence different types of postsynaptic glutamate receptors remains unresolved. Here we examine GABA(B) receptor modulation in layer 2/3 pyramidal neurons from the mouse prefrontal cortex. We use two-photon laser-scanning microscopy to study synaptic modulation at individual dendritic spines. Using two-photon optical quantal analysis, we first demonstrate robust presynaptic modulation of multivesicular release at single synapses. Using two-photon glutamate uncaging, we then reveal that GABA(B) receptors strongly inhibit NMDA receptor calcium signals. This postsynaptic modulation occurs via the PKA pathway and does not affect synaptic currents mediated by AMPA or NMDA receptors. This form of GABA(B) receptor modulation has widespread implications for the control of calcium-dependent neuronal function.

  8. NMDA receptors in dopaminergic neurons are crucial for habit learning.

    Science.gov (United States)

    Wang, Lei Phillip; Li, Fei; Wang, Dong; Xie, Kun; Wang, Deheng; Shen, Xiaoming; Tsien, Joe Z

    2011-12-22

    Dopamine is crucial for habit learning. Activities of midbrain dopaminergic neurons are regulated by the cortical and subcortical signals among which glutamatergic afferents provide excitatory inputs. Cognitive implications of glutamatergic afferents in regulating and engaging dopamine signals during habit learning, however, remain unclear. Here, we show that mice with dopaminergic neuron-specific NMDAR1 deletion are impaired in a variety of habit-learning tasks, while normal in some other dopamine-modulated functions such as locomotor activities, goal-directed learning, and spatial reference memories. In vivo neural recording revealed that dopaminergic neurons in these mutant mice could still develop the cue-reward association responses; however, their conditioned response robustness was drastically blunted. Our results suggest that integration of glutamatergic inputs to DA neurons by NMDA receptors, likely by regulating associative activity patterns, is a crucial part of the cellular mechanism underpinning habit learning.

  9. Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

    Energy Technology Data Exchange (ETDEWEB)

    Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki [Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Kume, Toshiaki [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Sciences, Kinki University School of Science and Engineering, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Akaike, Akinori [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Kawabata, Atsufumi, E-mail: kawabata@phar.kindai.ac.jp [Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan)

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. Black-Right-Pointing-Pointer Activation of ERK mediates the toxicity of hydrogen sulfide. Black-Right-Pointing-Pointer Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H{sub 2}S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H{sub 2}S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H{sub 2}S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.

  10. NMDA receptors in the basolateral amygdala and gustatory neophobia.

    Science.gov (United States)

    Figueroa-Guzmán, Yazmín; Reilly, Steve

    2008-05-19

    The attenuation of gustatory neophobia occurs during repeated exposures to an initially novel taste solution that is increasingly perceived as safe and familiar. The present study examined whether NMDA receptors in the basolateral region of the amygdala (BLA) are involved in this important behavioral phenomenon. The results, which show that the attenuation, but not initial occurrence, of gustatory neophobia is dependent upon NMDA receptors in the BLA, are discussed with reference to a similar finding involving NMDA receptors in the insular cortex.

  11. Anti-NMDA Receptor Encephalitis in a Pregnant Woman.

    Science.gov (United States)

    Kim, Jiyoung; Park, Seung Ha; Jung, Yu Ri; Park, Soon Won; Jung, Dae Soo

    2015-06-01

    Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is one of the most common types of autoimmune synaptic encephalitis. Anti-NMDA receptor encephalitis commonly occurs in young women with ovarian teratoma. It has variable clinical manifestations and treatment responses. Sometimes it is misdiagnosed as a psychiatric disorder or viral encephalitis. To the best of our knowledge, anti-NMDA receptor encephalitis is a rare condition in pregnant women. We report a case of anti-NMDA receptor encephalitis in a pregnant woman who presented with abnormal behavior, epileptic seizure, and hypoventilation.

  12. Influence of extremely low frequency magnetic fields on Ca2+ signaling and NMDA receptor functions in rat hippocampus.

    Science.gov (United States)

    Manikonda, Pavan K; Rajendra, P; Devendranath, D; Gunasekaran, B; Channakeshava; Aradhya, R S S; Sashidhar, R B; Subramanyam, C

    2007-02-14

    Extremely low frequency (ELFelectromagnetic fields affect several neuronal activities including memory. Because ELF magnetic fields cause altered Ca(2+) homeostasis in neural tissues, we examined their influence on Ca(2+) signaling enzymes in hippocampus and related them with NMDA receptor functions. Hippocampal regions were obtained from brains of 21-day-old rats that were exposed for 90 days to 50Hz magnetic fields at 50 and 100 microT intensities. In comparison to controls, ELF exposure caused increased intracellular Ca(2+) levels concomitant with increased activities of Ca(2+)-dependent protein kinase C (PKC), cAMP-dependent protein kinase and calcineurin as well as decreased activity of Ca(2+)-calmodulin-dependent protein kinase in hippocampal regions. Simultaneous ligand-binding studies revealed decreased binding to N-methyl-D-aspartic acid (NMDA) receptors. The combined results suggest that perturbed neuronal functions caused by ELF exposure may involve altered Ca(2+) signaling events contributing to aberrant NMDA receptor activities.

  13. Contribution of NMDA receptor-mediated component to the EPSP in mouse Schaffer collateral synapses under single pulse stimulation protocol.

    Science.gov (United States)

    Neagu, Bogdan; Strominger, Norman L; Carpenter, David O

    2008-11-13

    The degree to which NMDA receptors contribute to hippocampal CA(1) stratum radiatum excitatory postsynaptic potentials (EPSP) is a matter of debate. This experiment was designed to resolve the issue by documenting and positively identifying the elements of the NMDA dependent component in the extracellularly recorded stratum radiatum CA(1) field potential under low stimulation conditions and in the presence of physiologic levels of Mg(2+). We show that EPSP generation consists of activation of both AMPA and NMDA receptor channels, which mediate distinct components of the recorded field potential. We propose that the EPSP is a combination of two waves rather than one, which sometimes has been attributed to the exclusive activation of AMPA channels. Our data suggest that the three recorded peaks signify different events. The first peak reflects the presynaptic volley while the other two represent the actual EPSP. The first peak of the EPSP is determined mainly by flow of ions through AMPA channels. The second peak most likely is determined by the concurrence of two phenomena: ionic flow through NMDA channels and the source corresponding to the sink generated at the cell bodies in the pyramidal layer. The NMDA dependent component was recorded when Mg(2+) was present in physiological concentrations. The presynaptic volley and second peak do not saturate over a 10-fold increase of the stimulation charge and their amplitudes are highly correlated. The first peak amplitude rapidly saturates. The sensitivity of the recorded signals is different, the first peak being the most sensitive (1.25-0.26 mV/nC). Isolation of NMDA dependent components under physiological conditions when using a single pulse low stimulation protocol would allow more precise investigations of the NMDA dependent forms of synaptic plasticity.

  14. Augmented activity of the pelvic nerve afferent mediated by TRP channels in dextran sulfate sodium (DSS)-induced colitis of rats.

    Science.gov (United States)

    Makimura, Yukitoshi; Ito, Koichi; Kuwahara, Masayoshi; Tsubone, Hirokazu

    2012-08-01

    Enteritis has been recognized as a major symptom in domestic animals and human patients suffering from feed and food poisonings. The aim of the present study was to clarify the excitatory mechanism of the pelvic nerve afferent which may influence the occurrence of enteritis in response to nociceptive chemical stimuli of the colon in normal and abnormal rats with colitis induced by dextran sulfate sodium (DSS). The pelvic nerve afferent activity was markedly increased by colonic instillation of solution (0.5 ml) of acetic acid (5-25%) and capsaicin (100 μg/ml). The nerve activity was augmented by colonic instillation of capsaicin to a greater extent in rats with DSS-induced colitis than in normal control rats. This augmented activity by capsaicin was more prominent at one day (DSS-1) than at 8 day (DSS-8) after the administration of DSS. The increased nerve activity caused by capsaicin in DSS-1 and DSS-8 was significantly inhibited by pretreatment with ruthenium red, which is a nonselective inhibitor of TRP channels of unmyelinated C-fibers (nociceptors). In conclusion, it was elucidated that the nociceptive function of the pelvic nerve was largely elevated at one day after DSS-induced colitis and such increased function was mostly mediated by TRP channels.

  15. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Directory of Open Access Journals (Sweden)

    Elena eNosyreva

    2014-12-01

    Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

  16. Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K. (Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ (USA))

    1990-01-01

    8319, ((+-)-2-Amino-N-ethyl-alpha- (3-methyl-2-thienyl) benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced (3H) TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.

  17. Lead exposure impairs NMDA agonist-induced no production in pyramidal hippocampal cells

    Directory of Open Access Journals (Sweden)

    Seyed Nasser Ostad

    2006-03-01

    Full Text Available Chronic exposure to Lead (Pb affects neural functions in central nervous system (CNS particularly the learning and memory. On the other hand, alteration of calcium level in the CNS results in activation of NOS where it is expected to increase nitric oxide level in hippocampus. In this study the role of Lead exposure in NMDA induced NO production in pyramidal hippocampal cells (CA1HP was investigated. The NO level was determined by measurement of concentration of nitrite and nitrate as NO products using the metHb production at 401 nm. The ACBD (NMDA agonist-induced NO level was almost reduced to the control level (2.5 nM in the presence of 10 and 100 nM of Lead acetate. Lead acetate at concentrations which normally results in chronic toxicity did not increase the nitric oxide (NO production by CA1HP. One reason for this finding could be the interaction of Lead with NMDA receptors due to similarity of Pb2+ to Zn2+ ion. Another reason may be related to direct interaction of Lead with NMDA receptors that inhibit the stimulated NO production.

  18. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia

    Directory of Open Access Journals (Sweden)

    Colin Kehrer

    2008-04-01

    Full Text Available Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDAreceptor subtype in the etiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation-inhibition (E/I balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.

  19. NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

    Energy Technology Data Exchange (ETDEWEB)

    Tao-Cheng, Jung-Hwa [EM Facility, NINDS, NIH, Bethesda, MD (United States); Yang, Yijung [Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD (United States); Bayer, K. Ulrich [Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO (United States); Reese, Thomas S. [Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD (United States); Dosemeci, Ayse, E-mail: dosemeca@ninds.nih.gov [Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD (United States)

    2014-07-18

    Highlights: • NMDA-induces accumulation of Shank at the postsynaptic density. • Shank accumulation is preferential to the distal region of the postsynaptic density. • Shank accumulation is mediated by CaMKII. - Abstract: Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7–10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm.

  20. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

  1. BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A2A receptor is involved.

    Science.gov (United States)

    Martire, Alberto; Pepponi, Rita; Domenici, Maria Rosaria; Ferrante, Antonella; Chiodi, Valentina; Popoli, Patrizia

    2013-04-01

    NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2 ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs. In corticostriatal slices from wild-type mice and age-matched symptomatic R6/2 mice (a model of HD), NMDA application (75 μM) induced a transient or a permanent (i.e., toxic) reduction of field potential amplitude, respectively. BDNF (10 ng/mL) potentiated NMDA effects in wild-type, while it protected from NMDA toxicity in R6/2 mice. Both effects of BDNF were prevented by A2 AR blockade. The protective effect of BDNF against NMDA-induced toxicity was reproduced in a cellular model of HD. These findings may have very important implications for the neuroprotective potential of BDNF and A2 AR ligands in HD.

  2. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Science.gov (United States)

    Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul

    2013-01-01

    Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to

  3. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Directory of Open Access Journals (Sweden)

    Charles eDucrot

    2013-10-01

    Full Text Available Previous studies have shown that blockade of ventral midbrain (VM glutamate N-Methyl-D-Aspartate (NMDA receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VM neurons, a fast and short lasting depolarisation mediated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VM neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VM neuronal activity, we studied the effects of VM AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for two hours after bilateral VM microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(fquinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5ul/side and of a single dose (0.825 nmol/0.5ul/side of the NMDA antagonist, PPPA (2R,4S-4-(3-Phosphonopropyl-2-piperidinecarboxylic acid. NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VM sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected respectively into the anterior and posterior VM. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VM neurons, to modulate

  4. Effects of augmented trunk stabilization with external compression support on shoulder and scapular muscle activity and maximum strength during isometric shoulder abduction.

    Science.gov (United States)

    Jang, Hyun-jeong; Kim, Suhn-yeop; Oh, Duck-won

    2015-04-01

    The aim of the present study was to investigate the effects of augmented trunk stabilization with external compression support (ECS) on the electromyography (EMG) activity of shoulder and scapular muscles and shoulder abductor strength during isometric shoulder abduction. Twenty-six women volunteered for the study. Surface EMG was used to monitor the activity of the upper trapezius (UT), lower trapezius (LT), serratus anterior (SA), and middle deltoid (MD), and shoulder abductor strength was measured using a dynamometer during three experimental conditions: (1) no external support (condition-1), (2) pelvic support (condition-2), and (3) pelvic and thoracic supports (condition-3) in an active therapeutic movement device. EMG activities were significantly lower for UT and higher for MD during condition 3 than during condition 1 (p Shoulder abductor strength was significantly higher during condition 3 than during condition 1 (p muscle effort of the UT during isometric shoulder abduction and increasing shoulder abductor strength. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Augmented Reality in Astrophysics

    CERN Document Server

    Vogt, Frédéric P A

    2013-01-01

    Augmented Reality consists of merging live images with virtual layers of information. The rapid growth in the popularity of smartphones and tablets over recent years has provided a large base of potential users of Augmented Reality technology, and virtual layers of information can now be attached to a wide variety of physical objects. In this article, we explore the potential of Augmented Reality for astrophysical research with two distinct experiments: (1) Augmented Posters and (2) Augmented Articles. We demonstrate that the emerging technology of Augmented Reality can already be used and implemented without expert knowledge using currently available apps. Our experiments highlight the potential of Augmented Reality to improve the communication of scientific results in the field of astrophysics. We also present feedback gathered from the Australian astrophysics community that reveals evidence of some interest in this technology by astronomers who experimented with Augmented Posters. In addition, we discuss p...

  6. NMDA-Dependent Switch of proBDNF Actions on Developing GABAergic Synapses

    Science.gov (United States)

    Langlois, Anais; Diabira, Diabe; Ferrand, Nadine; Porcher, Christophe

    2013-01-01

    The brain-derived neurotrophic factor (BDNF) has emerged as an important messenger for activity-dependent development of neuronal network. Recent findings have suggested that a significant proportion of BDNF can be secreted as a precursor (proBDNF) and cleaved by extracellular proteases to yield the mature form. While the actions of proBDNF on maturation and plasticity of excitatory synapses have been studied, the effect of the precursor on developing GABAergic synapses remains largely unknown. Here, we show that regulated secretion of proBDNF exerts a bidirectional control of GABAergic synaptic activity with NMDA receptors driving the polarity of the plasticity. When NMDA receptors are activated during ongoing synaptic activity, regulated Ca2+-dependent secretion of proBDNF signals via p75NTR to depress GABAergic synaptic activity, while in the absence of NMDA receptors activation, secreted proBDNF induces a p75NTR-dependent potentiation of GABAergic synaptic activity. These results revealed a new function for proBDNF-p75NTR signaling in synaptic plasticity and a novel mechanism by which synaptic activity can modulate the development of GABAergic synaptic connections. PMID:22510533

  7. Cholesterol modulates open probability and desensitization of NMDA receptors

    Science.gov (United States)

    Korinek, Miloslav; Vyklicky, Vojtech; Borovska, Jirina; Lichnerova, Katarina; Kaniakova, Martina; Krausova, Barbora; Krusek, Jan; Balik, Ales; Smejkalova, Tereza; Horak, Martin; Vyklicky, Ladislav

    2015-01-01

    NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the CNS. Although these receptors are in direct contact with plasma membrane, lipid–NMDAR interactions are little understood. In the present study, we aimed at characterizing the effect of cholesterol on the ionotropic glutamate receptors. Whole-cell current responses induced by fast application of NMDA in cultured rat cerebellar granule cells (CGCs) were almost abolished (reduced to 3%) and the relative degree of receptor desensitization was increased (by seven-fold) after acute cholesterol depletion by methyl-β-cyclodextrin. Both of these effects were fully reversible by cholesterol repletion. By contrast, the responses mediated by AMPA/kainate receptors were not affected by cholesterol depletion. Similar results were obtained in CGCs after chronic inhibition of cholesterol biosynthesis by simvastatin and acute enzymatic cholesterol degradation to 4-cholesten-3-one by cholesterol oxidase. Fluorescence anisotropy measurements showed that membrane fluidity increased after methyl-β-cyclodextrin pretreatment. However, no change in fluidity was observed after cholesterol enzymatic degradation, suggesting that the effect of cholesterol on NMDARs is not mediated by changes in membrane fluidity. Our data show that diminution of NMDAR responses by cholesterol depletion is the result of a reduction of the open probability, whereas the increase in receptor desensitization is the result of an increase in the rate constant of entry into the desensitized state. Surface NMDAR population, agonist affinity, single-channel conductance and open time were not altered in cholesterol-depleted CGCs. The results of our experiments show that cholesterol is a strong endogenous modulator of NMDARs. Key points NMDA receptors (NMDARs) are tetrameric cation channels permeable to calcium; they mediate excitatory synaptic transmission in the CNS and their excessive activation can lead to

  8. Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

    Directory of Open Access Journals (Sweden)

    Ayako Kumagai

    2014-12-01

    Full Text Available Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds.

  9. Evaluation of agonist selectivity for the NMDA receptor ion channel in bilayer lipid membranes based on integrated single-channel currents.

    Science.gov (United States)

    Hirano, A; Sugawara, M; Umezawa, Y; Uchino, S; Nakajima-Iijima, S

    2000-06-01

    A new method for evaluating chemical selectivity of agonists to activate the N-methyl-D-aspartate (NMDA) receptor was presented by using typical agonists NMDA, L-glutamate and (2S, 3R, 4S)-2-(carboxycyclopropyl)glycine (L-CCG-IV) and the mouse epsilon1/zeta1 NMDA receptor incorporated in bilayer lipid membranes (BLMs) as an illustrative example. The method was based on the magnitude of an agonist-induced integrated single-channel current corresponding to the number of total ions passed through the open channel. The very magnitudes of the integrated single-channel currents were compared with the different BLMs as a new measure of agonist selectivity. The epsilon1/zeta1 NMDA receptor was partially purified from Chinese hamster ovary (CHO) cells expressing the epsilon1/zeta1 NMDA receptor and incorporated in BLMs formed by the tip-dip method. The agonist-induced integrated single-channel currents were obtained at 50 microM agonist concentration, where the integrated current for NMDA was shown to reach its saturated value. The obtained integrated currents were found to be (4.5 +/- 0.55) x 10(-13) C/s for NMDA, (5.8 +/- 0.72) x 10(-13) C/s for L-glutamate and (6.6 +/- 0.61) x 10(-13) C/s for L-CCG-IV, respectively. These results suggest that the agonist selectivity in terms of the total ion flux through the single epsilon1/zeta1 NMDA receptor is in the order of L-CCG-IV approximately = L-glutamate > NMDA.

  10. NMDA Receptor Modulators in the Treatment of Drug Addiction.

    Science.gov (United States)

    Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster

    2013-02-06

    Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  11. LOCALIZATION OF NMDA AND AMPA RECEPTORS IN RAT BARREL FIELD

    NARCIS (Netherlands)

    JAARSMA, D; SEBENS, JB; KORF, J

    1991-01-01

    The aim of this study was to asses the distribution of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) receptors in the barrel field of rat primary somatosensory (SI) cortex using light-microscopic in vitro autoradiography. NMDA receptors were labeled

  12. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Directory of Open Access Journals (Sweden)

    M. Foster Olive

    2013-02-01

    Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  13. Anti-NMDA-receptor antibody encephalitis in infants

    Directory of Open Access Journals (Sweden)

    Amr A. Matoq

    2015-01-01

    Conclusion: Infants with anti-NMDA-receptor antibody encephalitis can present with frank seizures or seizure mimics. Regardless, prompt recognition and aggressive treatment of anti-NMDA-receptor antibody encephalitis, while challenging, can quickly arrest deterioration and hasten recovery, thereby, limiting neurological morbidity.

  14. N-Methyl D-Aspartic Acid (NMDA Receptors and Depression

    Directory of Open Access Journals (Sweden)

    Enver Yusuf Sivrioglu

    2009-06-01

    Full Text Available The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more

  15. NOC/oFQ and NMDA contribute to piglet hypoxic ischemic hypotensive cerebrovasodilation impairment.

    Science.gov (United States)

    Armstead, William M

    2002-05-01

    Previous studies have observed that hypotensive pial artery dilation was blunted after hypoxia-ischemia. In unrelated studies, the opioid nociceptin/orphanin FQ (NOC/oFQ) was observed to contribute to hypoxic ischemic impairment of N-methyl-D-aspartate (NMDA)-induced pial dilation. This study determined the contribution of NOC/oFQ and NMDA to hypoxic ischemic hypotensive cerebrovasodilation impairment in newborn pigs equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased PO(2) to 33 +/- 3 mm Hg. Topical NOC/oFQ (10(-10) M), the cerebrospinal fluid concentration after hypoxia-ischemia, had no effect on pial artery diameter by itself but attenuated hypotension (mean arterial blood pressure decrease of 44 +/- 2%) -induced pial artery dilation (35 +/- 2% versus 22 +/- 3%). Hypotensive pial artery dilation was blunted by hypoxia-ischemia, but such dilation was partially protected by pretreatment with the putative NOC/oFQ receptor antagonist, [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M; 29 +/- 2%, sham control; 7 +/- 2%, hypoxia-ischemia; and 13 +/- 2%, hypoxia-ischemia and [F/G] NOC/oFQ (1-13) NH(2)). Coadministration of the NMDA antagonist MK801 (10(-5) M) with NOC/oFQ(10(-10) M) partially prevented hypotensive pial dilation impairment. Similarly, pretreatment with MK801 partially protected hypoxic ischemia impairment of hypotensive pial dilation (35 +/- 2%, sham control; 7 +/- 1%, hypoxia-ischemia; 22 +/- 2%, hypoxia-ischemia + MK801). These data show that NOC/oFQ and NMDA contribute to hypoxic ischemic hypotensive cerebrovasodilation impairment. These data suggest that NOC/oFQ modulation of NMDA vascular activity also contributes to such hypotensive impairment.

  16. Neuroprotection, excitotoxicicity and nmda antagonists Neuroproteção, excitotoxicidade e antagonistas do NMDA

    Directory of Open Access Journals (Sweden)

    RUBENS JOSÉ GAGLIARDI

    2000-06-01

    Full Text Available PURPOSE: To analyze the main aspects of neuroprotection and excitotoxicity. DISCUSSION: This is a significant theory on the pathophysiology of cerebral ischemia; it is based on the release of excitatory aminoacid (EAA, mainly glutamate. The sequence starts with a decrease of the blood flow and ends in neuronal death. The main stages of this reaction are herein presented and discussed. An in depth study of the effects of the excessive intracellular calcium is undertaken. Neuroprotectors (NP are a group of drugs that reduce the excitotoxicity, opposing the excessive release of EAA and its intracellular effects. Neuroprotectors represent a rational approach to stroke treatment and offer a number of potential advantages. They prevent or limit ischemia-induced damage. CONCLUSION: There are many experimental and clinical NP trials. A minimum of 800 trials are currently under study worldwide. The most important NP subgroups are: N-methyl D-aspartate (NMDA antagonists, gamma-amino butyric acid (GABA agonists, amino-hydroxy-methyl-isoxalone propionic acid (AMPA antagonists, reducers of intracellular Ca++ inhibitors of nitric oxide modulation pathway free radicals scavengers, sodium channel antagonists, glutamate release inhibitor, growth factors, hypothermia and potassium channel activators.PROPÓSITO: Analisar importantes aspectos da neuroproteção e da excitotoxicidade. DISCUSSÃO: Excitotoxicidade é teoria que explica os mecanismos básicos da fisiopatologia da isquemia cerebral; é baseada na liberação excessiva de amino-ácidos excitatórios (AAE, principalmente o glutamato. A sequência se inicia com o decréscimo do fluxo sanguíneo cerebral e termina com a morte neuronal. Os principais aspectos desta cadeia de reações são apresentados e discutidos. Os efeitos do excesso de cálcio intracelular são analisados. Neuroprotetores (NP são um grupo de drogas que reduzem a excitotoxicidade combatendo a excessiva liberação de AAE e os seus

  17. Inductively Coupled Augmented Railgun

    CERN Document Server

    Bahder, Thomas B

    2011-01-01

    We derive the non-linear dynamical equations for an augmented electromagnetic railgun, whose augmentation circuit is inductively coupled to the gun circuit. We solve these differential equations numerically using example parameter values. We find a complicated interaction between the augmentation circuit, gun circuit, and mechanical degrees of freedom, leading to a complicated optimization problem. For certain values of parameters, we find that an augmented electromagnetic railgun has an armature kinetic energy that is 42% larger than the same railgun with no augmentation circuit. Optimizing the parameters may lead to further increase in performance.

  18. Mental Workload and Situational Awareness Evaluation of APR1400 Engineered Safety Features- Component Control Activation Systems using Augmented Reality

    Energy Technology Data Exchange (ETDEWEB)

    Murungi, Mwongeera; Jung, JaeCheon [KEPCO International Nuclear Graduate School, Ulsan (Korea, Republic of)

    2016-10-15

    In the study, an Augmented Reality procedure guidance support system concept was designed and used as a tool for the measurement of mental workload and Situational awareness of an SRO (Senior Reactor Operator). The EOP was chosen as the scenario for testing because it is the one of the critical plant conditions that requires human intervention and it represents (one of the more) conservative approaches to the test scenarios that are possible. The system is expected to realize an improvement in the level of Situational Awareness and mental workload which have been demonstrated by previous studies to be directly linked with the system response to an emergency situation in the MCR. The planning and design of the project adhered to a Systems Engineering approach in order to provide an optimized framework for ensuring the successful implementation of the system design. Previous study and research into this topic has emphasized the importance of situational awareness in determining the human factor performance issues in the nuclear power plant Control Room operations. This paper broadly defined a technique that successfully used the operator’s mental workload (using NASATLX) and Situational Awareness (using SART) as quantifying measures to evaluate the performance of specific ESF-CCS functions based on human factors. These results show that an improvement of the SA/workload could lead to an improvement of the level of certainty that the emergency situation can be brought under control. It is expected that future development work in this area will yield an actualized Augmented Reality system that could incorporate MCR team control and possibly be implemented in the system validation of other I and C systems.

  19. On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Karlie N. Fedder

    2015-12-01

    Full Text Available Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases.

  20. NMDA and PACAP receptor signaling interact to mediate retinal-induced scn cellular rhythmicity in the absence of light.

    Directory of Open Access Journals (Sweden)

    Ian C Webb

    Full Text Available The "core" region of the suprachiasmatic nucleus (SCN, a central clock responsible for coordinating circadian rhythms, shows a daily rhythm in phosphorylation of extracellular regulated kinase (pERK. This cellular rhythm persists under constant darkness and, despite the absence of light, is dependent upon inputs from the eye. The neural signals driving this rhythmicity remain unknown and here the roles of glutamate and PACAP are examined. First, rhythmic phosphorylation of the NR1 NMDA receptor subunit (pNR1, a marker for receptor activation was shown to coincide with SCN core pERK, with a peak at circadian time (CT 16. Enucleation and intraocular TTX administration attenuated the peak in the pERK and pNR1 rhythms, demonstrating that activation of the NMDA receptor and ERK in the SCN core at CT16 are dependent on retinal inputs. In contrast, ERK and NR1 phosphorylation in the SCN shell region were unaffected by these treatments. Intraventricular administration of the NMDA receptor antagonist MK-801 also attenuated the peak in SCN core pERK, indicating that ERK phosphorylation in this region requires NMDA receptor activation. As PACAP is implicated in photic entrainment and is known to modulate glutamate signaling, the effects of a PAC1 receptor antagonist (PACAP 6-38 on SCN core pERK and pNR1 also were examined. PACAP 6-38 administration attenuated SCN core pERK and pNR1, suggesting that PACAP induces pERK directly, and indirectly via a modulation of NMDA receptor signaling. Together, these data indicate that, in the absence of light, retinal-mediated NMDA and PAC1 receptor activation interact to induce cellular rhythms in the SCN core. These results highlight a novel function for glutamate and PACAP release in the hamster SCN apart from their well-known roles in the induction of photic circadian clock resetting.

  1. Alterations in nigral NMDA and GABAA receptor control of the striatal dopamine level after repetitive exposures to nitrogen narcosis.

    Science.gov (United States)

    Lavoute, Cécile; Weiss, Michel; Rostain, Jean-Claude

    2008-07-01

    Nitrogen pressure exposure in rats results in decreased dopamine (DA) release at the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, demonstrating the narcotic potency of nitrogen. This effect is attributed to decreased excitatory and increased inhibitory inputs to dopaminergic neurons, involving a change in NMDA and GABA(A) receptor function. We investigated whether repetitive exposures to nitrogen modify the excitatory and inhibitory control of the dopaminergic nigro-striatal pathway. We used voltammetry to measure dopamine levels in freely-moving rats, implanted with dopamine-sensitive electrodes in the striatum. NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) were administered through a guide-cannula into the SNc, and their effects on striatal dopamine levels were measured under normobaric conditions, before and after five repetitive exposures to 1 MPa nitrogen. NMDA-mediated dopamine release was greater following repetitive exposures, AP7-mediated inhibition of glutamatergic input was blocked, suggesting that NMDA receptor sensitivity was increased and glutamate release reduced. Muscimol did not modify dopamine levels following repetitive exposures, whereas the effect of gabazine was greater after exposures than before. This suggested that interneuronal GABA(A) receptors were desensitized, leading to an increased GABAergic input at dopaminergic cells. Thus, repetitive nitrogen exposure induced persistent changes in glutamatergic and GABAergic control of dopaminergic neurons, resulting in decreased activity of the nigrostriatal pathway.

  2. NMDA and non-NMDA receptor gene expression following global brain ischemia in rats: effect of NMDA and non-NMDA receptor antagonists.

    Science.gov (United States)

    Pellegrini-Giampietro, D E; Pulsinelli, W A; Zukin, R S

    1994-03-01

    Transient forebrain or global ischemia in rats induces selective and delayed damage of hippocampal CA1 neurons. In a previous study, we have shown that expression of GluR2, the kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that governs Ca2+ permeability, is preferentially reduced in CA1 at a time point preceding neuronal degeneration. Postischemic administration of the selective AMPA receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), protects CA1 neurons against delayed death. In this study we examined the effects of NBQX (at a neuroprotective dose) and of MK-801 (a selective NMDA receptor antagonist, not protective in this model) on kainate/AMPA receptor gene expression changes after global ischemia. We also examined the effects of transient forebrain ischemia on expression of the NMDA receptor subunit NMDAR1. In ischemic rats treated with saline, GluR2 and GluR3 mRNAs were markedly reduced in CA1 but were unchanged in CA3 or dentate gyrus. GluR1 and NMDAR1 mRNAs were not significantly changed in any region examined. Administration of NBQX or MK-801 did not alter the ischemia-induced changes in kainate/AMPA receptor gene expression. These findings suggest that NBQX affords neuroprotection by a direct blockade of kainate/AMPA receptors, rather than by a modification of GluR2 expression changes.

  3. The gain of the baroreflex bradycardia is reduced by microinjection of NMDA receptor antagonists into the nucleus tractus solitarii of awake rats.

    Science.gov (United States)

    Frigero, M; Bonagamba, L G; Machado, B H

    2000-02-14

    The baroreflex activation with phenylephrine infusion produces a bradycardic response. In the present study, the role of NMDA receptors in the nucleus tractus solitarii (NTS) in the processing of the parasympathetic component of the baroreflex was evaluated using acid phosphonivaleric (AP-5), a selective NMDA receptor antagonist. Baroreflex activation was performed before and after bilateral microinjection of AP-5 into the intermediate commissural NTS (0.5 mm lateral to the midline). Microinjection of the vehicle (saline, 0.9%) or a dose of 2 nmol/50 nl of AP-5 into the NTS produced no effect on the gain of the baroreflex while a dose of 10 nmol/50 nl of AP-5 produced a significant reduction in the gain of the baroreflex 2 min after microinjection [-1.43+/-0.22 vs. -0. 43+/-0.03 bpm/mmHg, (n=6)], with a return to control levels 10 min after the microinjections. The dose of 10 nmol/50 nl was selective for NMDA receptors considering that the cardiovascular responses to microinjection of AMPA (0.05 pmol/50 nl), a non-NMDA receptor agonist, were not affected by this dose of AP-5 and the responses to microinjection of NMDA (2 nmol/50 nl) were blocked. The data show that the bradycardic response to baroreflex activation was blocked by AP-5 microinjected into the NTS, indicating that the neurotransmission of the parasympathetic component of the baroreflex is mediated by NMDA receptors in the NTS.

  4. Blockade of cannabinoid CB receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity

    DEFF Research Database (Denmark)

    Hansen, H.H.; Ramos, J.A.; Fernández-Ruiz, J.

    2002-01-01

    The ability of cannabinoid CB, receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB...... receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB/CB receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB and SR144528 for CB) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA......-induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB receptor function. In contrast, blockade of CB, but not CB, receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest...

  5. Restoration of adenylate cyclase responsiveness in murine myeloid leukemia permits inhibition of proliferation by hormone. Butyrate augments catalytic activity of adenylate cyclase.

    Science.gov (United States)

    Inhorn, L; Fleming, J W; Klingberg, D; Gabig, T G; Boswell, H S

    1988-04-01

    Mechanisms of leukemic cell clonal dominance may include aberrations of transmembrane signaling. In particular, neoplastic transformation has been associated with reduced capacity for hormone-stimulated adenylate cyclase activity. In the present study, prostaglandin E, a hormonal activator of adenylate cyclase that has antiproliferative activity in myeloid cells, and cholera toxin, an adenylate cyclase agonist that functions at a postreceptor site by activating the adenylate cyclase stimulatory GTP-binding protein (Gs), were studied for antiproliferative activity in two murine myeloid cell lines. FDC-P1, an interleukin 3 (IL 3)-dependent myeloid cell line and a tumorigenic IL 3-independent subline, FI, were resistant to these antiproliferative agents. The in vitro ability of the "differentiation" agent, sodium butyrate, to reverse their resistance to adenylate cyclase agonists was studied. The antiproliferative action of butyrate involved augmentation of transmembrane adenylate cyclase activity. Increased adenylate cyclase catalyst activity was the primary alteration of this transmembrane signaling group leading to the functional inhibitory effects on leukemia cells, although alterations in regulatory G-proteins appear to play a secondary role.

  6. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

    OpenAIRE

    Anticevic, Alan; Repovš, Grega

    2015-01-01

    however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brainʼs global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this di...

  7. Comparison of excitotoxic profiles of ATPA, AMPA, KA and NMDA in organotypic hippocampal slice cultures.

    Science.gov (United States)

    Kristensen, B W; Noraberg, J; Zimmer, J

    2001-10-26

    The excitotoxic profiles of (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid (ATPA), (RS)-2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainic acid (KA) and N-methyl-D-aspartate (NMDA) were evaluated using cellular uptake of propidium iodide (PI) as a measure for induced, concentration-dependent neuronal damage in hippocampal slice cultures. ATPA is in low concentrations a new selective agonist of the glutamate receptor subunit GluR5 confined to KA receptors and also in high concentrations an AMPA receptor agonist. The following rank order of estimated EC(50) values was found after 2 days of exposure: AMPA (3.7 mM)>NMDA (11 mM)=KA (13 mM)>ATPA (33 mM). Exposed to 30 microM ATPA, 3 microM AMPA and 10 microM NMDA, CA1 was the most susceptible subfield followed by fascia dentata and CA3. Using 8 microM KA, CA3 was the most susceptible subfield, followed by fascia dentata and CA1. In 100 microM concentrations, all four agonists induced the same, maximal PI uptake in all hippocampal subfields, corresponding to total neuronal degeneration. Using glutamate receptor antagonists, like GYKI 52466, NBQX and MK-801, inhibition data revealed that AMPA excitotoxicity was mediated primarily via AMPA receptors. Similar results were found for a high concentration of ATPA (30 microM). In low GluR5 selective concentrations (0.3-3 microM), ATPA did not induce an increase in PI uptake or a reduction in glutamic acid decarboxylase (GAD) activity of hippocampal interneurons. For KA, the excitotoxicity appeared to be mediated via both KA and AMPA receptors. NMDA receptors were not involved in AMPA-, ATPA- and KA-induced excitotoxicity, nor did NMDA-induced excitotoxicity require activation of AMPA and KA receptors. We conclude that hippocampal slice cultures constitute a feasible test system for evaluation of excitotoxic effects and mechanisms of new (ATPA) and classic (AMPA, KA and NMDA) glutamate receptor agonists. Comparison of concentration

  8. Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation.

    Science.gov (United States)

    Baudy, R B; Greenblatt, L P; Jirkovsky, I L; Conklin, M; Russo, R J; Bramlett, D R; Emrey, T A; Simmonds, J T; Kowal, D M; Stein, R P

    1993-02-01

    A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.

  9. AUGMENTATION-RELATED BRAIN PLASTICITY

    Directory of Open Access Journals (Sweden)

    Giovanni eDi Pino

    2014-06-01

    Full Text Available Today, the anthropomorphism of the tools and the development of neural interfaces require reconsidering the concept of human-tools interaction in the framework of human augmentation. This review analyzes the plastic process that the brain undergoes when it comes into contact with augmenting artificial sensors and effectors and, on the other hand, the changes that the use of external augmenting devices produces in the brain.Hitherto, few studies investigated the neural correlates of augmentation, but clues on it can be borrowed from logically-related paradigms: sensorimotor training, cognitive enhancement, cross-modal plasticity, sensorimotor functional substitution, use and embodiment of tools.Augmentation modifies function and structure of a number of areas, i.e. primary sensory cortices shape their receptive fields to become sensitive to novel inputs. Motor areas adapt the neuroprosthesis representation firing-rate to refine kinematics. As for normal motor outputs, the learning process recruits motor and premotor cortices and the acquisition of proficiency decreases attentional recruitment, focuses the activity on sensorimotor areas and increases the basal ganglia drive on the cortex. Augmentation deeply relies on the frontoparietal network. In particular, premotor cortex is involved in learning the control of an external effector and owns the tool motor representation, while the intraparietal sulcus extracts its visual features. In these areas, multisensory integration neurons enlarge their receptive fields to embody supernumerary limbs. For operating an anthropomorphic neuroprosthesis, the mirror system is required to understand the meaning of the action, the cerebellum for the formation of its internal model and the insula for its interoception. In conclusion, anthropomorphic sensorized devices can provide the critical sensory afferences to evolve the exploitation of tools through their embodiment, reshaping the body representation and the

  10. Creating augmented reality

    OpenAIRE

    Kuusisto, Raine

    2015-01-01

    Augmented reality (AR) is used in different occasions in our daily lives. The idea of an electronic display and spectacles that overlays data to people came in 1901. Augmented reality revolution started in 1990, it is a combination of real life and virtual reality. The beginning of AR is being examined from the very beginning of it. In 1999, it gained momentum when Hirokazu Kato published the ARToolkit to the open source community. After this, augmented reality has evolved everywhere, includi...

  11. The NMDA receptor ion channel: a site for binding of Huperzine A.

    Science.gov (United States)

    Gordon, R K; Nigam, S V; Weitz, J A; Dave, J R; Doctor, B P; Ved, H S

    2001-12-01

    Huperzine A (HUP-A), first isolated from the Chinese club moss Huperzia serrata, is a potent, reversible and selective inhibitor of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE) (Life Sci. 54: 991-997). Because HUP-A has been shown to penetrate the blood-brain barrier, is more stable than the carbamates used as pretreatments for organophosphate poisoning (OP) and the HUP-A:AChE complex has a longer half-life than other prophylactic sequestering agents, HUP-A has been proposed as a pretreatment drug for nerve agent toxicity by protecting AChE from irreversible OP-induced phosphonylation. More recently (NeuroReport 8: 963-968), pretreatment of embryonic neuronal cultures with HUP-A reduced glutamate-induced cell death and also decreased glutamate-induced calcium mobilization. These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-D-aspartate (NMDA) glutamate subtype receptor is found. We have now investigated the interaction of HUP-A with glutamate receptors. Freshly frozen cortex or synaptic plasma membranes were used, providing 60-90% specific radioligand binding. Huperzine A (< or =100 microM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist). In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo K(i) approximately 6 microM. Furthermore, when neuronal cultures were pretreated with HUP-A for 45 min prior to NMDA exposure, HUP-A dose-dependently inhibited the NMDA-induced toxicity. Although HUP-A has been implicated to interact with cholinergic receptors, it was without effect at 100 microM on muscarinic (measured by

  12. Mobile Augmented Reality Applications

    CERN Document Server

    Prochazka, David; Popelka, Ondrej; Stastny, Jiri

    2011-01-01

    Augmented reality have undergone considerable improvement in past years. Many special techniques and hardware devices were developed, but the crucial breakthrough came with the spread of intelligent mobile phones. This enabled mass spread of augmented reality applications. However mobile devices have limited hardware capabilities, which narrows down the methods usable for scene analysis. In this article we propose an augmented reality application which is using cloud computing to enable using of more complex computational methods such as neural networks. Our goal is to create an affordable augmented reality application suitable which will help car designers in by 'virtualizing' car modifications.

  13. Differential Effects of D-Cycloserine and ACBC at NMDA Receptors in the Rat Entorhinal Cortex Are Related to Efficacy at the Co-Agonist Binding Site.

    Science.gov (United States)

    Lench, Alex M; Robson, Emma; Jones, Roland S G

    2015-01-01

    Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

  14. High-mobility group Box-1 is involved in NMDA-induced retinal injury the in rat retina.

    Science.gov (United States)

    Sakamoto, Kenji; Mizuta, Aya; Fujimura, Kyosuke; Kurauchi, Yuki; Mori, Asami; Nakahara, Tsutomu; Ishii, Kunio

    2015-08-01

    High-mobility group Box-1 (HMGB1) is known to be released from injured cells and to induce an inflammatory response. Although HMGB1 was reported to mediate ischemia-reperfusion injury of the brain, its role in glutamate excitotoxicity of the retina remains controversial. Here, the authors demonstrated the evidence that HMGB1 is involved in the retinal damage induced by NMDA. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal injection of NMDA (200 nmol/eye) or HMGB1 protein derived from bovines (5-15 μg/eye). Intravitreal anti-HMGB1 IgY (5 μg/eye) was simultaneously administered with NMDA or HMGB1. Seven days later, animals were killed and 5-μm retinal sections through the optic nerve head were obtained. These specimens were subjected to morphometry. Intravitreal NMDA and HMGB1 protein evoked cell loss in the ganglion cell layer 7 days later. Intravitreal anti-HMGB1 IgY reduced these damages. Anti-HMGB1 IgY reduced the number of 8-hydroxy-deoxyguanosine (8-OHdG)-positive cells induced by intravitreal NMDA. Toll-like receptor 2/4 antagonist peptide, receptor for advanced glycation end-products (RAGE) antagonist peptide, and FPS-ZM1 significantly reduced the retinal damage induced by HMGB1 protein. The results in the present study suggest that HMGB1 is at least in part involved in NMDA-induced retinal injury, and probably induces cell death of retinal ganglion cells with increase of oxidative stress, via activation of toll-like receptor 2/4 and RAGE in the rat retina.

  15. ICAM-5 affects spine maturation by regulation of NMDA receptor binding to α-actinin

    Directory of Open Access Journals (Sweden)

    Lin Ning

    2015-01-01

    Full Text Available ICAM-5 is a negative regulator of dendritic spine maturation and facilitates the formation of filopodia. Its absence results in improved memory functions, but the mechanisms have remained poorly understood. Activation of NMDA receptors induces ICAM-5 ectodomain cleavage through a matrix metalloproteinase (MMP-dependent pathway, which promotes spine maturation and synapse formation. Here, we report a novel, ICAM-5-dependent mechanism underlying spine maturation by regulating the dynamics and synaptic distribution of α-actinin. We found that GluN1 and ICAM-5 partially compete for the binding to α-actinin; deletion of the cytoplasmic tail of ICAM-5 or ablation of the gene resulted in increased association of GluN1 with α-actinin, whereas internalization of ICAM-5 peptide perturbed the GluN1/α-actinin interaction. NMDA treatment decreased α-actinin binding to ICAM-5, and increased the binding to GluN1. Proper synaptic distribution of α-actinin requires the ICAM-5 cytoplasmic domain, without which α-actinin tended to accumulate in filopodia, leading to F-actin reorganization. The results indicate that ICAM-5 retards spine maturation by preventing reorganization of the actin cytoskeleton, but NMDA receptor activation is sufficient to relieve the brake and promote the maturation of spines.

  16. Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus

    Directory of Open Access Journals (Sweden)

    Dan Bing

    2015-03-01

    Full Text Available Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

  17. Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment.

    Directory of Open Access Journals (Sweden)

    Francesca Calabrese

    Full Text Available It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.

  18. [Transient brain ischemia: NMDA receptor modulation and delayed neuronal death].

    Science.gov (United States)

    Benquet, Pascal; Gee, Christine E; Gerber, Urs

    2008-02-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

  19. Confronting an Augmented Reality

    Science.gov (United States)

    Munnerley, Danny; Bacon, Matt; Wilson, Anna; Steele, James; Hedberg, John; Fitzgerald, Robert

    2012-01-01

    How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself ? In this article, we seek to initiate a discussion that focuses on these questions, and…

  20. Confronting an Augmented Reality

    Science.gov (United States)

    Munnerley, Danny; Bacon, Matt; Wilson, Anna; Steele, James; Hedberg, John; Fitzgerald, Robert

    2012-01-01

    How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself ? In this article, we seek to initiate a discussion that focuses on these questions, and…

  1. Augmented Spinor Space

    Institute of Scientific and Technical Information of China (English)

    Xiuhong FENG; Lin ZHU; Yanlin YU

    2007-01-01

    In this paper, based on the Pauli matrices, a notion of augmented spinor space is introduced, and a uniqueness of such augmented spinor space of rank n is proved. It may be expected that this new notion of spaces can be used in mathematical physics and geometry.

  2. Did augmenting the VERB campaign advertising in select communities have an effect on awareness, attitudes, and physical activity?

    Science.gov (United States)

    Berkowitz, Judy M; Huhman, Marian; Nolin, Mary Jo

    2008-06-01

    Although VERB was designed as a national media campaign, funding and donated media time enabled more-intensive advertising and marketing in certain communities. To investigate the effect of increased advertising on physical activity outcomes, six "high-dose" communities were selected to receive more hours of advertising and additional promotional activities. Longitudinal quasi-experimental design comparing outcomes in six communities that received additional VERB marketing activities with outcomes in a comparison group that received only the national dose of advertising. Two cohorts of dyads of youth aged 9-13 years (tweens) and one parent at baseline (2002), followed for 2 years. During the first year of the VERB campaign, each of the six high-dose communities received 50% more advertising and conducted special campaign activities. During the second year, only four of the six communities received the larger dose of advertising and additional promotional activities because of reduced funding. Awareness and understanding of VERB messages; attitudes about physical activity (self-efficacy, social influences, and outcome expectations); and physical activity behaviors. After 1 year, tweens in the high-dose communities reported higher levels of awareness and understanding of VERB and scored higher on the social influences scale than did tweens in a comparison group in areas that received only the national dose of advertising. After 2 years, tweens in the high-dose communities reported higher awareness and understanding of VERB, greater self-efficacy, more sessions of free-time physical activity per week, and were more active on the day before being surveyed than tweens in the comparison group who received the average national dose. Providing communities with a higher dose of marketing activities and sustaining those activities over time yields more positive outcomes.

  3. Convergent Transcription of Interferon-stimulated Genes by TNF-α and IFN-α Augments Antiviral Activity against HCV and HEV

    Science.gov (United States)

    Wang, Wenshi; Xu, Lei; Brandsma, Johannes H.; Wang, Yijin; Hakim, Mohamad S.; Zhou, Xinying; Yin, Yuebang; Fuhler, Gwenny M.; van der Laan, Luc J. W.; van der Woude, C. Janneke; Sprengers, Dave; Metselaar, Herold J.; Smits, Ron; Poot, Raymond A.; Peppelenbosch, Maikel P.; Pan, Qiuwei

    2016-01-01

    IFN-α has been used for decades to treat chronic hepatitis B and C, and as an off-label treatment for some cases of hepatitis E virus (HEV) infection. TNF-α is another important cytokine involved in inflammatory disease, which can interact with interferon signaling. Because interferon-stimulated genes (ISGs) are the ultimate antiviral effectors of the interferon signaling, this study aimed to understand the regulation of ISG transcription and the antiviral activity by IFN-α and TNF-α. In this study, treatment of TNF-α inhibited replication of HCV by 71 ± 2.4% and HEV by 41 ± 4.9%. Interestingly, TNF-α induced the expression of a panel of antiviral ISGs (2-11 fold). Blocking the TNF-α signaling by Humira abrogated ISG induction and its antiviral activity. Chip-seq data analysis and mutagenesis assay further revealed that the NF-κB protein complex, a key downstream element of TNF-α signaling, directly binds to the ISRE motif in the ISG promoters and thereby drives their transcription. This process is independent of interferons and JAK-STAT cascade. Importantly, when combined with IFN-α, TNF-α works cooperatively on ISG induction, explaining their additive antiviral effects. Thus, our study reveals a novel mechanism of convergent transcription of ISGs by TNF-α and IFN-α, which augments their antiviral activity against HCV and HEV. PMID:27150018

  4. The role of NMDA receptors of the medial septum and dorsal hippocampus on memory acquisition.

    Science.gov (United States)

    Khakpai, Fatemeh; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

    2016-04-01

    The glutamatergic neurons in the medial septal/diagonal band of broca (MS/DB) affect the hippocampal functions by modulating the septo-hippocampal neurons. Our study investigated the possible role of NMDA receptors of the medial septum nucleus (MS) and dorsal hippocampus (CA1) on memory acquisition in male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the MS and CA1. Rats were trained in a step-through type inhibitory avoidance task, and tested 24h after training to measure step-through latency as memory retrieval. Our results indicated that pre-training intra-MS or intra-CA1 infusions of NMDA (0.125 μg/rat) and D-AP7 (0.012 μg/rat) increased and decreased memory acquisition, respectively when compared to saline control group. Also, pre-training intra-CA1 and intra-MS injection of an effect dose of D-AP7 (0.012 μg/rat) along with an effect dose of NMDA (0.125 μg/rat) impaired memory acquisition. Interestingly, pre-training intra-CA1/MS infusion of D-AP7 (0.012 μg/rat) diminished memory response produced by pre-training injection of NMDA (0.125 μg/rat) in the MS/CA1, respectively (cross injection or bilateral injection). Also, all above doses of drugs did not alter locomotor activity. These results suggest that the glutamatergic pathway between the MS and CA1 regions is involved in memory acquisition process.

  5. Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

    Directory of Open Access Journals (Sweden)

    Roesler R.

    1998-01-01

    Full Text Available The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval. Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-µl infusion containing 5.0 µg of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5 or vehicle (phosphate-buffered saline, pH 7.4. Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean ± SEM number of conditioned responses (CRs during retention test session was 16.47 ± 1.78 in the vehicle group and 9.93 ± 1.59 in the AP5 group; P<0.05. Post-training infusion of AP5 did not affect retention (mean ± SEM number of conditioned responses during retention test session was 18.46 ± 1.94 in the vehicle group and 20.42 ± 2.38 in the AP5 group; P>0.10. This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.

  6. NMDA Receptor Antagonist Ketamine Distorts Object Recognition by Reducing Feedback to Early Visual Cortex.

    Science.gov (United States)

    van Loon, Anouk M; Fahrenfort, Johannes J; van der Velde, Bauke; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Scholte, H Steven; Lamme, Victor A F

    2016-05-01

    It is a well-established fact that top-down processes influence neural representations in lower-level visual areas. Electrophysiological recordings in monkeys as well as theoretical models suggest that these top-down processes depend on NMDA receptor functioning. However, this underlying neural mechanism has not been tested in humans. We used fMRI multivoxel pattern analysis to compare the neural representations of ambiguous Mooney images before and after they were recognized with their unambiguous grayscale version. Additionally, we administered ketamine, an NMDA receptor antagonist, to interfere with this process. Our results demonstrate that after recognition, the pattern of brain activation elicited by a Mooney image is more similar to that of its easily recognizable grayscale version than to the pattern evoked by the identical Mooney image before recognition. Moreover, recognition of Mooney images decreased mean response; however, neural representations of separate images became more dissimilar. So from the neural perspective, unrecognizable Mooney images all "look the same", whereas recognized Mooneys look different. We observed these effects in posterior fusiform part of lateral occipital cortex and in early visual cortex. Ketamine distorted these effects of recognition, but in early visual cortex only. This suggests that top-down processes from higher- to lower-level visual areas might operate via an NMDA pathway.

  7. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

    KAUST Repository

    Yang, Jiangyan

    2014-07-28

    L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.

  8. Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

    Directory of Open Access Journals (Sweden)

    Chun-Lei Zhang

    Full Text Available Methylphenidate (MPH, commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD. Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC. To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+ increase, but does not require PKA and extracellular Ca(2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

  9. Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons

    Directory of Open Access Journals (Sweden)

    Xanthi Antoniou

    2010-01-01

    Full Text Available The phosphorylation of Amyloid Precursor Protein (APP at Thr668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK, glycogen synthase kinase-3β (GSK-3β and cyclin-dependent kinase 5 (Cdk5 can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM for 30’-45’ led to an increase of P-APP Thr668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway.

  10. Scribble1/AP2 Complex Coordinates NMDA Receptor Endocytic Recycling

    Directory of Open Access Journals (Sweden)

    Nicolas H. Piguel

    2014-10-01

    Full Text Available The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.

  11. Neuromodulatory effect of Gαs- or Gαq-coupled G-protein-coupled receptor on NMDA receptor selectively activates the NMDA receptor/Ca2+/calcineurin/cAMP response element-binding protein-regulated transcriptional coactivator 1 pathway to effectively induce brain-derived neurotrophic factor expression in neurons.

    Science.gov (United States)

    Fukuchi, Mamoru; Tabuchi, Akiko; Kuwana, Yuki; Watanabe, Shinjiro; Inoue, Minami; Takasaki, Ichiro; Izumi, Hironori; Tanaka, Ayumi; Inoue, Ran; Mori, Hisashi; Komatsu, Hidetoshi; Takemori, Hiroshi; Okuno, Hiroyuki; Bito, Haruhiko; Tsuda, Masaaki

    2015-04-01

    Although coordinated molecular signaling through excitatory and modulatory neurotransmissions is critical for the induction of immediate early genes (IEGs), which lead to effective changes in synaptic plasticity, the intracellular mechanisms responsible remain obscure. Here we measured the expression of IEGs and used bioluminescence imaging to visualize the expression of Bdnf when GPCRs, major neuromodulator receptors, were stimulated. Stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor (PAC1), a Gαs/q-protein-coupled GPCR, with PACAP selectively activated the calcineurin (CN) pathway that is controlled by calcium signals evoked via NMDAR. This signaling pathway then induced the expression of Bdnf and CN-dependent IEGs through the nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1). Intracerebroventricular injection of PACAP and intraperitoneal administration of MK801 in mice demonstrated that functional interactions between PAC1 and NMDAR induced the expression of Bdnf in the brain. Coactivation of NMDAR and PAC1 synergistically induced the expression of Bdnf attributable to selective activation of the CN pathway. This CN pathway-controlled expression of Bdnf was also induced by stimulating other Gαs- or Gαq-coupled GPCRs, such as dopamine D1, adrenaline β, CRF, and neurotensin receptors, either with their cognate agonists or by direct stimulation of the protein kinase A (PKA)/PKC pathway with chemical activators. Thus, the GPCR-induced expression of IEGs in coordination with NMDAR might occur via the selective activation of the CN/CRTC1/CREB pathway under simultaneous excitatory and modulatory synaptic transmissions in neurons if either the Gαs/adenylate cyclase/PKA or Gαq/PLC/PKC-mediated pathway is activated.

  12. Augmented reality: a review.

    Science.gov (United States)

    Berryman, Donna R

    2012-01-01

    Augmented reality is a technology that overlays digital information on objects or places in the real world for the purpose of enhancing the user experience. It is not virtual reality, that is, the technology that creates a totally digital or computer created environment. Augmented reality, with its ability to combine reality and digital information, is being studied and implemented in medicine, marketing, museums, fashion, and numerous other areas. This article presents an overview of augmented reality, discussing what it is, how it works, its current implementations, and its potential impact on libraries.

  13. Augmented cystine-glutamate exchange by pituitary adenylate cyclase-activating polypeptide signaling via the VPAC1 receptor

    Science.gov (United States)

    Resch, Jon M.; Albano, Rebecca; Liu, XiaoQian; Hjelmhaug, Julie; Lobner, Doug; Baker, David A.; Choi, SuJean

    2014-01-01

    In the central nervous system, cystine import in exchange for glutamate through system xc− is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system xc− activity affects multiple aspects of cellular physiology and may contribute to disease states. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuronally-derived peptide that has already been demonstrated to modulate multiple aspects of glutamate signaling suggesting PACAP may also target activity of cystine-glutamate exchange via system xc−. In the current study, 24-hour treatment of primary cortical cultures containing neurons and glia with PACAP concentration-dependently increased system xc− function as measured by radiolabeled cystine uptake. Furthermore, the increase in cystine uptake was completely abolished by the system xc− inhibitor, (S)-4-carboxyphenylglycine (CPG), attributing increases in cystine uptake specifically to system xc− activity. Time course and quantitative PCR results indicate that PACAP signaling may increase cystine-glutamate exchange by increasing expression of xCT, the catalytic subunit of system xc−. Furthermore, the potentiation of system xc− activity by PACAP occurs via a PKA-dependent pathway that is not mediated by the PAC1R, but rather the shared vasoactive intestinal polypeptide receptor VPAC1R. Finally, assessment of neuronal, astrocytic, and microglial-enriched cultures demonstrated that only astrocyte-enriched cultures exhibit enhanced cystine uptake following both PACAP and VIP treatment. These data introduce a novel mechanism by which both PACAP and VIP regulate system xc− activity. PMID:25066643

  14. Toll-like receptor agonist augments virus-like particle-mediated protection from Ebola virus with transient immune activation.

    Directory of Open Access Journals (Sweden)

    Karen A O Martins

    Full Text Available Identifying safe and effective adjuvants is critical for the advanced development of protein-based vaccines. Pattern recognition receptor (PRR agonists are increasingly being explored as potential adjuvants, but there is concern that the efficacy of these molecules may be dependent on potentially dangerous levels of non-specific immune activation. The filovirus virus-like particle (VLP vaccine protects mice, guinea pigs, and nonhuman primates from viral challenge. In this study, we explored the impact of a stabilized dsRNA mimic, polyICLC, on VLP vaccination of C57BL/6 mice and Hartley guinea pigs. We show that at dose levels as low as 100 ng, the adjuvant increased the efficacy of the vaccine in mice. Antigen-specific, polyfunctional CD4 and CD8 T cell responses and antibody responses increased significantly upon inclusion of adjuvant. To determine whether the efficacy of polyICLC correlated with systemic immune activation, we examined serum cytokine levels and cellular activation in the draining lymph node. PolyICLC administration was associated with increases in TNFα, IL6, MCP1, MIP1α, KC, and MIP1β levels in the periphery and with the activation of dendritic cells (DCs, NK cells, and B cells. However, this activation resolved within 24 to 72 hours at efficacious adjuvant dose levels. These studies are the first to examine the polyICLC-induced enhancement of antigen-specific immune responses in the context of non-specific immune activation, and they provide a framework from which to consider adjuvant dose levels.

  15. Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors

    Science.gov (United States)

    den Hartog, Carolina R.; Gilstrap, Meghin; Eaton, Bethany; Lench, Daniel H.; Mulholland, Patrick J.; Homanics, Gregg. E.; Woodward, John J.

    2017-01-01

    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. Following repeated exposures to ethanol, these homeostatic responses may become unstable leading to an altered glutamatergic state that contributes to the escalations in drinking and cognitive deficits observed in alcohol-dependent subjects. An important unanswered question is whether ethanol-induced changes in NMDAR expression are modulated by the intrinsic sensitivity of the receptor to ethanol. In this study, we examined the effects of ethanol on NMDAR subunit expression in cortical (orbitofrontal, medial prefrontal), striatal (dorsal and ventral striatum) and limbic (dorsal hippocampus, basolateral amygdala) areas in mice genetically modified to express ethanol-resistant receptors (F639A mice). These mice have been previously shown to drink more ethanol than their wild-type counterparts and have altered behavioral responses to certain actions of ethanol. Following long-term voluntary drinking, F639A mice showed elevations in GluN2A but not GluN1 or GluN2B expression as compared to wild-type mice. Mice treated with repeated injections with ethanol (2–3.5 g/kg; i.p.) showed changes in NMDAR expression that varied in a complex manner with genotype, brain region, subunit type and exposure protocol all contributing to the observed response. F639A mice, but not wild-type mice, showed enhanced motor activity following repeated

  16. GA binding protein augments autophagy via transcriptional activation of BECN1-PIK3C3 complex genes.

    Science.gov (United States)

    Zhu, Wan; Swaminathan, Gayathri; Plowey, Edward D

    2014-09-01

    Macroautophagy is a vesicular catabolic trafficking pathway that is thought to protect cells from diverse stressors and to promote longevity. Recent studies have revealed that transcription factors play important roles in the regulation of autophagy. In this study, we have identified GA binding protein (GABP) as a transcriptional regulator of the combinatorial expression of BECN1-PIK3C3 complex genes involved in autophagosome initiation. We performed bioinformatics analyses that demonstrated highly conserved putative GABP sites in genes that encode BECN1/Beclin 1, several BECN1 interacting proteins, and downstream autophagy proteins including the ATG12-ATG5-ATG16L1 complex. We demonstrate that GABP binds to the promoter regions of BECN1-PIK3C3 complex genes and activates their transcriptional activities. Knockdown of GABP reduced BECN1-PIK3C3 complex transcripts, BECN1-PIK3C3 complex protein levels and autophagy in cultured cells. Conversely, overexpression of GABP increased autophagy. Nutrient starvation increased GABP-dependent transcriptional activity of BECN1-PIK3C3 complex gene promoters and increased the recruitment of GABP to the BECN1 promoter. Our data reveal a novel function of GABP in the regulation of autophagy via transcriptional activation of the BECN1-PIK3C3 complex.

  17. Media-Augmented Exercise Machines

    Science.gov (United States)

    Krueger, T.

    2002-01-01

    Cardio-vascular exercise has been used to mitigate the muscle and cardiac atrophy associated with adaptation to micro-gravity environments. Several hours per day may be required. In confined spaces and long duration missions this kind of exercise is inevitably repetitive and rapidly becomes uninteresting. At the same time, there are pressures to accomplish as much as possible given the cost- per-hour for humans occupying orbiting or interplanetary. Media augmentation provides a the means to overlap activities in time by supplementing the exercise with social, recreational, training or collaborative activities and thereby reducing time pressures. In addition, the machine functions as an interface to a wide range of digital environments allowing for spatial variety in an otherwise confined environment. We hypothesize that the adoption of media augmented exercise machines will have a positive effect on psycho-social well-being on long duration missions. By organizing and supplementing exercise machines, data acquisition hardware, computers and displays into an interacting system this proposal increases functionality with limited additional mass. This paper reviews preliminary work on a project to augment exercise equipment in a manner that addresses these issues and at the same time opens possibilities for additional benefits. A testbed augmented exercise machine uses a specialty built cycle trainer as both input to a virtual environment and as an output device from it using spatialized sound, and visual displays, vibration transducers and variable resistance. The resulting interactivity increases a sense of engagement in the exercise, provides a rich experience of the digital environments. Activities in the virtual environment and accompanying physiological and psychological indicators may be correlated to track and evaluate the health of the crew.

  18. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    Science.gov (United States)

    2016-10-01

    treatment and 2) to determine if the presence of PTSD affects prazosin efficacy for AUD. AUD are major causes of behavioral, medical, family , and...debilitating problem in active duty Service Members and is a frequent comorbidity of posttraumatic stress disorder (PTSD). Our pilot placebo...durability of prazosin effect on AUD in those randomized to prazosin in the RCT. 2. KEYWORDS: alcohol use disorder, prazosin, Service Member , PTSD

  19. The 5'-AMP-Activated Protein Kinase (AMPK Is Involved in the Augmentation of Antioxidant Defenses in Cryopreserved Chicken Sperm.

    Directory of Open Access Journals (Sweden)

    Thi Mong Diep Nguyen

    Full Text Available Semen cryopreservation is a unique tool for the management of animal genetic diversity. However, the freeze-thaw process causes biochemical and physical alterations which make difficult the restoration of sperm energy-dependent functions needed for fertilization. 5'-AMP activated protein kinase (AMPK is a key sensor and regulator of intracellular energy metabolism. Mitochondria functions are known to be severely affected during sperm cryopreservation with deleterious oxidative and peroxidative effects leading to cell integrity and functions damages. The aim of this study was thus to examine the role of AMPK on the peroxidation/antioxidant enzymes defense system in frozen-thawed sperm and its consequences on sperm functions. Chicken semen was diluted in media supplemented with or without AMPK activators (AICAR or Metformin [MET] or inhibitor (Compound C [CC] and then cryopreserved. AMPKα phosphorylation, antioxidant enzymes activities, mitochondrial potential, ATP, citrate, viability, acrosome reaction ability (AR and various motility parameters were negatively affected by the freeze-thaw process while reactive oxygen species (ROS production, lipid peroxidation (LPO and lactate concentration were dramatically increased. AICAR partially restored superoxide dismutase (SOD, Glutathione Peroxidase (GPx and Glutathione Reductase (GR, increased ATP, citrate, and lactate concentration and subsequently decreased the ROS and LPO (malondialdehyde in frozen-thawed semen. Motility parameters were increased (i.e., + 23% for motility, + 34% for rapid sperm as well as AR (+ 100%. MET had similar effects as AICAR except that catalase activity was restored and that ATP and mitochondrial potential were further decreased. CC showed effects opposite to AICAR on SOD, ROS, LPO and AR and motility parameters. Taken together, our results strongly suggest that, upon freeze-thaw process, AMPK stimulated intracellular anti-oxidative defense enzymes through ATP regulation

  20. Augmenting the Antifungal Activity of an Oxidizing Agent with Kojic Acid: Control of Penicillium Strains Infecting Crops

    Directory of Open Access Journals (Sweden)

    Jong H. Kim

    2014-11-01

    Full Text Available Oxidative treatment is one of the strategies for preventing Penicillium contamination in crops/foods. The antifungal efficacy of hydrogen peroxide (H2O2; oxidant was investigated in Penicillium strains by using kojic acid (KA as a chemosensitizing agent, which can enhance the susceptibility of pathogens to antifungal agents. Co-application of KA with H2O2 (chemosensitization resulted in the enhancement of antifungal activity of either compound, when compared to the independent application of each agent alone. Of note, heat enhanced the activity of H2O2 to a greater extent during chemosensitization, whereby the minimum inhibitory or minimum fungicidal concentrations of H2O2 was decreased up to 4 or 13 fold, respectively, at 35–45 °C (heat, when compared to that at 28 °C (normal growth temperature. However, heat didn’t increase the antifungal activity of KA, indicating specificity exists between heat and types of antifungals applied. The effect of chemosensitization was also strain-specific, where P. expansum (both parental and fludioxonil-resistant mutants or P. italicum 983 exhibited relatively higher susceptibility to the chemosensitization, comparing to other Penicillium strains tested. Collectively, chemosensitization can serve as a potent antifungal strategy to lower effective dosages of toxic antifungal substances, such as H2O2. This can lead to coincidental lowering of environmental and health risks.

  1. INFORMATION VIA AUGMENTED

    OpenAIRE

    Tetteh, Sampson

    2015-01-01

    The vast majority of mobile technology today has developed over the past dec-ades. The thirst for information and communication has brought about high data transfer speed on modern mobile handset devices. This makes it possible for Augmented Reality to be used on mobile phones. Vaasa University of Applied Science, Technobothnia science resource center and Lumivaara Museum saw the importance of information and decided to embark on a pilot project where Augmented Reality will not be only us...

  2. Distinct regions within the GluN2C subunit regulate the surface delivery of NMDA receptors

    Directory of Open Access Journals (Sweden)

    Katarina eLichnerova

    2014-11-01

    Full Text Available N-methyl-D-aspartate (NMDA receptors mediate fast excitatory synaptic transmission in the mammalian central nervous system. The activation of NMDA receptors plays a key role in brain development, synaptic plasticity, and memory formation, and is a major contributor to many neuropsychiatric disorders. Here, we investigated the mechanisms that underlie the trafficking of GluN1/GluN2C receptors. Using an approach combining molecular biology, microscopy, and electrophysiology in mammalian cell lines and cultured cerebellar granule cells, we found that the surface delivery of GluN2C-containing receptors is reduced compared to GluN2A- and GluN2B-containing receptors. Furthermore, we identified three distinct regions within the N-terminus, M3 transmembrane domain, and C-terminus of GluN2C subunits that are required for proper intracellular processing and surface delivery of NMDA receptors. These results shed new light on the regulation of NMDA receptor trafficking, and these findings can be exploited to develop new strategies for treating some forms of neuropsychiatric disorders.

  3. The Development of Mobile Augmented Reality

    Science.gov (United States)

    2012-01-01

    This chapter provides a high-level overview of fifteen years of augmented reality research that was sponsored by the U.S. Office of Naval Research...years by a number of university and industrial research laboratories. It laid the groundwork for the development of many commercial mobile augmented ... reality (AR) applications that are currently available for smartphones and tablets. Furthermore, it helped shape a number of ongoing research activities in mobile AR.

  4. Magnetohydrodynamic Augmented Propulsion Experiment

    Science.gov (United States)

    Litchford, Ron J.; Cole, John; Lineberry, John; Chapman, Jim; Schmidt, Harold; Cook, Stephen (Technical Monitor)

    2002-01-01

    that an MHD accelerator can be an effective augmentation system for increasing engine exhaust velocity. More specifically, the experiment is intended to show that electromagnetic effects are effective at producing flow acceleration whereas electrothermal effects do not cause unacceptable heating of the working fluid. The MHD accelerator was designed as an externally diagonalized segmented Faraday channel, which will be inserted into an existing 2-tesla electromagnet. This allows the external power to be connected through two terminals thereby minimizing the complexity and cost associated with powering each segment independently. The design of the accelerator and other components in the flow path has been completed and fabrication activities are underway. This paper provides a full description of MAPX including performance analysis, design, and test plans, and current status.

  5. Confronting an augmented reality

    Directory of Open Access Journals (Sweden)

    John Hedberg

    2012-08-01

    Full Text Available How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself? In this article, we seek to initiate a discussion that focuses on these questions, and suggest that they be used as drivers for research into effective educational applications of augmented reality. We discuss how multi-modal, sensorial augmentation of reality links to existing theories of education and learning, focusing on ideas of cognitive dissonance and the confrontation of new realities implied by exposure to new and varied perspectives. We also discuss connections with broader debates brought on by the social and cultural changes wrought by the increased digitalisation of our lives, especially the concept of the extended mind. Rather than offer a prescription for augmentation, our intention is to throw open debate and to provoke deep thinking about what interacting with and creating an augmented reality might mean for both teacher and learner.

  6. The A3 adenosine receptor attenuates the calcium rise triggered by NMDA receptors in retinal ganglion cells.

    Science.gov (United States)

    Zhang, Mei; Hu, Huiling; Zhang, Xiulan; Lu, Wennan; Lim, Jason; Eysteinsson, Thor; Jacobson, Kenneth A; Laties, Alan M; Mitchell, Claire H

    2010-01-01

    The A(3) adenosine receptor is emerging as an important regulator of neuronal signaling, and in some situations receptor stimulation can limit excitability. As the NMDA receptor frequently contributes to neuronal excitability, this study examined whether A(3) receptor activation could alter the calcium rise accompanying NMDA receptor stimulation. Calcium levels were determined from fura-2 imaging of isolated rat retinal ganglion cells as these neurons possess both receptor types. Brief application of glutamate or NMDA led to repeatable and reversible elevations of intracellular calcium. The A(3) agonist Cl-IB-MECA reduced the response to both glutamate and NMDA. While adenosine mimicked the effect of Cl-IB-MECA, the A(3) receptor antagonist MRS 1191 impeded the block by adenosine, implicating a role for the A(3) receptor in response to the natural agonist. The A(1) receptor antagonist DPCPX provided additional inhibition, implying a contribution from both A(1) and A(3) adenosine receptors. The novel A(3) agonist MRS 3558 (1'S,2'R,3'S,4'R,5'S)-4-(2-chloro-6-(3-chlorobenzylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo [3.1.0] hexane-1-carboxamide and mixed A(1)/A(3) agonist MRS 3630 (1'S,2'R,3'S,4'R,5'S)-4-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo [3.1.0] hexane-1-carboxamide also inhibited the calcium rise induced by NMDA. Low levels of MRS 3558 were particularly effective, with an IC(50) of 400 pM. In all cases, A(3) receptor stimulation inhibited only 30-50% of the calcium rise. In summary, stimulation of the A(3) adenosine receptor by either endogenous or synthesized agonists can limit the calcium rise accompanying NMDA receptor activation. It remains to be determined if partial block of the calcium rise by A(3) agonists can modify downstream responses to NMDA receptor stimulation.

  7. Copper(II) oxide nanoparticles augment antifilarial activity of Albendazole: In vitro synergistic apoptotic impact against filarial parasite Setaria cervi.

    Science.gov (United States)

    Zafar, Atif; Ahmad, Irshad; Ahmad, Ajaz; Ahmad, Masood

    2016-03-30

    Mass treatment of lymphatic filariasis with Albendazole (ABZ), a therapeutic benzimidazole, is fraught with serious limitations such as possible drug resistance and poor macrofilaricidal activity. Therefore, we need to develop new ABZ-based formulations to improve its antifilarial effectiveness. CuO nanoparticles were used as an adjuvant with ABZ to form ABZ-CuO nanocomposite, which was characterized by UV-vis spectroscopy, FT-IR, AFM and SEM. Antifilarial activity of nanocomposite was evaluated using relative motility assay and dye exclusion test in dark and under UV light. ROS generation, antioxidant levels, lipid peroxidation and DNA fragmentation in nanocomposite treated parasites were estimated. Biophysical techniques were employed to ascertain the mode of binding of nanocomposite to parasitic DNA. Nanocomposite increases parasite mortality as compared to ABZ in dark, and its antifilarial effect was increased further under UV light. Elevated ROS production and decline of parasitic-GST and GSH levels were observed in nanocomposite treated worms in dark, and these effects were pronounced further under UV light. Nanocomposite leads to higher DNA fragmentation as compared to ABZ alone. Further, we found that nanocomposite binds parasitic DNA in an intercalative manner where it generates ROS to induce DNA damage. Thus, oxidative stress production due to ROS generation and consequent DNA fragmentation leads to apoptosis in worms. This is the first report supporting CuO nanoparticles as a potential adjuvant with ABZ against filariasis along with enhanced antifilarial activity of nanocomposite under UV light. These findings, thus, indicate that development of ABZ-loaded nanoparticle compounds may serve as promising leads for filariasis treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Dietary n-3 PUFAs augment caspase 8 activation in Staphylococcal aureus enterotoxin B stimulated T-cells.

    Science.gov (United States)

    Gill, R; Jen, K L; McCabe, M J J; Rosenspire, A

    2016-10-15

    Epidemiological studies have linked consumption of n-3 PUFAs with a variety of beneficial health benefits, particularly with respect to putative anti-inflammatory effects. Unfortunately, many of these results remain somewhat controversial because in most instances there has not been a linkage to specific molecular mechanisms. For instance, dietary exposure to low levels of mercury has been shown to be damaging to neural development, but concomitant ingestion of n-3 PUFAs as occurs during consumption of fish, has been shown to counteract the detrimental effects. As the mechanisms mediating the neurotoxicity of environmental mercury are not fully delineated, it is difficult to conceptualize a testable molecular mechanism explaining how n-3 PUFAs negate its neurotoxic effects. However, environmental exposure to mercury also has been linked to increased autoimmunity. By way of a molecular understanding of this immuno-toxic association, disruption of CD95 signaling is well established as a triggering factor for autoimmunity, and we have previously shown that environmentally relevant in vitro and dietary exposures to mercury interfere with CD95 signaling. In particular we have shown that activation of caspase 8, as well as downstream activation of caspase 3, in response to CD95 agonist stimulation is depressed by mercury. More recently we have shown in vitro that the n-3 PUFA docosahexaenoic acid counteracts the negative effect of mercury on CD95 signaling by restoring caspase activity. We hypothesized that concomitant ingestion of n-3 PUFAs with mercury might be protective from the immuno-toxic effects of mercury, as it is with mercury's neuro-toxic effects, and in the case of immuno-toxicity this would be related to restoration of CD95 signal strength. We now show that dietary ingestion of n-3 PUFAs generally promotes CD95 signaling by upregulating caspase 8 activation. Apart from accounting for the ability of n-3 PUFAs to specifically counteract autoimmune sequelae of

  9. Anti-Pseudomonas aeruginosa IgY antibodies promote bacterial opsonization and augment the phagocytic activity of polymorphonuclear neutrophils

    DEFF Research Database (Denmark)

    Thomsen, Kim; Christophersen, Lars; Jensen, Peter Østrup

    2016-01-01

    Moderation of polymorphonuclear neutrophils (PMNs) as part of a critical defense against invading pathogens may offer a promising therapeutic approach to supplement the antibiotic eradication of Pseudomonas aeruginosa infection in non-chronically infected cystic fibrosis (CF) patients. We have...... observed that egg yolk antibodies (IgY) harvested from White leghorn chickens that target P. aeruginosa opsonize the pathogen and enhance the PMN-mediated respiratory burst and subsequent bacterial killing in vitro. The effects on PMN phagocytic activity were observed in different Pseudomonas aeruginosa...

  10. Low doses of the NMDA receptor antagonists, MK-801, PEAQX, and ifenprodil, induces social facilitation in adolescent male rats.

    Science.gov (United States)

    Morales, Melissa; Varlinskaya, Elena I; Spear, Linda P

    2013-08-01

    Adolescents display high levels of interactions with peers relative to other age groups, with these interactions further enhanced by ethanol under some circumstances. Understanding of the neural mechanisms underlying these high levels of social interactions is important given that alcohol use is initiated during adolescence and adolescents tend to report drinking for social reasons. Given that ethanol's effects are associated in part with functional antagonism of the NMDA receptor system, the current experiment explored the role of NMDA antagonists for facilitating adolescent social behavior. Adolescent male Sprague-Dawley rats were challenged acutely with either the non-competitive NMDA antagonist, MK-801 (0.01, 0.03mg/kg), the NR2A antagonist, PEAQX (1.25, 3.75mg/kg) or the NR2B antagonist, ifenprodil (0.75, 2.25mg/kg) 30min prior to a 10-min social interaction test. All compounds generally increased overall social activity (i.e., sum of social investigation, contact behavior, and play), with ifenprodil also significantly enhancing play and social contact behaviors. Although the frequencies of peer-directed social behaviors were typically greater following administration with these NMDA antagonists, social preference, indexed via the number of crossovers to the side with the partner relative to crossovers away, was significantly reduced in MK-801 and PEAQX-treated rats. None of these changes were associated with concomitant alterations in overall locomotor activity under these test circumstances. These data support the suggestion that the increases in social interactions observed in adolescents following acute ethanol may be driven in part by NMDA receptor antagonism - particularly of the NR2B subunit - given that ifenprodil stimulated social behavior in a manner similar to that produced by low doses of ethanol. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. NMDA GluN2B receptors involved in the antidepressant effects of curcumin in the forced swim test.

    Science.gov (United States)

    Zhang, Lin; Xu, Tianyuan; Wang, Shuang; Yu, Lanqing; Liu, Dexiang; Zhan, Renzhi; Yu, Shu Yan

    2013-01-10

    The antidepressant-like effect of curcumin, a major active component of Curcuma longa, has been previously demonstrated in the forced swimming test. However, the mechanism of this beneficial effect on immobility scores, which is used to evaluate antidepressants, remains largely uncharacterized. The present study attempts to investigate the effects of curcumin on depressive-like behavior with a focus upon the possible contribution of N-methyl-D-aspartate (NMDA) subtype glutamate receptors in this antidepressant-like effect of curcumin. Male mice were pretreated with specific receptor antagonists to different NMDA receptor subtypes such as CPP, NVP-AAM077 and Ro25-6981 as well as to a partial NMDA receptor agonist, D-cycloserine (DCS), prior to administration of curcumin to observe the effects on depressive behavior as measured by immobility scores in the forced swim test. We found that pre-treatment of mice with CPP, a broad-spectrum competitive NMDA receptor antagonist, blocked the anti-immobility effect of curcumin, suggesting the involvement of the glutamate-NMDA receptors. While pretreatment with NVP-AAM077 (the GluN2A-preferring antagonist) did not affect the anti-immobility effect of curcumin, Ro25-6981 (the GluN2B-preferring antagonist) was found to prevent the effect of curcumin in the forced swimming test. Furthermore, pre-treatment with a sub-effective dose of DCS potentiated the anti-immobility effect of a sub-effective dose of curcumin in the forced swimming test. Taken together, these results suggest that curcumin shows antidepressant-like effects in mice and the activation of GluN2B-containing NMDARs is likely to play a predominate role in this beneficial effect. Therefore, the antidepressant-like effect of curcumin in the forced swim test may be mediated, at least in part, by the glutamatergic system.

  12. Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1β and NMDA stimulation.

    Science.gov (United States)

    Gardoni, Fabrizio; Boraso, Mariaserena; Zianni, Elisa; Corsini, Emanuela; Galli, Corrado L; Cattabeni, Flaminio; Marinovich, Marina; Di Luca, Monica; Viviani, Barbara

    2011-02-11

    Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that contributes to neuronal injury in various degenerative diseases, and is therefore a potential therapeutic target. It exerts its biological effect by activating the interleukin-1 receptor type I (IL-1RI) and recruiting a signalling core complex consisting of the myeloid differentiation primary response protein 88 (MyD88) and the IL-1R accessory protein (IL-1RAcP). This pathway has been clearly described in the peripheral immune system, but only scattered information is available concerning the molecular composition and distribution of its members in neuronal cells. The findings of this study show that IL-1RI and its accessory proteins MyD88 and IL-1RAcP are differently distributed in the hippocampus and in the subcellular compartments of primary hippocampal neurons. In particular, only IL-1RI is enriched at synaptic sites, where it co-localises with, and binds to the GluN2B subunit of NMDA receptors. Furthermore, treatment with NMDA increases IL-1RI interaction with NMDA receptors, as well as the surface expression and localization of IL-1RI at synaptic membranes. IL-1β also increases IL-1RI levels at synaptic sites, without affecting the total amount of the receptor in the plasma membrane. Our results reveal for the first time the existence of a dynamic and functional interaction between NMDA receptor and IL-1RI systems that could provide a molecular basis for IL-1β as a neuromodulator in physiological and pathological events relying on NMDA receptor activation.

  13. Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1β and NMDA stimulation

    Directory of Open Access Journals (Sweden)

    Marinovich Marina

    2011-02-01

    Full Text Available Abstract Interleukin-1β (IL-1β is a pro-inflammatory cytokine that contributes to neuronal injury in various degenerative diseases, and is therefore a potential therapeutic target. It exerts its biological effect by activating the interleukin-1 receptor type I (IL-1RI and recruiting a signalling core complex consisting of the myeloid differentiation primary response protein 88 (MyD88 and the IL-1R accessory protein (IL-1RAcP. This pathway has been clearly described in the peripheral immune system, but only scattered information is available concerning the molecular composition and distribution of its members in neuronal cells. The findings of this study show that IL-1RI and its accessory proteins MyD88 and IL-1RAcP are differently distributed in the hippocampus and in the subcellular compartments of primary hippocampal neurons. In particular, only IL-1RI is enriched at synaptic sites, where it co-localises with, and binds to the GluN2B subunit of NMDA receptors. Furthermore, treatment with NMDA increases IL-1RI interaction with NMDA receptors, as well as the surface expression and localization of IL-1RI at synaptic membranes. IL-1β also increases IL-1RI levels at synaptic sites, without affecting the total amount of the receptor in the plasma membrane. Our results reveal for the first time the existence of a dynamic and functional interaction between NMDA receptor and IL-1RI systems that could provide a molecular basis for IL-1β as a neuromodulator in physiological and pathological events relying on NMDA receptor activation.

  14. Oxygen plasma surface modification augments poly(L-lactide-co-glycolide) cytocompatibility toward osteoblasts and minimizes immune activation of macrophages.

    Science.gov (United States)

    Scislowska-Czarnecka, Anna; Szmigiel, Dariusz; Genet, Michel; Dupont-Gillain, Christine; Pamula, Elzbieta; Kolaczkowska, Elzbieta

    2015-12-01

    Here, we report on modification of one of the model biomedical polymers, poly L-lactide-co-glycolide (PLGA; 85:15), by reactive ion etching (RIE) oxygen plasma treatment. PLGA's major disadvantage is high hydrophobicity which restrains binding of cell-adhesive proteins and host cells. In the current approach, we aimed to answer two questions: (1) will only short (10 s) and moderate (20-200 mTorr, 45-90 W) RIE oxygen plasma treatment, leading to decrease of water contact angle by only up to 10°, sufficiently improve PLGA adherence to cells, and (2) how will this affect osteoblasts and activation of the immune system? All obtained modified PLGAs had improved hydrophilicity but unaltered roughness (as revealed by water contact angle measurements, X-ray photoelectron spectroscopy, and atomic force microscopy) resulting in significantly improved adhesion of osteoblasts (MG-63) and their low activation. Importantly, macrophages (RAW 264.7), one of the key cells initiating inflammation and bone resorption, responded significantly less vigorously to the modified polymers, expressing/releasing lower amounts of nitric oxide, matrix metalloproteinases (MMP-9), and pro-inflammatory cytokines (TNF-α, IL-6, IL-12p70, IFN-γ, IL-10). We conclude that already slight RIE oxygen plasma modification of PLGA is sufficient to improve its surface properties, and enhance cytocompatibility. Most importantly, this type of modification prevents excessive immune response.

  15. Cortical hypometabolism demonstrated by PET in relapsing NMDA receptor encephalitis.

    Science.gov (United States)

    Pillai, Sekhar C; Gill, Deepak; Webster, Richard; Howman-Giles, Robert; Dale, Russell C

    2010-09-01

    N-methyl-d-aspartate (NMDA) receptor encephalitis is a newly defined type of autoimmune encephalitis. Two girls (age 3 years, case 1, and 7 years, case 2) with relapsing NMDA receptor encephalitis each had the classic clinical features of encephalopathy, movement disorders, psychiatric symptoms, seizures, insomnia, and mild autonomic dysfunction. Both patients had persistent neuropsychiatric disability, despite immune therapies. Positron emission tomography (PET) scans were performed during clinical relapse at 6 weeks (case 1) and 5 months (case 2). In both cases, the scans demonstrated reduced fluorodeoxyglucose metabolism in the cerebral cortex, with the temporal regions being most affected. PET imaging was more sensitive than magnetic resonance imaging in these patients. In contrast, the one previous report of acute NMDA receptor encephalitis indicated cortical hypermetabolism. Thus, NMDA receptor encephalitis may be associated with variable PET findings, possibly dependent upon the timing of the study, or other factors. Future studies should investigate whether cortical hypometabolism is associated with a relapsing course, and whether it is predictive of a poorer outcome in NMDA receptor encephalitis.

  16. A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice.

    Science.gov (United States)

    Aksenov, Vadim; Long, Jiangang; Liu, Jiankang; Szechtman, Henry; Khanna, Parul; Matravadia, Sarthak; Rollo, C David

    2013-02-01

    We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.

  17. Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists

    DEFF Research Database (Denmark)

    Conti, Paola; De Amici, Marco; Grazioso, Giovanni

    2004-01-01

    acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active, neither as agonists nor as antagonists, at 1 mM on metabotropic receptors (mGluR1, -2, -4, and -5 expressed in CHO cell lines). Conversely, the pair of stereoisomers 8A/8B showed a remarkable affinity......, antagonist potency, and selectivity for NMDA receptors, when tested on ionotropic glutamate receptors. The affinity of 8A proved to be 5 times higher than that of diastereomer 8B (K(i) values 0.21 and 0.96 microM, respectively). Furthermore, compounds 8A and 8B exhibited a noteworthy anticonvulsant activity...

  18. Keyhole limpet hemocyanin augmented the killing activity, cytokine production and proliferation of NK cells, and inhibited the proliferation of Meth A sarcoma cells in vitro

    Directory of Open Access Journals (Sweden)

    Md. Moklesur Rahman Sarker

    2014-01-01

    Full Text Available Objective: Keyhole limpet hemocyanin (KLH is a popular tumor vaccine carrier protein and an immunostimulant. The present study aimed to investigate the immunoregulatory activity of KLH on cytotoxicity, cytokines production, and proliferation of natural killer (NK cells. Moreover, antiproliferative activity of KLH on Meth A sarcoma cells was studied. Materials and Methods: Cytotoxicity was determined with killing ability of NK cells against yeast artificial chromosome (YAC-1 cells. Interferon-gamma (IFN-γ and tumor necrosis factor-alpha (TNF-α productions by NK cells were measured by enzyme-linked immunosorbent assay (ELISA. Proliferations of NK and Meth A cells were determined by [ 3 H]thymidine incorporated proliferation and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT methods, respectively. Results: KLH at 6.25, 12.5, and 25 μg/well augmented cytotoxicity of NK cells against YAC-1 cells by 2.5, three, and five-times, respectively. KLH at 25 μg/well enhanced IFN-γ and TNF-α productions by 17- and 23-folds, respectively. The proliferation of NK cells was three times stimulated by KLH. The proliferation of Meth A cells was markedly inhibited by all the doses; the highest (4-folds higher inhibition was observed at a dose of KLH (25 μg/well. Conclusion: The study demonstrated the anticancer activity of KLH acting through the induction of NK cells and inhibition of cancer cells. KLH, therefore, may be a good candidate for an anticancer agent alone or in combination with other chemotherapeutic agents.

  19. Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze.

    Science.gov (United States)

    Dunn, R W; Corbett, R; Fielding, S

    1989-10-01

    The effects of several 5-HT1A agonists and excitatory amino acid antagonists were compared to the standard benzodiazepines, diazepam and chlordiazepoxide (CDP) in two assays predictive of anxiolytic activity, the social interaction and elevated plus maze procedures. Indicative of anxiolytic effects the 5-HT1A agonists, buspirone, gepirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) all significantly increased social interaction time and open arm exploration time in the social interaction and elevated plus maze procedures, respectively. Likewise, anxiolytic activity in these assays were also produced by the competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (AP-5), 2-amino-7-phosphonoheptanoic acid (AP-7), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the non-competitive NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) while NMDA produced anxiogenic effects. Furthermore, the anxiolytic effects of these agents were of equal magnitude to the benzodiazepines. These two classes of compounds were differentiated in the yohimbine-induced seizure assay, with the NMDA antagonists dose dependently antagonizing seizures similar to the benzodiazepines while the 5-HT1A agonists were inactive. These results suggest that the 5-HT1A agonists and the NMDA antagonists may be potential non-classical anxiolytic agents with different mechanisms of action.

  20. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.

    Science.gov (United States)

    Hurton, Lenka V; Singh, Harjeet; Najjar, Amer M; Switzer, Kirsten C; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A; Champlin, Richard E; Cooper, Laurence J N

    2016-11-29

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR(+) T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19(+) leukemia. Long-lived T cells were CD45RO(neg)CCR7(+)CD95(+), phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR(+) T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

  1. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

    Science.gov (United States)

    Hurton, Lenka V.; Singh, Harjeet; Najjar, Amer M.; Switzer, Kirsten C.; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A.; Champlin, Richard E.; Cooper, Laurence J. N.

    2016-01-01

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials. PMID:27849617

  2. Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

    Energy Technology Data Exchange (ETDEWEB)

    Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr. (Department of Anatomy and Reproductive Biology, School of Medicine, University of Hawaii, Honolulu (USA))

    1991-04-01

    The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative {sup 14}C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions.

  3. The role of NMDA and non-NMDA receptors in the NTS in mediating three distinct sympathoinhibitory reflexes.

    Science.gov (United States)

    Sartor, Daniela M; Verberne, Anthony J M

    2007-12-01

    Cholecystokinin (CCK) elicits a sympathetic vasomotor reflex that is implicated in gastrointestinal circulatory control. We sought to determine (1) the site in the solitary tract nucleus (NTS) responsible for mediating this reflex and (2) the possible involvement of excitatory amino acid (EAA) receptors. In addition, we sought to determine whether the NTS site responsible for mediating the baroreflex (phenylephrine, PE, 10 microg/kg i.v.) and the von Bezold-Jarisch reflex (phenylbiguanide, PBG, 10 microg/kg i.v) overlap with that involved in the CCK-induced reflex (CCK, 4 microg/kg, i.v.), and to compare the relative importance of NMDA and non-NDMA receptors in these reflexes. In separate experiments, the effects of PE, PBG, and CCK on mean arterial blood pressure, heart rate, and splanchnic sympathetic nerve discharge were tested before and after bilateral microinjection into the NTS of the gamma-aminobutyric acid(A) (GABA(A)) agonist muscimol, the EAA antagonist kynurenate, the NMDA receptor antagonist D: (-)-2-amino-5-phosphopentanoic acid (AP-5), the non-NMDA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), AP-5 + NBQX, or vehicle. While all treatments (except vehicle) significantly attenuated/abolished/reversed the splanchnic sympathoinhibitory responses to PE, PBG, and CCK, the extent of blockade varied between the different treatment groups. Both NMDA and non-NMDA receptors were essential to the baroreflex and the von Bezold-Jarisch reflex, whereas the CCK reflex was more dependent on non-NMDA receptors. Muscimol, kynurenate, and AP-5 + NBQX significantly attenuated the bradycardic responses to PE and PBG (P NTS responsible for eliciting all three reflexes, NMDA and non-NMDA receptors are recruited differentially for the full expression of these reflexes. The CCK-induced sympathoinhibitory reflex is unique in that it relies predominantly on non-NMDA receptors in the NTS and elicits bradycardic effects that

  4. Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors

    Science.gov (United States)

    Maya-López, Marisol; Colín-González, Ana Laura; Aguilera, Gabriela; de Lima, María Eduarda; Colpo-Ceolin, Ana; Rangel-López, Edgar; Villeda-Hernández, Juana; Rembao-Bojórquez, Daniel; Túnez, Isaac; Luna-López, Armando; Lazzarini-Lechuga, Roberto; González-Puertos, Viridiana Yazmín; Posadas-Rodríguez, Pedro; Silva-Palacios, Alejandro; Königsberg, Mina; Santamaría, Abel

    2017-01-01

    The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington’s disease patients. Herein, the effects of WIN55,212-2 were tested on different endpoints of the 3-NP-induced toxicity in rat brain synaptosomes and striatal tissue. Motor activity was also evaluated. The 3-NP (1 mM)-induced mitochondrial dysfunction and lipid peroxidation was attenuated by WIN55,212-2 (1 µM) in synaptosomal fractions. The intrastriatal bilateral injection of 3-NP (500 nmol/µL) to rats increased lipid peroxidation and locomotor activity, augmented the rate of cell damage, and decreased the striatal density of neuronal cells. These alterations were accompanied by transcriptional changes in the NMDA (NR1 subunit) content. The administration of WIN55212-2 (1 mg/kg, i.p.) to rats for six consecutive days, before the 3-NP injection, exerted preventive effects on all alterations elicited by the toxin. The prevention of the 3-NP-induced NR1 transcriptional alterations by the CBr agonist together with the increase of CB1 content suggest an early reduction of the excitotoxic process via CBr activation. Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies.

  5. EVALUATING THE NMDA-GLUTAMATE RECEPTOR AS A SITE OF ACTION FOR TOLUENE, IN VIVO

    Science.gov (United States)

    In vitro, toluene disrupts the function of NMDA-glutamate receptors, indicating that effects on NMDA receptor function may contribute to toluene neurotoxicity. NMDA-glutamate receptors are widely present in the visual system and contribute to pattern-elicited visual evoked potent...

  6. Everything Augmented: On the Real in Augmented Reality

    Directory of Open Access Journals (Sweden)

    Hanna Schraffenberger

    2014-12-01

    Full Text Available What is augmented in Augmented Reality (AR? In this paper, we review existing opinions and show how little consensus exists on this matter. Subsequently, we approach the question from a theoretical and technology-independent perspective. We identify spatial and content-based relationships between the virtual and the real as being decisive for AR and come to the conclusion that virtual content augments that to which it relates. Subsequently, we categorize different forms of AR based on what is augmented. We distinguish between augmented environments, augmented objects, augmented humans and augmented content and consider the possibility of augmented perception. The categories are illustrated with AR (art works and conceptual differences between them are pointed out. Moreover, we discuss what the real contributes to AR and how it can shape (future AR experiences. A summary of our findings and suggestions for future research and practice, such as research into multimodal and crossmodal AR, conclude the paper.

  7. Prototyping Augmented Reality

    CERN Document Server

    Mullen, Tony

    2011-01-01

    Learn to create augmented reality apps using Processing open-source programming language Augmented reality (AR) is used all over, and you may not even realize it. Smartphones overlay data onto live camera views to show homes for sale, restaurants, or historical sites. American football broadcasts use AR to show the invisible first-down line on the field to TV viewers. Nike and Budweiser, among others, have used AR in ads. Now, you can learn to create AR prototypes using 3D data, Processing open-source programming language, and other languages. This unique book is an easy-to-follow guide on how

  8. Augmented marked graphs

    CERN Document Server

    Cheung, King Sing

    2014-01-01

    Petri nets are a formal and theoretically rich model for the modelling and analysis of systems. A subclass of Petri nets, augmented marked graphs possess a structure that is especially desirable for the modelling and analysis of systems with concurrent processes and shared resources.This monograph consists of three parts: Part I provides the conceptual background for readers who have no prior knowledge on Petri nets; Part II elaborates the theory of augmented marked graphs; finally, Part III discusses the application to system integration. The book is suitable as a first self-contained volume

  9. Collaboration in Augmented Reality

    OpenAIRE

    Lukosch, S.; Billinghurst, M; Alem, L.; Kiyokawa, K.

    2015-01-01

    Augmented Reality (AR) is a technology that allows users to view and interact in real time with virtual images seamlessly superimposed over the real world. AR systems can be used to create unique collaborative experiences. For example, co-located users can see shared 3D virtual objects that they interact with, or a user can annotate the live video view of a remote worker, enabling them to collaborate at a distance. The overall goal is to augment the face-to-face collaborative experience, or t...

  10. Augmented reality som wearable

    DEFF Research Database (Denmark)

    Buhl, Mie; Rahn, Annette

    2015-01-01

    Artiklen omhandler design og implementering af Augmented Reality (AR) i form af en wearable i sygeplejerskeuddannelsens anatomiundervisning, mere specifikt undervisning i lungeanatomi og respiration, med fokus på potentialer for visuel læring. Projektet undersøger, hvordan en udviklet AR-applikat......Artiklen omhandler design og implementering af Augmented Reality (AR) i form af en wearable i sygeplejerskeuddannelsens anatomiundervisning, mere specifikt undervisning i lungeanatomi og respiration, med fokus på potentialer for visuel læring. Projektet undersøger, hvordan en udviklet AR...

  11. Characterisation of the expression of NMDA receptors in human astrocytes.

    Directory of Open Access Journals (Sweden)

    Ming-Chak Lee

    Full Text Available Astrocytes have long been perceived only as structural and supporting cells within the central nervous system (CNS. However, the discovery that these glial cells may potentially express receptors capable of responding to endogenous neurotransmitters has resulted in the need to reassess astrocytic physiology. The aim of the current study was to characterise the expression of NMDA receptors (NMDARs in primary human astrocytes, and investigate their response to physiological and excitotoxic concentrations of the known endogenous NMDAR agonists, glutamate and quinolinic acid (QUIN. Primary cultures of human astrocytes were used to examine expression of these receptors at the mRNA level using RT-PCR and qPCR, and at the protein level using immunocytochemistry. The functionality role of the receptors was assessed using intracellular calcium influx experiments and measuring extracellular lactate dehydrogenase (LDH activity in primary cultures of human astrocytes treated with glutamate and QUIN. We found that all seven currently known NMDAR subunits (NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B are expressed in astrocytes, but at different levels. Calcium influx studies revealed that both glutamate and QUIN could activate astrocytic NMDARs, which stimulates Ca2+ influx into the cell and can result in dysfunction and death of astrocytes. Our data also show that the NMDAR ion channel blockers, MK801, and memantine can attenuate glutamate and QUIN mediated cell excitotoxicity. This suggests that the mechanism of glutamate and QUIN gliotoxicity is at least partially mediated by excessive stimulation of NMDARs. The present study is the first to provide definitive evidence for the existence of functional NMDAR expression in human primary astrocytes. This discovery has significant implications for redefining the cellular interaction between glia and neurons in both physiological processes and pathological conditions.

  12. Modeling of aerodynamic forces in the Laplace domain with minimum number of augmented states for the design of active flutter suppression systems

    Science.gov (United States)

    Nissim, E.

    1989-01-01

    A method is proposed by which an aeroservoelastic problem is brought to a state-space form with a minimum number of augmented aerodynamic terms. The examples treated in this work relate to NASA's Drone for Aerodynamic and Structural Testing-Aerodynamic Research Wing 1 (DAST-ARW1) and to the YF-17 fighter model. It is shown that in all cases considered, the method yields a very good accuracy regarding the flutter parameters and the dynamic behavior of the systems, using only two augmented aerodynamic states. The method should prove useful in the design of lower order control laws based on optimal control theory.

  13. Mapping and deciphering neural codes of NMDA receptor-dependent fear memory engrams in the hippocampus.

    Directory of Open Access Journals (Sweden)

    Hongmiao Zhang

    Full Text Available Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS and unconditioned foot-shock (US can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for "what at when" information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.

  14. Homology modeling of NR2B modulatory domain of NMDA receptor and analysis of ifenprodil binding.

    Science.gov (United States)

    Marinelli, Luciana; Cosconati, Sandro; Steinbrecher, Thomas; Limongelli, Vittorio; Bertamino, Alessia; Novellino, Ettore; Case, David A

    2007-10-01

    NMDA receptors are glutamate-gated ion channels (iGluRs) that are involved in several important physiological functions such as neuronal development, synaptic plasticity, learning, and memory. Among iGluRs, NMDA receptors have been perhaps the most actively investigated for their role in chronic neurodegeneration such as Alzheimer's, Parkinson's, and Huntington's diseases. Recent studies have shown that the NTD of subunit NR2B modulates ion channel gating through the binding of allosteric modulators such as the prototypical compound ifenprodil. In the present paper, the construction of a three-dimensional model for the NR2B modulatory domain is described and docking calculations allow, for the first time, definition of the ifenprodil binding pose at an atomic level and fully explain all the available structure-activity relationships. Moreover, in an attempt to add further insight into the ifenprodil mechanism of action, as it is not completely clear if it binds and stabilizes an open or a closed conformation of the NR2B modulatory domain, a matter, which is fundamental for the rational design of NMDA antagonists, MD simulations followed by an MM-PBSA analysis were performed. These calculations reveal that the closed conformation of the R1-R2 domain, rather than the open, constitutes the high affinity binding site for ifenprodil and that a profound stabilization of the closed conformation upon ifenprodil binding occurs. Thus, for a rational design and/or for virtual screening experiments, the closed conformation of the R1-R2 domain should be taken into account and our 3D model can provide valuable hints for the design of NR2B-selective antagonists.

  15. A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice.

    Science.gov (United States)

    Poleszak, Ewa; Wlaź, Piotr; Szewczyk, Bernadeta; Wlaź, Aleksandra; Kasperek, Regina; Wróbel, Andrzej; Nowak, Gabriel

    2011-11-01

    Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and D: -cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and D: -cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or D: -cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and D: -cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by D: -serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.

  16. Towards Pervasive Augmented Reality: Context-Awareness in Augmented Reality.

    Science.gov (United States)

    Grubert, Jens; Langlotz, Tobias; Zollmann, Stefanie; Regenbrecht, Holger

    2017-06-01

    Augmented Reality is a technique that enables users to interact with their physical environment through the overlay of digital information. While being researched for decades, more recently, Augmented Reality moved out of the research labs and into the field. While most of the applications are used sporadically and for one particular task only, current and future scenarios will provide a continuous and multi-purpose user experience. Therefore, in this paper, we present the concept of Pervasive Augmented Reality, aiming to provide such an experience by sensing the user's current context and adapting the AR system based on the changing requirements and constraints. We present a taxonomy for Pervasive Augmented Reality and context-aware Augmented Reality, which classifies context sources and context targets relevant for implementing such a context-aware, continuous Augmented Reality experience. We further summarize existing approaches that contribute towards Pervasive Augmented Reality. Based our taxonomy and survey, we identify challenges for future research directions in Pervasive Augmented Reality.

  17. Augmented Reality i naturfagsundervisningen

    DEFF Research Database (Denmark)

    Radmer, Ole; Surland, Mogens; Nielsen, Birgitte Lund

    2016-01-01

    Augmented Reality (AR) giver ny mulighed for, at elever kan lave undersøgelser i naturfag med enkel teknologi, hvor animationer og simulationer kobles med det virkelige fænomen. I workshoppen kan I afprøve AR eksempler, udviklet i et internationalt EU projekt. Der vil være noget, der direkte kan...

  18. Augmented reality som wearable

    DEFF Research Database (Denmark)

    Buhl, Mie; Rahn, Annette

    2015-01-01

    Artiklen omhandler design og implementering af Augmented Reality (AR) i form af en wearable i sygeplejerskeuddannelsens anatomiundervisning, mere specifikt undervisning i lungeanatomi og respiration, med fokus på potentialer for visuel læring. Projektet undersøger, hvordan en udviklet AR...

  19. Augmented Reality og kulturarv

    DEFF Research Database (Denmark)

    Nielsen, Mikkel Kirkedahl Lysholm

    2013-01-01

    Museerne står overfor at skulle omfavne den digitale kultur i håndteringen af den store mængde viden, institutionerne repræsenterer. Augmented Reality-systemer forbinder ved hjælp af moderne teknologi det virtuelle med det virkelige, og kan derfor synes som en oplagt anvendelsesmulighed i...

  20. Augmented Reality Binoculars.

    Science.gov (United States)

    Oskiper, Taragay; Sizintsev, Mikhail; Branzoi, Vlad; Samarasekera, Supun; Kumar, Rakesh

    2015-05-01

    In this paper we present an augmented reality binocular system to allow long range high precision augmentation of live telescopic imagery with aerial and terrain based synthetic objects, vehicles, people and effects. The inserted objects must appear stable in the display and must not jitter and drift as the user pans around and examines the scene with the binoculars. The design of the system is based on using two different cameras with wide field of view and narrow field of view lenses enclosed in a binocular shaped shell. Using the wide field of view gives us context and enables us to recover the 3D location and orientation of the binoculars much more robustly, whereas the narrow field of view is used for the actual augmentation as well as to increase precision in tracking. We present our navigation algorithm that uses the two cameras in combination with an inertial measurement unit and global positioning system in an extended Kalman filter and provides jitter free, robust and real-time pose estimation for precise augmentation. We have demonstrated successful use of our system as part of information sharing example as well as a live simulated training system for observer training, in which fixed and rotary wing aircrafts, ground vehicles, and weapon effects are combined with real world scenes.

  1. Augmented reality som wearable

    DEFF Research Database (Denmark)

    Buhl, Mie; Rahn, Annette

    2015-01-01

    Artiklen omhandler design og implementering af Augmented Reality (AR) i form af en wearable i sygeplejerskeuddannelsens anatomiundervisning, mere specifikt undervisning i lungeanatomi og respiration, med fokus på potentialer for visuel læring. Projektet undersøger, hvordan en udviklet AR...

  2. Augmented Reality og kulturarv

    DEFF Research Database (Denmark)

    Nielsen, Mikkel Kirkedahl Lysholm

    2013-01-01

    Museerne står overfor at skulle omfavne den digitale kultur i håndteringen af den store mængde viden, institutionerne repræsenterer. Augmented Reality-systemer forbinder ved hjælp af moderne teknologi det virtuelle med det virkelige, og kan derfor synes som en oplagt anvendelsesmulighed i...

  3. Collaboration in Augmented Reality

    NARCIS (Netherlands)

    Lukosch, S.; Billinghurst, M.; Alem, L.; Kiyokawa, K.

    2015-01-01

    Augmented Reality (AR) is a technology that allows users to view and interact in real time with virtual images seamlessly superimposed over the real world. AR systems can be used to create unique collaborative experiences. For example, co-located users can see shared 3D virtual objects that they int

  4. Collaboration in Augmented Reality

    NARCIS (Netherlands)

    Lukosch, S.; Billinghurst, M.; Alem, L.; Kiyokawa, K.

    2015-01-01

    Augmented Reality (AR) is a technology that allows users to view and interact in real time with virtual images seamlessly superimposed over the real world. AR systems can be used to create unique collaborative experiences. For example, co-located users can see shared 3D virtual objects that they int

  5. Collaborative augmented reality environments

    DEFF Research Database (Denmark)

    Büscher, Monika; Christensen, Michael; Grønbæk, Kaj

    2000-01-01

    This paper describes Manufaktur, a prototype of a concept and infrastructure that goes beyond the classical CVE systems toward a collaborative augmented reality environment, where users? documents and objects appear as live representations in a 3D workspace. Manufaktur supports collaborative...

  6. Open-channel blockers of the NMDA receptor complex.

    Science.gov (United States)

    Albensi, Benedict C; Ilkanich, Erin

    2004-11-01

    A variety of compounds have been shown to limit or prevent excitotoxicity by blocking N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. However, many first-generation NMDA antagonists did not live up to clinical expectations in trials of acute brain injury because of the manifestation of multiple side effects. In spite of this, development of NMDA antagonists continues, where some of the newer agents block excitotoxicity through alternative mechanisms. For example, blockers selective to the NR2B subunit or agents that block metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are currently under investigation. Several years ago, the arylalkylamine spider toxins were demonstrated to function as open-channel blockers similar to memantine, which was very recently approved by the U.S. FDA for use in patients with Alzheimer's dementia. With this said, programs focusing on NMDA antagonism via alternative mechanisms may still hold promise for treating acute injury and even chronic forms of dementia.

  7. [Anti-NMDA receptor encephalitis: two paediatric cases].

    Science.gov (United States)

    González-Toro, M Cristina; Jadraque-Rodríguez, Rocío; Sempere-Pérez, Ángela; Martínez-Pastor, Pedro; Jover-Cerdá, Jenaro; Gómez-Gosálvez, Francisco

    2013-12-01

    Introduccion. La encefalitis asociada a anticuerpos antirreceptores de N-metil-D-aspartato (NMDA) es una patologia neurologica autoinmune documentada en la poblacion pediatrica de manera creciente en los ultimos años. Se presentan dos casos de nuestra experiencia con clinica similar. Casos clinicos. Caso 1: niña de 5 años que inicia un cuadro de convulsiones y alteracion de conciencia, asociando trastornos del movimiento y regresion de habilidades previamente adquiridas que evoluciona a autismo. Caso 2: niña de 13 años que presenta hemiparesia izquierda, movimientos anomalos, trastorno de conducta y disautonomia. En ambos casos se obtienen anticuerpos antirreceptores de NMDA positivos en el liquido cefalorraquideo y se diagnostican de encefalitis antirreceptor de NMDA. En el primer caso se inicia el tratamiento con perfusion intravenosa de corticoides e inmunoglobulinas y es necesario asociar rituximab. En el segundo, corticoides e inmunoglobulinas. La evolucion fue favorable en ambas pacientes, con una leve alteracion del lenguaje como secuela en el primer caso y una recaida en el segundo caso, con resolucion completa. Conclusion. La encefalitis antirreceptor de NMDA es un trastorno tratable y es importante el diagnostico y tratamiento precoz, ya que mejora el pronostico y disminuye las recaidas.

  8. [Two cases of anti-NMDA receptor encephalitis].

    Science.gov (United States)

    Nakamura, Kazue; Takahashi, Tsutomu; Matsuoka, Tadasu; Kido, Mikio; Uehara, Takashi; Suzuki, Michio

    2011-01-01

    Anti-NMDA receptor encephalitis, reported by Dalmau et al., is a paraneoplastic encephalitis frequently associated with ovarian teratoma. After the manifestation of schizophrenia-like psychotic symptoms in the initial stage, serious neurological symptoms such as convulsions and central hypoventilation develop. We report two cases of 17-year-old girls with anti-NMDA receptor encephalitis who exhibited different clinical courses. Case 1 showed a typical course of anti-NMDA receptor encephalitis associated with sustained consciousness disturbance requiring long-term artificial respiration. Case 2 underwent surgery for an ovarian teratoma in the early stages of the disorder, did not show convulsions or central hypoventilation, and recovered without any sequelae. Early resection of the ovarian teratoma and the immune suppression therapy may have contributed to the rapid recovery and favorable outcome in case 2. Psychiatrists are the first to see a majority of patients with anti-NMDA receptor encephalitis because of psychiatric symptoms and behavioral changes observed in the initial stage. For successful treatment, psychiatrists need to cooperate with neurologists and gynecologists early in the course of this disorder. Psychiatrists' knowledge of the symptoms and clinical course of this form of encephalitis is essential for early detection and adequate treatment, which may be life-saving and contribute to good functional outcomes.

  9. [Anti-NMDA-receptor encephalitis. An interdisciplinary clinical picture].

    Science.gov (United States)

    Prüss, H; Dalmau, J; Arolt, V; Wandinger, K-P

    2010-04-01

    Anti-NMDA-receptor encephalitis is a severe and considerably underdiagnosed form of encephalitis with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, hypoventilation, epileptic seizures, autonomic dysfunction and dyskinesias. Most patients are primarily seen by psychiatrists, often on the assumption of a drug-induced psychosis. Anti-NMDA-receptor encephalitis had initially been described in young women with ovarian teratoma, but is also common in women without tumour, in men and in children. The diagnosis is based on the characteristic clinical picture, supporting findings of brain MRI, electroencephalogram and cerebrospinal fluid (CSF), and the presence of highly specific autoantibodies directed against the NR1 subunit of NMDA-type glutamate receptors in the serum or CSF. In particular, anti-NMDA-receptor encephalitis must be excluded in patients with 'encephalitis of unknown cause'. In principle, the prognosis is favourable and recovery from symptoms can be expected even after prolonged intensive care treatment and mechanical ventilation. However, improvement correlates with prompt identification of the disorder, early immunotherapy and - in the case of a malignancy - with complete tumour removal. Patient care requires an interdisciplinary approach including neurologists, psychiatrists, paediatricians, oncologists and gynaecologists.

  10. The participation of NMDA receptors, PKC, and MAPK in the formation of memory following operant conditioning in Lymnaea

    Directory of Open Access Journals (Sweden)

    Rosenegger David

    2010-08-01

    Full Text Available Abstract Background Memory is the ability to store, retain, and later retrieve information that has been learned. Intermediate term memory (ITM that persists for up to 3 h requires new protein synthesis. Long term memory (LTM that persists for at least 24 h requires: DNA transcription, RNA translation, and the trafficking of newly synthesized proteins. It has been shown in a number of different model systems that NMDA receptors, protein kinase C (PKC and mitogen activated protein kinase (MAPK are all involved in the memory formation process. Results Here we show that snails trained in control conditions are capable of forming, depending on the training procedure used, either ITM or LTM. However, blockage of NMDA receptors (MK 801, inhibition of PKC (GF109203X hydrochloride and MAPK activity (UO126 prevent the formation of both ITM and LTM. Conclusions The injection of either U0126 or GF109203X, which inhibit MAPK and PKC activity respectively, 1 hour prior to training results in the inhibition of both ITM and LTM formation. We further found that NMDA receptor activity was necessary in order for both ITM and LTM formation.

  11. GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice.

    Science.gov (United States)

    Oliveira-Pinto, Juliana; Paes-Branco, Danielle; Cristina-Rodrigues, Fabiana; Krahe, Thomas E; Manhães, Alex C; Abreu-Villaça, Yael; Filgueiras, Cláudio C

    2015-01-01

    Both NMDA receptor blockade and GABAA receptor overactivation during the brain growth spurt may contribute to the hyperactivity phenotype reminiscent of attention-deficit/hyperactivity disorder. Here, we evaluated the effects of exposure to MK801 (a NMDA antagonist) and/or to muscimol (a GABAA agonist) during the brain growth spurt on locomotor activity of juvenile Swiss mice. This study was carried out in two separate experiments. In the first experiment, pups received a single i.p. injection of either saline solution (SAL), MK801 (MK, 0.1, 0.3 or 0.5 mg/kg) or muscimol (MU, 0.02, 0.1 or 0.5 mg/kg) at the second postnatal day (PND2), and PNDs 4, 6 and 8. In the second experiment, we investigated the effects of a combined injection of MK (0.1 mg/kg) and MU (doses: 0.02, 0.1 or 0.5 mg/kg) following the same injection schedule of the first experiment. In both experiments, locomotor activity was assessed for 15 min at PND25. While MK promoted a dose-dependent increase in locomotor activity, exposure to MU failed to elicit significant effects. The combined exposure to the highest dose of MU and the lowest dose of MK induced marked hyperactivity. Moreover, the combination of the low dose of MK and the high dose of MU resulted in a reduced activity in the center of the open field, suggesting an increased anxiety-like behavior. These findings suggest that, during the brain growth spurt, the blockade of NMDA receptors induces juvenile locomotor hyperactivity whereas hyperactivation of GABAA receptors does not. However, GABAA overactivation during this period potentiates the effects of NMDA blockade in inducing locomotor hyperactivity. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury.

    Science.gov (United States)

    Li, Ying; Korgaonkar, Akshata A; Swietek, Bogumila; Wang, Jianfeng; Elgammal, Fatima S; Elkabes, Stella; Santhakumar, Vijayalakshmi

    2015-02-01

    Concussive brain injury results in neuronal degeneration, microglial activation and enhanced excitability in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like receptor 4 (TLR4). Recent studies indicate that immune mediators can modulate neuronal excitability. Since non-specific agents that reduce TLR4 signaling can limit post-traumatic neuropathology, we examined whether TLR4 signaling contributes to early changes in dentate excitability after brain injury. Concussive brain injury caused a transient increase in hippocampal TLR4 expression within 4h, which peaked at 24h. Post-injury increase in TLR4 expression in the dentate gyrus was primarily neuronal and persisted for one week. Acute, in vitro treatment with TLR4 ligands caused bidirectional modulation of dentate excitability in control and brain-injured rats, with a reversal in the direction of modulation after brain injury. TLR4 antagonists decreased, and agonist increased, afferent-evoked dentate excitability one week after brain injury. NMDA receptor antagonist did not occlude the ability of LPS-RS, a TLR4 antagonist, to decrease post-traumatic dentate excitability. LPS-RS failed to modulate granule cell NMDA EPSCs but decreased perforant path-evoked non-NMDA EPSC peak amplitude and charge transfer in both granule cells and mossy cells. Our findings indicate an active role for TLR4 signaling in early post-traumatic dentate hyperexcitability. The novel TLR4 modulation of non-NMDA glutamatergic currents, identified herein, could represent a general mechanism by which immune activation influences neuronal excitability in neurological disorders that recruit sterile inflammatory responses. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor.

    Science.gov (United States)

    Chen, Xiangyuan; Wu, Qichao; You, Li; Chen, Sisi; Zhu, Minmin; Miao, Changhong

    2017-01-15

    Propofol is a commonly used intravenous anesthetic, and could attenuate cancer cells malignant potential via inhibiting hypoxia-inducible factor-1α (HIF-1α) expression. However, the mechanism is still inclusive. In the present study, we mainly focus on the mechanism by which propofol down-regulated HIF-1α expression and malignant potential in pancreatic cancer cells. Human pancreatic cancer cells (Miapaca-2 and Panc-1) in vitro and murine pancreatic cancer cell (Panc02) in vivo were used to assess the effect of propofol on vascular endothelial growth factor (VEGF) expression and migration of pancreatic cancer cells. Propofol inhibited cells migration, expression of VEGF and HIF-1α, phosphorylation of extracellular regulated protein kinases (ERK), AKT, Ca(2+)/calmodulin dependent protein kinases II (CaMK II), and Ca(2+) concentration in a concentration-dependent manner (5, 25, 50, 100μM). Furthermore, MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMK II, could inhibit the expression of VEGF, HIF-1a, p-AKT, p-ERK, p-CaMK II in vitro, growth of tumor and VEGF expression in vivo, which were similar to the effect of propofol. In addition, the anti-tumor effect of propofol could be counteracted by rapastinel, an activator of NMDA receptor. Our study indicated that propofol suppressed VEGF expression and migration ability of pancreatic cancer cells in vitro and in vivo, probably via inhibiting NMDA receptor. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Modulation of functional EEG networks by the NMDA antagonist nitrous oxide.

    Directory of Open Access Journals (Sweden)

    Levin Kuhlmann

    Full Text Available Parietal networks are hypothesised to play a central role in the cortical information synthesis that supports conscious experience and behavior. Significant reductions in parietal level functional connectivity have been shown to occur during general anesthesia with propofol and a range of other GABAergic general anesthetic agents. Using two analysis approaches (1 a graph theoretic analysis based on surrogate-corrected zero-lag correlations of scalp EEG, and (2 a global coherence analysis based on the EEG cross-spectrum, we reveal that sedation with the NMDA receptor antagonist nitrous oxide (N2O, an agent that has quite different electroencephalographic effects compared to the inductive general anesthetics, also causes significant alterations in parietal level functional networks, as well as changes in full brain and frontal level networks. A total of 20 subjects underwent N2O inhalation at either 20%, 40% or 60% peak N2O/O2 gas concentration levels. N2O-induced reductions in parietal network level functional connectivity (on the order of 50% were exclusively detected by utilising a surface Laplacian derivation, suggesting that superficial, smaller spatial scale, cortical networks were most affected. In contrast reductions in frontal network functional connectivity were optimally discriminated using a common-reference derivation (reductions on the order of 10%, indicating that the NMDA antagonist N2O induces spatially coherent and widespread perturbations in frontal activity. Our findings not only give important weight to the idea of agent invariant final network changes underlying drug-induced reductions in consciousness, but also provide significant impetus for the application and development of multiscale functional analyses to systematically characterise the network level cortical effects of NMDA receptor related hypofunction. Future work at the source space level will be needed to verify the consistency between cortical network changes seen

  15. Anti-NMDA-R encephalitis: Should we consider extreme delta brush as electrical status epilepticus?

    Science.gov (United States)

    Chanson, Eve; Bicilli, Élodie; Lauxerois, Michel; Kauffmann, Sophie; Chabanne, Russell; Ducray, François; Honnorat, Jérome; Clavelou, Pierre; Rosenberg, Sarah

    2016-02-01

    Seizures are common clinical manifestations in anti-N-methyl-d-aspartate receptor (anti-NMDA-R) encephalitis, among other neurological and psychiatric symptoms. During the course of the disease, some specific EEG patterns have been described: generalized rhythmic delta activity (GRDA) and extreme delta brush (EDB). In comatose patients, the association of these EEG abnormalities with subtle motor manifestations can suggest ongoing non-convulsive status epilepticus (NCSE). We report the case of a 28-year-old woman admitted for a clinical presentation typical of anti-NMDA-R encephalitis, which was confirmed by CSF analysis. She was rapidly intubated because of severe dysautonomia and disturbed consciousness. Clinical examination revealed subtle paroxysmal and intermittent myoclonic and tonic movements, correlated on video-EEG with GRDA and/or EDB. NCSE was then suspected, but electroclinical manifestations persisted despite many anti-epileptic drugs combinations, or reappeared when barbiturate anesthesia was decreased. In order to confirm or dismiss the diagnosis, intracranial pressure (ICP) and surface video-EEG monitoring were performed simultaneously and revealed no ICP increase, thus being strongly against a diagnosis of seizures. Sedation was progressively weaned, and clinical condition as well as EEG appearance progressively improved. Literature review revealed 11 similar cases, including 2 with focal NCSE. Of the nine other cases, NCSE diagnosis was finally excluded in 5 cases. NCSE diagnosis in association with anti-NMDA-R encephalitis is sometimes very difficult and its occurrence might be overestimated. Video-EEG is highly recommended and more invasive techniques may sometimes be necessary.

  16. Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Alvarado, M.; Budinger, T.F.; Grossman, R.; Hensley, K.; West, M.S.; Kotake, Y.; Ono, M.; Floyd, R.A.

    2001-12-10

    Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl-tert-butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hours after endotoxin injection. Animals were killed 7 days post-injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open-channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (2-3 fold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (>50 percent) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl-tert-butyl nitrone treatment resulted in a partial inhibition ({approx}25 percent decrease) of the lipopolysaccharide-induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide-induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.

  17. Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion.

    Science.gov (United States)

    Im, Doo Soon; Jeon, Jeong Wook; Lee, Jin Soo; Won, Seok Joon; Cho, Sung Ig; Lee, Yong Beom; Gwag, Byoung Joo

    2012-05-21

    Excess activation of ionotropic glutamate receptors and iron is believed to contribute to free radical production and neuronal death following hypoxic ischemia. We examined the possibility that both NMDA receptor activation and iron overload determine spatial and temporal patterns of free radical production after transient middle cerebral artery occlusion (tMCAO) in male Sprague-Dawley rats. Mitochondrial free radical (MFR) levels were maximally increased in neurons in the core at 1 h and 24 h after tMCAO. Early MFR production was blocked by administration of MK-801, an NMDA receptor antagonist, but not deferoxamine, an iron chelator. Neither MK-801 nor deferoxamine attenuated late MFR production in the core. Increased MFRs were observed in penumbral neurons within 6 h and gradually increased over 24 h after tMCAO. Slowly-evolving MFRs in the core and penumbra were accompanied by iron overload. Deferoxamine blocked iron overload but reduced MFR production only in the penumbra. Combined MK-801/deferoxamine reduced late MFR production in both core and penumbra in an additive manner. Combination therapy significantly ameliorated infarction compared with monotherapy. These findings suggest that the NMDA receptor activation and iron overload mediate late MFR production and infarction after tMCAO. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Brain purine metabolism and xanthine dehydrogenase/oxidase conversion in hyperammonemia are under control of NMDA receptors and nitric oxide.

    Science.gov (United States)

    Kaminsky, Yury; Kosenko, Elena

    2009-10-19

    In hyperammonemia, a decrease in brain ATP can be a result of adenine nucleotide catabolism. Xanthine dehydrogenase (XD) and xanthine oxidase (XO) are the end steps in the purine catabolic pathway and directly involved in depletion of the adenylate pool in the cell. Besides, XD can easily be converted to XO to produce reactive oxygen species in the cell. In this study, the effects of acute ammonia intoxication in vivo on brain adenine nucleotide pool and xanthine and hypoxanthine, the end degradation products of adenine nucleotides, during the conversion of XD to XO were studied. Injection of rats with ammonium acetate was shown to lead to the dramatic decrease in the ATP level, adenine nucleotide pool size and adenylate energy charge and to the great increase in hypoxanthine and xanthine 11 min after the lethal dose indicating rapid degradation of adenylates. Conversion of XD to XO in hyperammonemic rat brain was evidenced by elevated XO/XD activity ratio. Injection of MK-801, a NMDA receptor blocker, prevented ammonia-induced catabolism of adenine nucleotides and conversion of XD to XO suggesting that in vivo these processes are mediated by activation of NMDA receptors. The in vitro dose-dependent effects of sodium nitroprusside, a NO donor, on XD and XO activities are indicative of the direct modification of the enzymes by nitric oxide. This is the first report evidencing the increase in brain xanthine and hypoxanthine levels and adenine nucleotide breakdown in acute ammonia intoxication and NMDA receptor-mediated prevention of these alterations.

  19. Effects of intracerebroventricular NMDA and non-NMDA receptor agonists or antagonists on general anesthesia of propofol in mice

    Institute of Scientific and Technical Information of China (English)

    XU Aijun; DUAN Shiming; TIAN Yuke

    2007-01-01

    The efiects of intracerebroventricular(icv)agonists and antagonists of N-methyl-D-aspartate(NMDA)and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the general anesthesia of propofol were studied.A tohal of 144 Kunming mice,male and female with body mass of(22±3)g,were used.Part One of the Experiment:a total of 104 Kunming mice,male and female,were randomly divided into 13 groups.Intracerebroventricular artificial cerebral fluid (aCSF)or different doses of NMDA,AMPA,MK-801 or NBOX was iniected immediately after intravenously administered propofol 25 mg/kg and the recovery time following the loss of righting reflex (LORR)was recorded.Part Two of the Experiment:a total of 40 Kunming female mice were divided randomly into 5 groups and iniected with icv aCSF or NMDA.AMPA.MK-801 or NBQX after intraperitoneally administered propofol 50 mg/kg.The pain threshold of the mice was then investigated by hot-plate test(HPPT).NMDA(0.05 or 0.075μg,icv)or AMPA(0.05 μg,icv)exhibited no effects on the LORR,but NMDA(0.1 μg,icv)or AMPA(0.075 or 0.1 μg,icv)prolonged the LORR significantly compared with the aCSF group(P<0.05,P<0.01).The LORR of the 2 μg MK-801 group had no changes,while those of the 4 or 8 μg MK-801 groups were prolonged significantly.The LORR of the 0.5,2 or 4 μg NBQX groups were all prolonged significantly.NMDA 0.05 μg or AMPA 0.05 μg decreased the pain threshold slightly but did not differ in effect compared with the aCSF group;2 μg MK-801 or 0.5 μg NBQX both increased the pain threshold significantly.Our results indicate that propofol produces general anesthesia partly through an interaction with brain NMDA and AMPA receptors in mice.

  20. AR DOC: Augmented reality documentaries

    DEFF Research Database (Denmark)

    Vistisen, Peter

    2014-01-01

    Augmented Reality Documentaries (AR DOC) er et ’lille’ Shareplay projekt (ansøgte midler augmented reality cross media løsninger, til at skabe engagerende publikumsformidling...... indenfor oplevelsesindustrien. Projektet har genereret ny viden omkring, hvordan fysisk og digital formidling kan understøttes via Augmented Reality som formidlingsformat....

  1. NMDA antagonist, but not nNOS inhibitor, requires AMPA receptors in the ventromedial prefrontal cortex (vmPFC) to induce antidepressant-like effects

    DEFF Research Database (Denmark)

    Pereira, V. S.; Wegener, Gregers; Joca, S. R.

    2013-01-01

    Depressed individuals and stressed animals show enhanced levels of glutamate and neuronal nitric oxide synthase (nNOS) activity in limbic structures, including the vmPFC. Systemic administration of glutamatergic NMDA receptor antagonists or inhibitors of nitric oxide (NO) synthesis induces antide...

  2. Severely impaired learning and altered neuronal morphology in mice lacking NMDA receptors in medium spiny neurons.

    Directory of Open Access Journals (Sweden)

    Lisa R Beutler

    Full Text Available The striatum is composed predominantly of medium spiny neurons (MSNs that integrate excitatory, glutamatergic inputs from the cortex and thalamus, and modulatory dopaminergic inputs from the ventral midbrain to influence behavior. Glutamatergic activation of AMPA, NMDA, and metabotropic receptors on MSNs is important for striatal development and function, but the roles of each of these receptor classes remain incompletely understood. Signaling through NMDA-type glutamate receptors (NMDARs in the striatum has been implicated in various motor and appetitive learning paradigms. In addition, signaling through NMDARs influences neuronal morphology, which could underlie their role in mediating learned behaviors. To study the role of NMDARs on MSNs in learning and in morphological development, we generated mice lacking the essential NR1 subunit, encoded by the Grin1 gene, selectively in MSNs. Although these knockout mice appear normal and display normal 24-hour locomotion, they have severe deficits in motor learning, operant conditioning and active avoidance. In addition, the MSNs from these knockout mice have smaller cell bodies and decreased dendritic length compared to littermate controls. We conclude that NMDAR signaling in MSNs is critical for normal MSN morphology and many forms of learning.

  3. AMI : Augmented Michelson Interferometer

    OpenAIRE

    Furio, David; Hachet, Martin; Guillet, Jean-Paul; Bousquet, Bruno; Fleck, Stéphanie; Reuter, Patrick; Canioni, Lionel

    2015-01-01

    International audience; Experiments in optics are essential for learning and understanding physical phenomena. The problem with these experiments is that they are generally time consuming for both their construction and their maintenance, potentially dangerous through the use of laser sources, and often expensive due to high technology optical components.We propose to simulate such experiments by way of hybrid systems that exploit both spatial augmented reality and tangible interaction. In pa...

  4. Augmented Reality als Bildungsenhancement?

    OpenAIRE

    Damberger, Thomas

    2015-01-01

    Die Realität, die sich mithilfe von Datenbrillen und Smartphone Applikationen in die virtuelle Welt hinein ausdehnt, erfährt eine Form des Enhancements. Ein solches Enhancement kann unter bestimmten Voraussetzungen als Bildungsenhancement verstanden werden. Der Text befasst sich mit Formen der erweiterten Realität, ferner mit dem, um was es wesentlich bei der Bildung geht und zuletzt mit den Bedingungen, die erforderlich sind, um diesem Wesentlichen mit Hilfe von augmented reality besser zum ...

  5. AUGMENTED REALITY BASED ASSISTANCE

    Directory of Open Access Journals (Sweden)

    N.R.Raajan

    2013-04-01

    Full Text Available The concept of Augmented Reality can be explained as a superimposition of computer generated two dimensional or three dimensional objects over the real time scene acquired into thecapturing device. Thus Augmented Reality adds additional information to the real scene and this can be implemented with the help of markers. The development of the application is simple and easier in case of AR. This idea is extended to the development of Augmented Reality based book that act as a tour guide. This travel guide can give all the basic information regarding the necessities of a finer travel around the places of the destinations. The application will detect the markers found in the real scene and superimpose them with multimedia data giving enormous information. The application can also be made to redirect to the web links for easy access of certain other utilities by interaction. The same idea can also be utilized in engineering laboratories to understand the working of the circuit by visualizing the working of the same circuit where the diagram itself can be used as a marker and thus enhancing the self learning among the students.

  6. NMDA-dependent mechanisms only affect the BOLD response in the rat dentate gyrus by modifying local signal processing

    Science.gov (United States)

    Tiede, Regina; Krautwald, Karla; Fincke, Anja; Angenstein, Frank

    2012-01-01

    The role of N-methyl--aspartate (NMDA) receptor-mediated mechanisms in the formation of a blood oxygen level-dependent (BOLD) response was studied using electrical stimulation of the right perforant pathway. Stimulation of this fiber bundle triggered BOLD responses in the right hippocampal formation and in the left entorhinal cortex. The perforant pathway projects to and activates the dentate gyrus monosynaptically, activation in the contralateral entorhinal cortex is multisynaptic and requires forwarding and processing of signals. Application of the NMDA receptor antagonist MK801 during stimulation had no effect on BOLD responses in the right dentate gyrus, but reduced the BOLD responses in the left entorhinal cortex. In contrast, application of MK801 before the first stimulation train reduced the BOLD response in both regions. Electrophysiological recordings revealed that the initial stimulation trains changed the local processing of the incoming signals in the dentate gyrus. This altered electrophysiological response was not further changed by a subsequent application of MK801, which is in agreement with an unchanged BOLD response. When MK801 was present during the first stimulation train, a dissimilar electrophysiological response pattern was observed and corresponds to an altered BOLD response, indicating that NMDA-dependent mechanisms indirectly affect the BOLD response, mainly via modifying local signal processing and subsequent propagation. PMID:22167232

  7. Caffeine withdrawal syndrome in social interaction test in mice: effects of the NMDA receptor channel blockers, memantine and neramexane.

    Science.gov (United States)

    Sukhotina, I A; Zvartau, E E; Danysz, W; Bespalov, A Y

    2004-05-01

    Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.

  8. NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons.

    Science.gov (United States)

    Molosh, Andrei I; Sajdyk, Tammy J; Truitt, William A; Zhu, Weiguo; Oxford, Gerry S; Shekhar, Anantha

    2013-06-01

    Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y1 receptor (Y1R) isoform. Activation of Y1Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y1Rs on synaptic transmission in the BLA. Activating Y1Rs by [Leu(31),Pro(34)]-NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABAA-mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y1R antagonist, PD160170. Intracellular GDP-β-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA- and GABAA-mediated currents. Thus, both the NMDA and GABAA effects of Y1R activation in the BLA are G-protein-mediated and cAMP-dependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABAA-mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABAA-mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABAA-mediated eIPSCs and Epac deactivation reducing NMDA-mediated eEPSCs. This multipathway regulation of NMDA- and GABAA-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

  9. Selective shunting of the NMDA EPSP component by the slow afterhyperpolarization in rat CA1 pyramidal neurons.

    Science.gov (United States)

    Fernández de Sevilla, David; Fuenzalida, Marco; Porto Pazos, Ana B; Buño, Washington

    2007-05-01

    Pyramidal neuron dendrites express voltage-gated conductances that control synaptic integration and plasticity, but the contribution of the Ca(2+)-activated K(+)-mediated currents to dendritic function is not well understood. Using dendritic and somatic recordings in rat hippocampal CA1 pyramidal neurons in vitro, we analyzed the changes induced by the slow Ca(2+)-activated K(+)-mediated afterhyperpolarization (sAHP) generated by bursts of action potentials on excitatory postsynaptic potentials (EPSPs) evoked at the apical dendrites by perforant path-Schaffer collateral stimulation. Both the amplitude and decay time constants of EPSPs (tau(EPSP)) were reduced by the sAHP in somatic recordings. In contrast, the dendritic EPSP amplitude remained unchanged, whereas tau(EPSP) was reduced. Temporal summation was reduced and spatial summation linearized by the sAHP. The amplitude of the isolated N-methyl-D-aspartate component of EPSPs (EPSP(NMDA)) was reduced, whereas tau(NMDA) was unaffected by the sAHP. In contrast, the sAHP did not modify the amplitude of the isolated EPSP(AMPA) but reduced tau(AMPA) both in dendritic and somatic recordings. These changes are attributable to a conductance increase that acted mainly via a selective "shunt" of EPSP(NMDA) because they were absent under voltage clamp, not present with imposed hyperpolarization simulating the sAHP, missing when the sAHP was inhibited with isoproterenol, and reduced under block of EPSP(NMDA). EPSPs generated at the basal dendrites were similarly modified by the sAHP, suggesting both a somatic and apical dendritic location of the sAHP channels. Therefore the sAHP may play a decisive role in the dendrites by regulating synaptic efficacy and temporal and spatial summation.

  10. 人迹地图:数据增强设计的支持平台%Human Activity Map:The Platform for Data Augmented Design

    Institute of Scientific and Technical Information of China (English)

    茅明睿; 储妍; 张鹏英; 沈忱

    2016-01-01

    手机信令、公共交通刷卡记录等大数据,以及来自商业网站和政府网站的开放数据共同促进了“新数据环境”的形成;时空行为数据是新数据环境下最有价值的数据类型之一,但规划设计行业的新数据应用问题仍然没能得到有效解决。分析了数据来源、分析工具和应用结合3方面的难点,在获取了全国范围的互联网LBS(Location Based Service)数据的基础上,对其从时间、空间和组群3个维度进行了解构和重组,率项目团队开发了人迹地图时空行为规划分析平台,提供了人流分析、锚点分析、人群分析和城市画像等功能,编写了基于人迹地图平台的《数据增强设计手册》框架,初步支撑了若干个规划项目,并探讨了人迹地图在未来规划设计中的价值。%‘Big data’ such as mobile phone signaling, public transportation smart card records and ‘open data’ from commercial websites and government websites jointly promote the formation of the ‘new data environment’.Spatial-temporal behavior data is one of the most valuable types in the new data environment, but the problem of new data application in urban planning and design still can’t be effectively resolved. This paper analyzes three dififculties: the data source, analysis tools and applications combination.Through cooperating with internet DMP (data management platform), the author obtains internet LBS (Location Based Service) data of 3 billion mobile devices and deconstructs and reorganizes the data from three dimensions:the time, the space and the group and developes a planning analysis platform: human activity map.The platform provides analyses about stream of people, anchor, groups and city proifle. The author writes the frame of Data Augmented Design Manual based on the platform of human activity map, assists of several planning projects, and discusses the value of human activity map in the future planning.

  11. Augmented Reality to Access Dam Cracks Information

    Directory of Open Access Journals (Sweden)

    Fabiana Frata Furlan Peres

    2016-03-01

    Full Text Available Augmented reality technology is a tool with great potential for application in several areas, including engineering. During the early phases of the enterprise life cycle, as design and construction, augmented reality has been widely used. Concrete dams, during operation and maintenance phase, require regular inspections as part of the necessary activities to keep their structural safety. Cracks are common pathology in these structures that must be detected, mapped and measured as their evolution may evidence structure compromising, need for maintenance or intervention. In this context this paper aims to present a prototype to access in situ the dam cracks information through the use of augmented reality, thus giving a contribution to the effectiveness and efficiency of inspections

  12. NMDA receptors and fear extinction: implications for cognitive behavioral therapy.

    Science.gov (United States)

    Davis, Michael

    2011-01-01

    Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyi-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy.

  13. Efficacies of treatments for anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Wang, Hsiuying

    2016-01-01

    Treatments for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis include immunotherapy with steroids, intravenous immunoglobulin, plasma exchange, or plasmapheresis as first-line treatments, immunotherapy with rituximab or cyclophosphamide as second-line treatments, and tumor removal. In this systematic review, we evaluated previous studies and examined the association between certain microRNAs and anti-NMDA receptor encephalitis to investigate the performance of different treatment combinations. The efficacies of different combinations of treatments classified into the following four categories were compared: (I) intravenous immunoglobulin administration, (II) plasmapheresis or plasma exchange, (III) treatment with rituximab or cyclophosphamide and (IV) tumor removal. Statistical analyses showed that treatment combinations including at least two of these categories resulted in higher efficacy rates than treatment with a single form of therapy. These findings suggest that if a patient is not recovering, converting to other therapies is more likely to result in early recovery than continuing on the original therapy.

  14. PACAP modulates the consolidation and extinction of the contextual fear conditioning through NMDA receptors.

    Science.gov (United States)

    Schmidt, S D; Myskiw, J C; Furini, C R G; Schmidt, B E; Cavalcante, L E; Izquierdo, I

    2015-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has a broad spectrum of biological functions including neurotransmitter, neurotrophic and neuroprotective. Moreover, it has been suggested that PACAP plays a role in the modulation of learning and memory as well as on the modulation of glutamate signaling. Thus, in the current study we investigated in the CA1 region of hippocampus and in the basolateral amygdala (BLA) the role of PACAP in the consolidation and extinction of contextual fear conditioning (CFC) and the interaction between PACAP and NMDA receptors. Male rats with cannulae implanted in the CA1 region of the hippocampus or in the BLA received immediately after the training or extinction training of the CFC infusions of the Vehicle, PACAP-38 (40 pg/side), PACAP 6-38 (40 pg/side) or PACAP 6-38 plus D-serine (50 μg/side). After 24h, the animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of hippocampus, PACAP participates in the consolidation and extinction of the CFC, and in the BLA, PACAP participates only in the consolidation of the CFC. Additionally, the results suggest that the action of PACAP on the consolidation and extinction of the CFC is mediated by the glutamate NMDA receptors.

  15. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.

    Science.gov (United States)

    Carlén, M; Meletis, K; Siegle, J H; Cardin, J A; Futai, K; Vierling-Claassen, D; Rühlmann, C; Jones, S R; Deisseroth, K; Sheng, M; Moore, C I; Tsai, L-H

    2012-05-01

    Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.

  16. Conditional knockout of NMDA receptors in dopamine neurons prevents nicotine-conditioned place preference.

    Directory of Open Access Journals (Sweden)

    Lei Phillip Wang

    Full Text Available Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction.

  17. Molecular lock regulates binding of glycine to a primitive NMDA receptor.

    Science.gov (United States)

    Yu, Alvin; Alberstein, Robert; Thomas, Alecia; Zimmet, Austin; Grey, Richard; Mayer, Mark L; Lau, Albert Y

    2016-11-01

    The earliest metazoan ancestors of humans include the ctenophore Mnemiopsis leidyi The genome of this comb jelly encodes homologs of vertebrate ionotropic glutamate receptors (iGluRs) that are distantly related to glycine-activated NMDA receptors and that bind glycine with unusually high affinity. Using ligand-binding domain (LBD) mutants for electrophysiological analysis, we demonstrate that perturbing a ctenophore-specific interdomain Arg-Glu salt bridge that is notably absent from vertebrate AMPA, kainate, and NMDA iGluRs greatly increases the rate of recovery from desensitization, while biochemical analysis reveals a large decrease in affinity for glycine. X-ray crystallographic analysis details rearrangements in the binding pocket stemming from the mutations, and molecular dynamics simulations suggest that the interdomain salt bridge acts as a steric barrier regulating ligand binding and that the free energy required to access open conformations in the glycine-bound LBD is largely responsible for differences in ligand affinity among the LBD variants.

  18. NMDA-induced burst discharge in guinea pig trigeminal motoneurons in vitro.

    Science.gov (United States)

    Kim, Y I; Chandler, S H

    1995-07-01

    1. The responses of guinea pig trigeminal motoneurons (TMNs) to N-methyl-D,L-aspartate (NMA) were studied using brain stem slice preparations and whole cell patch-clamp (n = 89) or conventional microelectrode (n = 22) recording techniques. The primary goals of this study were to determine whether N-methyl-D-aspartate (NMDA) receptor activation would produce spontaneous bursting activity in TMNs and, if so, the underlying mechanisms responsible for the generation of these bursts. 2. Bath-applied NMA (100-300 microM, n = 80) in standard perfusion medium elicited depolarization, increase in apparent input resistance (Rinp), and rhythmic burst discharges (1-90 s in duration) from TMNs. These effects were blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5, 30 microM, n = 6), but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5-10 microM, n = 10). Furthermore, the burst-inducing effect of NMA was not mimicked by the non-NMDA receptor agonists kainate (KA, 5-10 microM, n = 6) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 5-10 microM, n = 5). 3. In tetrodotoxin (TTX) treatment conditions (n = 13), NMA elicited depolarization, an increase in apparent Rinp, and rhythmic membrane potential oscillations without action potential bursts (i.e., plateau potentials), suggesting that the effects of NMA observed in the TTX-free condition resulted from activation of postsynaptic NMDA receptors. 4. Graded depolarization of neurons (n = 20) by intracellular direct current injection generally led to a graded increase in frequency and duration of the NMA-induced bursts and plateau potentials until these rhythmic events eventually became transformed into continuous spike discharge and maintained depolarization, respectively. Removal of Mg2+ from the perfusion medium (n = 11) also turned the bursts and plateau potentials into continuous spike discharge and maintained depolarization, respectively

  19. Transient brain ischemia: NMDA receptor modulation and delayed neuronal death

    OpenAIRE

    Benquet, Pascal; Gee, Christine E.; Gerber, Urs

    2008-01-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiolo...

  20. Increased NMDA receptor inhibition at an increased Sevoflurane MAC

    Directory of Open Access Journals (Sweden)

    Brosnan Robert J

    2012-06-01

    Full Text Available Abstract Background Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC. Methods Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 μL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL plus 0.4 mg/mL dizocilpine (MK-801 was administered intrathecally at 4 μL/min, and the post-dizocilpine sevoflurane MAC was measured. Results Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P  Conclusions Glycine receptor antagonism increases NMDA receptor antagonism by sevoflurane at MAC. The magnitude of anesthetic effects on a given ion channel may therefore depend on the magnitude of its effects on other receptors that modulate neuronal excitability.

  1. The PARP inhibitor benzamide protects against kainate and NMDA but not AMPA lesioning of the mouse striatum in vivo.

    Science.gov (United States)

    Cosi, Cristina; Guerin, Karen; Marien, Marc; Koek, Wouter; Rollet, Karin

    2004-01-16

    Overactivation of poly(ADP-ribose) polymerase (PARP) in response to genotoxic insults can cause cell death by energy deprivation. We previously reported that neurotoxic amounts of kainic acid (KA) injected into the rat striatum produce time-dependent changes in striatal PARP activity in vivo. Here, we have investigated the time-course of KA-induced toxicity and the effects of the PARP inhibitor benzamide on KA, AMPA and NMDA neurotoxicities in vivo, by measuring changes in the volume of the lesion and in NAD+ and ATP levels induced by the intra-striatal injection of these excitotoxins in C57Bl/6N mice. The KA-induced lesion volume was dependent on the amount of toxin injected and the survival time. The lesion was well developed at 48 h and was almost undetectable after one week. KA produced an extensive astrogliosis at one week. Benzamide partially prevented both KA- and NMDA- but not AMPA-induced lesions when measured at 48 h after the treatment. The effects of benzamide appeared to be in part related to changes in energy metabolism, since KA produced decreases in striatal levels of NAD+ and ATP that were partially prevented by benzamide at 48 h and which returned to control levels at one week. NMDA did not affect NAD+ and induced little alteration in ATP levels. Benzamide had no effect on AMPA-induced decreases in either NAD+ or ATP levels at 48 h. These results (1) indicate that PARP overactivation and energy depletion could be responsible in part for the cellular demise during the development of the lesion induced by KA; (2) confirm that PARP is involved in NMDA but not AMPA toxicities; (3) suggest the existence of differences between KA and AMPA-mediated toxicities; and (4) provide further evidence supporting PARP as a novel target for new drug treatments against neurodegenerative disorders.

  2. Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function

    KAUST Repository

    Kiraly, D. D.

    2011-08-31

    The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.

  3. Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus.

    Science.gov (United States)

    Hayashi, Yuichiro; Nabeshima, Yoko; Kobayashi, Katsunori; Miyakawa, Tsuyoshi; Tanda, Koichi; Takao, Keizo; Suzuki, Hidenori; Esumi, Eisaku; Noguchi, Shigeru; Matsuda, Yukiko; Sasaoka, Toshikuni; Noda, Tetsuo; Miyazaki, Jun-ichi; Mishina, Masayoshi; Funabiki, Kazuo; Nabeshima, Yo-ichi

    2014-06-04

    Voltage-dependent block of the NMDA receptor by Mg2+ is thought to be central to the unique involvement of this receptor in higher brain functions. However, the in vivo role of the Mg2+ block in the mammalian brain has not yet been investigated, because brain-wide loss of the Mg2+ block causes perinatal lethality. In this study, we used a brain-region specific knock-in mouse expressing an NMDA receptor that is defective for the Mg2+ block in order to test its role in neural information processing. We devised a method to induce a single amino acid substitution (N595Q) in the GluN2A subunit of the NMDA receptor, specifically in the hippocampal dentate gyrus in mice. This mutation reduced the Mg2+ block at the medial perforant path-granule cell synapse and facilitated synaptic potentiation induced by high-frequency stimulation. The mutants had more stable hippocampal place fields in the CA1 than the controls did, and place representation showed lower sensitivity to visual differences. In addition, behavioral tests revealed that the mutants had a spatial working memory deficit. These results suggest that the Mg2+ block in the dentate gyrus regulates hippocampal spatial information processing by attenuating activity-dependent synaptic potentiation in the dentate gyrus.

  4. Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats.

    Science.gov (United States)

    Krawczyk, Michal; deBacker, Julian; Mason, Xenos; Jones, Andrea A; Dumont, Eric C

    2014-06-03

    Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.

  5. Recovery from severe frontotemporal dysfunction at 3years after N-methyl-d-aspartic acid (NMDA) receptor antibody encephalitis.

    Science.gov (United States)

    Leypoldt, Frank; Gelderblom, Mathias; Schöttle, Daniel; Hoffmann, Sascha; Wandinger, Klaus-Peter

    2013-04-01

    Encephalitis associated with antibodies against N-methyl-d-aspartic acid (NMDA) receptor is characterized by severe memory deficits, decreased consciousness, epileptic seizures and movement disorders and occurs most commonly in young women. Recovery is mostly good but little is known about the disease course in patients whose treatment has been delayed severely. We present a 16-year-old girl with a 36-month follow-up. A single course of methylprednisolone attenuated some symptoms but severe and incapacitating frontotemporal syndrome remained. Second-line treatment with rituximab was initiated 12months after the onset of symptoms. A surprising recovery occurred 18months after treatment and 30months after onset. Recovery in NMDA receptor antibody-associated encephalitis can be severely delayed and does not have to be linear. Whether delayed therapy contributed to recovery in this patient cannot be answered with certainty. Spontaneous recovery independent of therapy is possible, as it has been observed previously as late as 3years after onset. Although serum antibodies disappeared with recovery in this patient, previous cases have shown serum antibodies to be unreliable markers of disease activity. Second-line treatment, especially with substances as well tolerated as rituximab, should at least be considered in NMDA receptor encephalitis with persistent neuropsychiatric syndromes after first-line therapy.

  6. NMDA receptor antagonists extend the sensitive period for imprinting.

    Science.gov (United States)

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

  7. Catatonic Syndrome in Anti-NMDA Receptor Encephalitis

    Science.gov (United States)

    Mythri, Starlin Vijay; Mathew, Vivek

    2016-01-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a newly recognised autoimmune condition. With its typical clinical pattern, consistent association with the presence of auto antibodies and rapid improvement with immunotherapy, this condition is giving insights into the boundaries between psychiatry and other neurosciences, and is opening avenues for future research. In a young lady who presented with catatonia, we considered anti-NMDA receptor encephalitis, after ruling out other aetiologies. After a positive antibody test we treated her with immunotherapy. She showed gradual improvement in her psychotic and catatonic symptoms. Knowledge regarding the nature and function of NMDA receptors and pathophysiology of this particular encephalitis is important for psychiatric practice. The great opportunity for research in this area due to its association with psychotic disorders is evident but an appeal to temper the enthusiasm by considering the historical lessons learnt from Karl Jaspers’ critique of General Paresis of Insane, is in place. Catatonic syndrome has to be conceptualised broadly and should be recognised with a separate nosological position. PMID:27114630

  8. Synthesis and NMDA receptor affinity of fluorinated dioxadrol analogues.

    Science.gov (United States)

    Banerjee, Ashutosh; Schepmann, Dirk; Wünsch, Bernhard

    2010-06-01

    A series of dioxadrol analogues with fluorine substituents in position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. The key step in the synthesis was the fluorination of diastereomeric piperidones 6a and 6c as well as diastereomeric alcohols 9a and 9c with DAST. The reaction of the alcohols 9a and 9c took place with inversion of configuration. After removal of the Cbz-protective group, the NMDA receptor affinities of the resulting secondary amines 8a, 8c, 12b, and 12d were investigated in receptor binding studies. It was shown that the like-configuration of the ring junction was crucial for high NMDA receptor affinity. An axially oriented fluorine atom in position 4 led to 2-(2,2-diphenyl-1,3-dioxolan-4-yl)-4-fluoropiperidine (12d, WMS-2517) with a K(i)-value of 27nM. The NMDA receptor affinity of 8c (WMS-2513) with an additional fluorine atom in equatorial 4-position was slightly reduced (K(i)=81 nM). Both fluorinated dioxadrol derivatives 8c and 12d showed high selectivity against sigma(1) and sigma(2) receptors as well as the polyamine binding site of NR2B receptors.

  9. Catatonic syndrome in anti-NMDA receptor encephalitis

    Directory of Open Access Journals (Sweden)

    Starlin Vijay Mythri

    2016-01-01

    Full Text Available Anti-N-methyl-D-aspartate (NMDA receptor encephalitis is a newly recognised autoimmune condition. With its typical clinical pattern, consistent association with the presence of auto antibodies and rapid improvement with immunotherapy, this condition is giving insights into the boundaries between psychiatry and other neurosciences, and is opening avenues for future research. In a young lady who presented with catatonia, we considered anti-NMDA receptor encephalitis, after ruling out other aetiologies. After a positive antibody test we treated her with immunotherapy. She showed gradual improvement in her psychotic and catatonic symptoms. Knowledge regarding the nature and function of NMDA receptors and pathophysiology of this particular encephalitis is important for psychiatric practice. The great opportunity for research in this area due to its association with psychotic disorders is evident but an appeal to temper the enthusiasm by considering the historical lessons learnt from Karl Jaspers′ critique of General Paresis of Insane, is in place. Catatonic syndrome has to be conceptualised broadly and should be recognised with a separate nosological position.

  10. Alcohol and NMDA Receptor: Current research and future direction

    Directory of Open Access Journals (Sweden)

    Raman eChandrasekar

    2013-05-01

    Full Text Available The brain is one of the major targets of alcohol actions. Most of the excitatory synaptic transmission in the central nervous system is mediated by NMDA receptors. However, one of the most devastating effects of alcohol leads to brain shrinkage, loss of nerve cells at specific regions through a mechanism involving excitotoxicity, oxidative stress. Earlier studies have indicated that chronic exposure to ethanol both in vivo and in vitro, increases NR1 and NR2B gene expression and their polypeptide levels. The effect of alcohol and molecular changes on the regulatory process, which modulates NMDAR functions including factors altering transcription, translation, post-translational modifications and protein expression, as well as those influencing their interactions with different regulatory proteins (downstream effectors are incessantly increasing at the cellular level. Further, I discuss the various genetically altered mice approaches that have been used to study NMDA receptor subunits and their functional implication. In a recent countable review, epigenetic dimension (i.e., histone modification-induced chromatin remodeling and DNA methylation, in the process of alcohol related neuroadapation is one of the key molecular mechanisms in alcohol mediated NMDAR alteration. Here, I provide a recount on what has already been achieved, current trends and how the future research/studies of the NMDA receptor might lead to even greater engagement with many possible new insights into the neurobiology and treatment of alcoholism.

  11. Alcohol and NMDA receptor: current research and future direction.

    Science.gov (United States)

    Chandrasekar, Raman

    2013-01-01

    The brain is one of the major targets of alcohol actions. Most of the excitatory synaptic transmission in the central nervous system is mediated by N-methyl-D-aspartate (NMDA) receptors. However, one of the most devastating effects of alcohol leads to brain shrinkage, loss of nerve cells at specific regions through a mechanism involving excitotoxicity, oxidative stress. Earlier studies have indicated that chronic exposure to ethanol both in vivo and in vitro, increases NR1 and NR2B gene expression and their polypeptide levels. The effect of alcohol and molecular changes on the regulatory process, which modulates NMDAR functions including factors altering transcription, translation, post-translational modifications, and protein expression, as well as those influencing their interactions with different regulatory proteins (downstream effectors) are incessantly increasing at the cellular level. Further, I discuss the various genetically altered mice approaches that have been used to study NMDA receptor subunits and their functional implication. In a recent countable review, epigenetic dimension (i.e., histone modification-induced chromatin remodeling and DNA methylation, in the process of alcohol related neuroadaptation) is one of the key molecular mechanisms in alcohol mediated NMDAR alteration. Here, I provide a recount on what has already been achieved, current trends and how the future research/studies of the NMDA receptor might lead to even greater engagement with many possible new insights into the neurobiology and treatment of alcoholism.

  12. Catatonic Syndrome in Anti-NMDA Receptor Encephalitis.

    Science.gov (United States)

    Mythri, Starlin Vijay; Mathew, Vivek

    2016-01-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a newly recognised autoimmune condition. With its typical clinical pattern, consistent association with the presence of auto antibodies and rapid improvement with immunotherapy, this condition is giving insights into the boundaries between psychiatry and other neurosciences, and is opening avenues for future research. In a young lady who presented with catatonia, we considered anti-NMDA receptor encephalitis, after ruling out other aetiologies. After a positive antibody test we treated her with immunotherapy. She showed gradual improvement in her psychotic and catatonic symptoms. Knowledge regarding the nature and function of NMDA receptors and pathophysiology of this particular encephalitis is important for psychiatric practice. The great opportunity for research in this area due to its association with psychotic disorders is evident but an appeal to temper the enthusiasm by considering the historical lessons learnt from Karl Jaspers' critique of General Paresis of Insane, is in place. Catatonic syndrome has to be conceptualised broadly and should be recognised with a separate nosological position.

  13. Augmenting Clozapine With Sertindole

    DEFF Research Database (Denmark)

    Nielsen, Jimmi; Emborg, Charlotte; Gydesen, Susanne

    2012-01-01

    randomized 1:1 to either sertindole 16 mg or placebo, and assessment was done at baseline and after 6 and 12 weeks. Assessment included the Positive and Negative Syndrome Scale, Clinical Global Impression, Udvalg for Kliniske Undersøgelser, World Health Organization Quality of Life Brief, Drug Attitude...... Inventory, fasting glucose, lipids, and electrocardiogram. Clozapine augmentation with sertindole was not superior to placebo regarding total score or subscale score of the Positive and Negative Syndrome Scale, Clinical Global Impression, World Health Organization Quality of Life Brief, or Drug Attitude...

  14. Mutually Augmented Cognition

    Science.gov (United States)

    Friesdorf, Florian; Pangercic, Dejan; Bubb, Heiner; Beetz, Michael

    In mac, an ergonomic dialog-system and algorithms will be developed that enable human experts and companions to be integrated into knowledge gathering and decision making processes of highly complex cognitive systems (e.g. Assistive Household as manifested further in the paper). In this event we propose to join algorithms and methodologies coming from Ergonomics and Artificial Intelligence that: a) make cognitive systems more congenial for non-expert humans, b) facilitate their comprehension by utilizing a high-level expandable control code for human experts and c) augment representation of such cognitive system into “deep representation” obtained through an interaction with human companions.

  15. Radiative Augmented Combustion.

    Science.gov (United States)

    1985-08-12

    86-0085 In 00I to RADIATIVE AUGMENTED COMBUSTION MOSHE LAVID M.L. ENERGIA , INC. P.O. BOX 1468 1 PRINCETON, NEW JERSEY 08542 AUGUST 1985 *.. plo...Combustion conducted at M.L. ENERGIA . It is funded by the Air Force Office of Scientific Research under Contract No. F49620-83-C-0133, with Dr. J.M...reported. It covers the second year of the contract, from July 15, 1984 through July 14, 1985. The work was performed at ENERGIA , Princeton, New Jersey

  16. Augmented Reality Oculus Rift

    OpenAIRE

    Höll, Markus; Heran, Nikolaus; Lepetit, Vincent

    2016-01-01

    This paper covers the whole process of developing an Augmented Reality Stereoscopig Render Engine for the Oculus Rift. To capture the real world in form of a camera stream, two cameras with fish-eye lenses had to be installed on the Oculus Rift DK1 hardware. The idea was inspired by Steptoe \\cite{steptoe2014presence}. After the introduction, a theoretical part covers all the most neccessary elements to achieve an AR System for the Oculus Rift, following the implementation part where the code ...

  17. Anti-NMDA Receptor antibody encephalitis with concomitant detection of Varicella zoster virus.

    Science.gov (United States)

    Solís, Natalia; Salazar, Lucrecia; Hasbun, Rodrigo

    2016-10-01

    The typical presentation of anti-NMDA (N-Methyl-d-Aspartate) receptor encephalitis involves young women with psychiatric, neurologic and autonomic symptoms; it is often associated with mature ovarian teratomas. NMDA receptor encephalitis has been described following Herpes simplex virus (HSV) encephalitis. This case describes a classic presentation of anti-NMDA receptor encephalitis with the concomitant presence of Varicella zoster virus in the cerebrospinal fluid.

  18. NMDA-mediated and Self-induced Bdnf Exon IV Transcriptions are Differentially Regulated in Cultured Cortical Neurons

    OpenAIRE

    Zheng, Fei; Wang, Hongbing

    2009-01-01

    Activity-dependent transcriptional up-regulation of bdnf (brain-derived neurotrophic factor) is involved in regulating many aspects of neuronal functions. The NMDA (N-methyl-D-aspartic acid)-mediated and BDNF-mediated exon IV transcription may represent mechanistically different responses, and relevant to activity-dependent changes in neurons. We found that the activities of ERK (extracellular signal-regulated kinase), CaM KII/IV (calmodulin-dependent protein kinase II and IV), PI3K (phosphoi...

  19. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis.

    Science.gov (United States)

    Wandinger, Klaus-Peter; Saschenbrecker, Sandra; Stoecker, Winfried; Dalmau, Josep

    2011-02-01

    Anti-NMDA-receptor encephalitis is a severe, treatable and potentially reversible disorder presenting with memory deficits, psychiatric symptoms and seizures. Initially described in young patients with ovarian teratoma, the disease is meanwhile increasingly recognized also in women without tumours, in men and in children. The presence of anti-glutamate receptor (type NMDA) autoantibodies in serum or cerebrospinal fluid is specific for this novel and widely underdiagnosed disorder. Early recognition is crucial since prognosis largely depends on adequate immunotherapy and, in paraneoplastic cases, complete tumour removal. Indirect immunofluorescence using NMDA-type glutamate receptors recombinantly expressed in human cells is a highly competent method for diagnosing anti-NMDA-receptor encephalitis.

  20. The role of NMDA receptors in human eating behavior: evidence from a case of anti-NMDA receptor encephalitis

    OpenAIRE

    Perogamvros, Lampros; Schnider, Armin; Leemann, Béatrice Anne Valérie

    2012-01-01

    Research in animal models has implicated N-methyl-D-aspartate (NMDA) receptors (NMDARs) in the control of food intake. Until now, these findings have been not replicated in humans. Here we describe a 22-year-old woman with anti-NMDAR encephalitis and no prior neurological or psychiatric history. Her clinical course was marked by successive eating disorders: anorexia followed by hyperphagia. We propose that, much as they do in other animals, NMDARs in humans interact with the neuroendocrine, h...

  1. Augmented Reality for Science Education

    DEFF Research Database (Denmark)

    Brandt, Harald; Nielsen, Birgitte Lund; Georgsen, Marianne

    2015-01-01

    Augmented reality (AR) holds great promise as a learning tool. So far, however, most research has looked at the technology itself – and AR has been used primarily for commercial purposes. As a learning tool, AR supports an inquiry-based approach to science education with a high level of student...... involvement. The AR-sci-project (Augmented Reality for SCIence education) addresses the issue of applying augmented reality in developing innovative science education and enhancing the quality of science teaching and learning....

  2. Augmented Reality for Science Education

    DEFF Research Database (Denmark)

    Brandt, Harald; Nielsen, Birgitte Lund; Georgsen, Marianne

    Augmented reality (AR) holds great promise as a learning tool. So far, however, most research has looked at the technology itself – and AR has been used primarily for commercial purposes. As a learning tool, AR supports an inquiry-based approach to science education with a high level of student...... involvement. The AR-sci-project (Augmented Reality for SCIence education) addresses the issue of applying augmented reality in developing innovative science education and enhancing the quality of science teaching and learning....

  3. Local constraints in either the GluN1 or GluN2 subunit equally impair NMDA receptor pore opening

    Science.gov (United States)

    Talukder, Iehab

    2011-01-01

    The defining functional feature of N-methyl-d-aspartate (NMDA) receptors is activation gating, the energetic coupling of ligand binding into opening of the associated ion channel pore. NMDA receptors are obligate heterotetramers typically composed of glycine-binding GluN1 and glutamate-binding GluN2 subunits that gate in a concerted fashion, requiring all four ligands to bind for subsequent opening of the channel pore. In an individual subunit, the extracellular ligand-binding domain, composed of discontinuous polypeptide segments S1 and S2, and the transmembrane channel–forming domain, composed of M1–M4 segments, are connected by three linkers: S1–M1, M3–S2, and S2–M4. To study subunit-specific events during pore opening in NMDA receptors, we impaired activation gating via intrasubunit disulfide bonds connecting the M3–S2 and S2–M4 in either the GluN1 or GluN2A subunit, thereby interfering with the movement of the M3 segment, the major pore-lining and channel-gating element. NMDA receptors with gating impairments in either the GluN1 or GluN2A subunit were dramatically resistant to channel opening, but when they did open, they showed only a single-conductance level indistinguishable from wild type. Importantly, the late gating steps comprising pore opening to its main long-duration open state were equivalently affected regardless of which subunit was constrained. Thus, the NMDA receptor ion channel undergoes a pore-opening mechanism in which the intrasubunit conformational dynamics at the level of the ligand-binding/transmembrane domain (TMD) linkers are tightly coupled across the four subunits. Our results further indicate that conformational freedom of the linkers between the ligand-binding and TMDs is critical to the activation gating process. PMID:21746848

  4. Crime Scenes as Augmented Reality

    DEFF Research Database (Denmark)

    Sandvik, Kjetil

    2010-01-01

    Using the concept of augmented reality, this article will investigate how places in various ways have become augmented by means of different mediatization strategies. Augmentation of reality implies an enhancement of the places' emotional character: a certain mood, atmosphere or narrative surplus......, physical damage: they are all readable and interpretable signs. As augmented reality the crime scene carries a narrative which at first is hidden and must be revealed. Due to the process of investigation and the detective's ability to reason and deduce, the crime scene as place is reconstructed as virtual...

  5. Augmented reality in medical education?

    National Research Council Canada - National Science Library

    Kamphuis, Carolien; Barsom, Esther; Schijven, Marlies; Christoph, Noor

    2014-01-01

    .... Educational technology and more specifically augmented reality (AR) has the potential to offer a highly realistic situated learning experience supportive of complex medical learning and transfer...

  6. Crime Scenes as Augmented Reality

    DEFF Research Database (Denmark)

    Sandvik, Kjetil

    2010-01-01

    Using the concept of augmented reality, this article will investigate how places in various ways have become augmented by means of different mediatization strategies. Augmentation of reality implies an enhancement of the places' emotional character: a certain mood, atmosphere or narrative surplus......, physical damage: they are all readable and interpretable signs. As augmented reality the crime scene carries a narrative which at first is hidden and must be revealed. Due to the process of investigation and the detective's ability to reason and deduce, the crime scene as place is reconstructed as virtual...

  7. Inhibition of the NMDA receptor/Nitric Oxide pathway in the dorsolateral periaqueductal gray causes anxiolytic-like effects in rats submitted to the Vogel conflict test

    Directory of Open Access Journals (Sweden)

    Guimarães Francisco S

    2009-09-01

    Full Text Available Abstract Background Several studies had demonstrated the involvement of the dorsolateral portion of periaqueductal grey matter (dlPAG in defensive responses. This region contains a significant number of neurons containing the enzyme nitric oxide synthase (NOS and previous studies showed that non-selective NOS inhibition or glutamate NMDA-receptor antagonism in the dlPAG caused anxiolytic-like effects in the elevated plus maze. Methods In the present study we verified if the NMDA/NO pathway in the dlPAG would also involve in the behavioral suppression observed in rats submitted to the Vogel conflict test. In addition, the involvement of this pathway was investigated by using a selective nNOS inhibitor, Nω-propyl-L-arginine (N-Propyl, 0.08 nmol/200 nL, a NO scavenger, carboxy-PTIO (c-PTIO, 2 nmol/200 nL and a specific NMDA receptor antagonist, LY235959 (4 nmol/200 nL. Results Intra-dlPAG microinjection of these drugs increased the number of punished licks without changing the number of unpunished licks or nociceptive threshold, as measure by the tail flick test. Conclusion The results indicate that activation of NMDA receptors and increased production of NO in the dlPAG are involved in the anxiety behavior displayed by rats in the VCT.

  8. Synergistic antidepressant-like effect of the joint administration of caffeine and NMDA receptor ligands in the forced swim test in mice.

    Science.gov (United States)

    Serefko, Anna; Szopa, Aleksandra; Wlaź, Aleksandra; Wośko, Sylwia; Wlaź, Piotr; Poleszak, Ewa

    2016-04-01

    The optimal treatment of depressed patients remains one of the most important challenges concerning depression. The identification of the best treatment strategies and development of new, safer, and more effective agents are crucial. The glutamatergic system seems to be a promising drug target, and consequently the use of the NMDA receptor ligands, particularly in co-administration with other substances exerting the antidepressant activity, has emerged among the new ideas. The objective of this study was to examine the effect of caffeine on the performance of mice treated with various NMDA modulators in the forced swim test. We demonstrated a significant interaction between caffeine (5 mg/kg) and the following NMDA receptor ligands: MK-801 (an antagonist binding in the ion channel, 0.05 mg/kg), CGP 37849 (an antagonist of the glutamate site, 0.312 mg/kg), L-701,324 (an antagonist of the glycine site, 1 mg/kg), and D-cycloserine (a high-efficacy partial agonist of the glycine site, 2.5 mg/kg), while the interaction between caffeine and the inorganic modulators, i.e., Zn(2+) (2.5 mg/kg) and Mg(2+) (10 mg/kg), was not considered as significant. Based on the obtained results, the simultaneous blockage of the adenosine and NMDA receptors may be a promising target in the development of new antidepressants.

  9. Chronic NMDA administration to rats increases brain pro-apoptotic factors while decreasing anti-Apoptotic factors and causes cell death

    Directory of Open Access Journals (Sweden)

    Rapoport Stanley I

    2009-09-01

    Full Text Available Abstract Background Chronic N-Methyl-d-aspartate (NMDA administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days to rats would alter expression of pro- and anti-apoptotic factors in frontal cortex, compared with vehicle control. Results Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3ζ was increased, as well as Fluoro-Jade B (FJB staining, a marker of neuronal loss. Conclusion This alteration in the balance between pro- and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity.

  10. The Effect of an Augmented Reality Enhanced Mathematics Lesson on Student Achievement and Motivation

    Science.gov (United States)

    Estapa, Anne; Nadolny, Larysa

    2015-01-01

    The purpose of the study was to assess student achievement and motivation during a high school augmented reality mathematics activity focused on dimensional analysis. Included in this article is a review of the literature on the use of augmented reality in mathematics and the combination of print with augmented reality, also known as interactive…

  11. The Effect of an Augmented Reality Enhanced Mathematics Lesson on Student Achievement and Motivation

    Science.gov (United States)

    Estapa, Anne; Nadolny, Larysa

    2015-01-01

    The purpose of the study was to assess student achievement and motivation during a high school augmented reality mathematics activity focused on dimensional analysis. Included in this article is a review of the literature on the use of augmented reality in mathematics and the combination of print with augmented reality, also known as interactive…

  12. Potentiation of NMDA receptor-dependent cell responses by extracellular high mobility group box 1 protein.

    Directory of Open Access Journals (Sweden)

    Marco Pedrazzi

    Full Text Available BACKGROUND: Extracellular high mobility group box 1 (HMGB1 protein can operate in a synergistic fashion with different signal molecules promoting an increase of cell Ca(2+ influx. However, the mechanisms responsible for this effect of HMGB1 are still unknown. PRINCIPAL FINDINGS: Here we demonstrate that, at concentrations of agonist per se ineffective, HMGB1 potentiates the activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR in isolated hippocampal nerve terminals and in a neuroblastoma cell line. This effect was abolished by the NMDA channel blocker MK-801. The HMGB1-facilitated NMDAR opening was followed by activation of the Ca(2+-dependent enzymes calpain and nitric oxide synthase in neuroblastoma cells, resulting in an increased production of NO, a consequent enhanced cell motility, and onset of morphological differentiation. We have also identified NMDAR as the mediator of HMGB1-stimulated murine erythroleukemia cell differentiation, induced by hexamethylenebisacetamide. The potentiation of NMDAR activation involved a peptide of HMGB1 located in the B box at the amino acids 130-139. This HMGB1 fragment did not overlap with binding sites for other cell surface receptors of HMGB1, such as the advanced glycation end products or the Toll-like receptor 4. Moreover, in a competition assay, the HMGB1((130-139 peptide displaced the NMDAR/HMGB1 interaction, suggesting that it comprised the molecular and functional site of HMGB1 regulating the NMDA receptor complex. CONCLUSION: We propose that the multifunctional cytokine-like molecule HMGB1 released by activated, stressed, and damaged or necrotic cells can facilitate NMDAR-mediated cell responses, both in the central nervous system and in peripheral tissues, independently of other known cell surface receptors for HMGB1.

  13. PARAMETERS OF AUGMENTED REALITY AND ITS USE IN EDUCATION

    Directory of Open Access Journals (Sweden)

    JEŘÁBEK, Tomáš

    2013-12-01

    Full Text Available This article examines the issue of augmented reality and possibilities of its application in education. It briefly reports on selected results of a broader survey focused on technological, psychological, physiological and didactical aspects of the issue. It presumes that augmented reality has its unique place in technical teaching tools since it is a technological-perception concept, which in certain didactical situations creates more suitable perceptual environment than real environment itself on one hand, or virtual environment on the other. It focuses on identification of the technological-functional properties and specifics of augmented reality systems and on verification of model examples of augmented reality applications in school practice. It characterizes the course and results of empirical research project based on a descriptive case study exploring the cases of implementing selected application solutions of augmented reality into learning experience in accordance with the model of pro-active action research.

  14. Augmented reality system

    Science.gov (United States)

    Lin, Chien-Liang; Su, Yu-Zheng; Hung, Min-Wei; Huang, Kuo-Cheng

    2010-08-01

    In recent years, Augmented Reality (AR)[1][2][3] is very popular in universities and research organizations. The AR technology has been widely used in Virtual Reality (VR) fields, such as sophisticated weapons, flight vehicle development, data model visualization, virtual training, entertainment and arts. AR has characteristics to enhance the display output as a real environment with specific user interactive functions or specific object recognitions. It can be use in medical treatment, anatomy training, precision instrument casting, warplane guidance, engineering and distance robot control. AR has a lot of vantages than VR. This system developed combines sensors, software and imaging algorithms to make users feel real, actual and existing. Imaging algorithms include gray level method, image binarization method, and white balance method in order to make accurate image recognition and overcome the effects of light.

  15. Pure laparoscopic augmentation ileocystoplasty.

    Science.gov (United States)

    Rebouças, Rafael B; Monteiro, Rodrigo C; Souza, Thiago N S de; Aragão, Augusto J de; Burity, Camila R T; Nóbrega, Júlio C de A; Oliveira, Natália S C de; Abrantes, Ramon B; Dantas Júnior, Luiz B; Cartaxo Filho, Ricardo; Negromonte, Gustavo R P; Sampaio, Rafael da C R; Britto, Cesar A

    2014-01-01

    Guillain-Barre syndrome is an acute neuropathy that rarely compromises bladder function. Conservative management including clean intermittent catheterization and pharmacotherapy is the primary approach for hypocompliant contracted bladder. Surgical treatment may be used in refractory cases to improve bladder compliance and capacity in order to protect the upper urinary tract. We describe a case of pure laparoscopic augmentation ileocystoplasty in a patient affected by Guillain-Barre syndrome. A 15-year-old female, complaining of voiding dysfunction, recurrent urinary tract infection and worsening renal function for three months. A previous history of Guillain-Barre syndrome on childhood was related. A voiding cystourethrography showed a pine-cone bladder with moderate post-void residual urine. The urodynamic demonstrated a hypocompliant bladder and small bladder capacity (190 mL) with high detrusor pressure (54 cmH2O). Nonsurgical treatments were attempted, however unsuccessfully.

  16. NAESA Augmentation Pilot Project

    Science.gov (United States)

    Hoover, John J.

    1998-01-01

    This project was one project within the Native American Earth and Space Academy (NAESA). NAESA is a national initiative comprised of several organizations that support programs which focus on 1) enhancing the technological, scientific and pedagogical skills of K-14 teachers who instruct Native Americans, 2) enhancing the understanding and applications of science, technology, and engineering of college-bound Native Americans and teaching them general college "survival skills" (e.g., test taking, time management, study habits), 3) enhancing the scientific and pedagogical skills of the faculty of tribally-controllcd colleges and community colleges with large Native American enrollments, and 4) strengthening the critical relationships between students, their parents, tribal elders, and their communities. This Augmentation Pilot Project focused on the areas of community-school alliances and intemet technology use in teaching and learning and daily living addressing five major objectives.

  17. Magnetohydrodynamic Augmented Propulsion Experiment

    Science.gov (United States)

    Litchford, Ron J.

    2008-01-01

    Over the past several years, efforts have been under way to design and develop an operationally flexible research facility for investigating the use of cross-field MHD accelerators as a potential thrust augmentation device for thermal propulsion systems. The baseline configuration for this high-power experimental facility utilizes a 1.5-MWe multi-gas arc-heater as a thermal driver for a 2-MWe MHD accelerator, which resides in a large-bore 2-tesla electromagnet. A preliminary design study using NaK seeded nitrogen as the working fluid led to an externally diagonalized segmented MHD channel configuration based on an expendable heat-sink design concept. The current status report includes a review of engineering/design work and performance optimization analyses and summarizes component hardware fabrication and development efforts, preliminary testing results, and recent progress toward full-up assembly and testing

  18. Augmented Virtual Reality Laboratory

    Science.gov (United States)

    Tully-Hanson, Benjamin

    2015-01-01

    Real time motion tracking hardware has for the most part been cost prohibitive for research to regularly take place until recently. With the release of the Microsoft Kinect in November 2010, researchers now have access to a device that for a few hundred dollars is capable of providing redgreenblue (RGB), depth, and skeleton data. It is also capable of tracking multiple people in real time. For its original intended purposes, i.e. gaming, being used with the Xbox 360 and eventually Xbox One, it performs quite well. However, researchers soon found that although the sensor is versatile, it has limitations in real world applications. I was brought aboard this summer by William Little in the Augmented Virtual Reality (AVR) Lab at Kennedy Space Center to find solutions to these limitations.

  19. Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity through the alleviation of mitochondrial dysfunction

    Directory of Open Access Journals (Sweden)

    Cui A

    2017-04-01

    Full Text Available Ai-Ling Cui,1 Ying-Hua Zhang,2 Jian-Zhong Li,3 Tianbin Song,4 Xue-Min Liu,1 Hui Wang,2 Ce Zhang,5 Guo-Lin Ma,6 Hui Zhang,7 Kefeng Li8 1Anatomy Department, Changzhi Medical College, Changzhi, Shanxi, 2Key Laboratory of Tissue Regeneration of Henan Province, Xinxiang Medical University, Xinxiang, Henan, 3Clinical Laboratory of Heji Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 4Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, 5Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 6Department of Radiology, China-Japan Friendship Hospital, Beijing, 7Department of Radiology, First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 8School of Medicine, University of California – San Diego, San Diego, CA, USA Abstract: N-methyl-D-aspartate (NDMA receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer’s disease (AD and Parkinson’s disease. However, no effective treatments for the same have been developed so far. Humanin (HN is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 µmol/L dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 µmol/L led to significant increases of mitochondrial succinate dehydrogenase (SDH activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS and nitric

  20. Augmented Reality Comes to Physics

    Science.gov (United States)

    Buesing, Mark; Cook, Michael

    2013-01-01

    Augmented reality (AR) is a technology used on computing devices where processor-generated graphics are rendered over real objects to enhance the sensory experience in real time. In other words, what you are really seeing is augmented by the computer. Many AR games already exist for systems such as Kinect and Nintendo 3DS and mobile apps, such as…

  1. Augmented Reality Comes to Physics

    Science.gov (United States)

    Buesing, Mark; Cook, Michael

    2013-01-01

    Augmented reality (AR) is a technology used on computing devices where processor-generated graphics are rendered over real objects to enhance the sensory experience in real time. In other words, what you are really seeing is augmented by the computer. Many AR games already exist for systems such as Kinect and Nintendo 3DS and mobile apps, such as…

  2. Augmented Reality in Sports: Today and Tomorrow

    Directory of Open Access Journals (Sweden)

    Zafer BOZYER

    2015-08-01

    Full Text Available The rapid change experienced in the field of Information Technologies makes the informati cs more tangible in daily life. Today, it became possible to encounter with the informatics applications almost all the disciplines. As a matter of course, many informatics applications are put into the practice regarding the sports discipline. Because of the condition that the power of information processing has increased and the studies on wearable technol ogies in addition to the expert system design, augmented reality (AR has become a topic which gains imp ortance in the field of sports. There are many studies that are conducted with the aim of increasing the efficiency of physical activities done in many sports branches, ensuring a more fair management of competitions and providing the opportunity for spectators to watch the competitions in a more comfortable and efficient way. In this study; the information about the current augmented reality practices th at are used in various sports branches has been given and the mobile and interactive augmented reality practices which are possible to be seen in future have been mentioned. In addition, there is an augmented reality practice which is designed with the aim of ensuring that the shoots of sports people who are interested in archery, are more stable and of ensuring that the trainings and exercises are more efficient by stating to the sports people whether he or she is in the right position for shoot which is c alled as T shape seen at the time of releasing the arrow.

  3. Effects of an NMDA antagonist on the auditory mismatch negativity response to transcranial direct current stimulation.

    Science.gov (United States)

    Impey, Danielle; de la Salle, Sara; Baddeley, Ashley; Knott, Verner

    2016-09-13

    Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which uses a weak constant current to alter cortical excitability and activity temporarily. tDCS-induced increases in neuronal excitability and performance improvements have been observed following anodal stimulation of brain regions associated with visual and motor functions, but relatively little research has been conducted with respect to auditory processing. Recently, pilot study results indicate that anodal tDCS can increase auditory deviance detection, whereas cathodal tDCS decreases auditory processing, as measured by a brain-based event-related potential (ERP), mismatch negativity (MMN). As evidence has shown that tDCS lasting effects may be dependent on N-methyl-D-aspartate (NMDA) receptor activity, the current study investigated the use of dextromethorphan (DMO), an NMDA antagonist, to assess possible modulation of tDCS's effects on both MMN and working memory performance. The study, conducted in 12 healthy volunteers, involved four laboratory test sessions within a randomised, placebo and sham-controlled crossover design that compared pre- and post-anodal tDCS over the auditory cortex (2 mA for 20 minutes to excite cortical activity temporarily and locally) and sham stimulation (i.e. device is turned off) during both DMO (50 mL) and placebo administration. Anodal tDCS increased MMN amplitudes with placebo administration. Significant increases were not seen with sham stimulation or with anodal stimulation during DMO administration. With sham stimulation (i.e. no stimulation), DMO decreased MMN amplitudes. Findings from this study contribute to the understanding of underlying neurobiological mechanisms mediating tDCS sensory and memory improvements.

  4. Increased NMDA receptor inhibition at an increased Sevoflurane MAC.

    Science.gov (United States)

    Brosnan, Robert J; Thiesen, Roberto

    2012-06-06

    Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC) could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC. Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF) containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 μL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL) plus 0.4 mg/mL dizocilpine (MK-801) was administered intrathecally at 4 μL/min, and the post-dizocilpine sevoflurane MAC was measured. Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P MAC. The magnitude of anesthetic effects on a given ion channel may therefore depend on the magnitude of its effects on other receptors that modulate neuronal excitability.

  5. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

    DEFF Research Database (Denmark)

    Kocerha, Jannet; Faghihi, Mohammad Ali; Lopez-Toledano, Miguel A

    2009-01-01

    N-methyl-D-aspartate (NMDA) glutamate receptors are regulators of fast neurotransmission and synaptic plasticity in the brain. Disruption of NMDA-mediated glutamate signaling has been linked to behavioral deficits displayed in psychiatric disorders such as schizophrenia. Recently, noncoding RNA m...

  6. NMDA receptors are not required for pattern completion during associative memory recall.

    Directory of Open Access Journals (Sweden)

    Bing Mei

    Full Text Available Pattern completion, the ability to retrieve complete memories initiated by subsets of external cues, has been a major focus of many computation models. A previously study reports that such pattern completion requires NMDA receptors in the hippocampus. However, such a claim was derived from a non-inducible gene knockout experiment in which the NMDA receptors were absent throughout all stages of memory processes as well as animal's adult life. This raises the critical question regarding whether the previously described results were truly resulting from the requirement of the NMDA receptors in retrieval. Here, we have examined the role of the NMDA receptors in pattern completion via inducible knockout of NMDA receptors limited to the memory retrieval stage. By using two independent mouse lines, we found that inducible knockout mice, lacking NMDA receptor in either forebrain or hippocampus CA1 region at the time of memory retrieval, exhibited normal recall of associative spatial reference memory regardless of whether retrievals took place under full-cue or partial-cue conditions. Moreover, systemic antagonism of NMDA receptor during retention tests also had no effect on full-cue or partial-cue recall of spatial water maze memories. Thus, both genetic and pharmacological experiments collectively demonstrate that pattern completion during spatial associative memory recall does not require the NMDA receptor in the hippocampus or forebrain.

  7. Subtle alterations in NMDA-stimulated cyclic GMP levels following lateral fluid percussion brain injury.

    Science.gov (United States)

    Temple, M D; Delahunty, T M; Hamm, R J; Phillips, L L; Lyeth, B G; Povlishock, J T

    2001-01-01

    This study examined whether NMDA-stimulated cyclic GMP levels were altered at two different time points following lateral fluid percussion injury. At 60 min and 15 days postinjury, the left and right hippocampi were dissected and chopped into mini-prisms. Each hippocampus was divided into five equal parts and incubated with either the phosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine, 500 microM) alone, IBMX and N-methyl-D-aspartic acid (NMDA) OR IBMX, NMDA, and glycine (10 MM). Two concentrations of NMDA were used: 500 or 1,000 microM. Tissues were then assayed for levels of cyclic GMP. Results indicated that there were no changes in basal levels of cyclic GMP at either postinjury time point. At 60 min postinjury, there were no significant main effects for injury or drug concentration. There was a significant injury x side interaction effect with increased levels of NMDA-stimulated cyclic GMP in the hippocampus ipsilateral to the injury impact and decreased cyclic GMP levels in the contralateral hippocampus. There were no significant alterations in NMDA-stimulated cyclic GMP levels at 15 days postinjury. The data from this study indicated that NMDA-stimulated cyclic GMP accumulation is differentially altered in the hippocampus ipsilateral and contralateral to the site of the injury at 1 h after injury, but is normalized by 15 days postinjury. These findings implicate NMDA-mediated intracellular signaling processes in the acute excitotoxic response to injury.

  8. Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

    Science.gov (United States)

    Vinckier, F; Gaillard, R; Palminteri, S; Rigoux, L; Salvador, A; Fornito, A; Adapa, R; Krebs, M O; Pessiglione, M; Fletcher, P C

    2016-07-01

    A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.

  9. All quiet on the neuronal front: NMDA receptor inhibition by prion protein.

    Science.gov (United States)

    Steele, Andrew D

    2008-05-01

    The normal function of the prion protein (PrP)-the causative agent of mad cow or prion disease-has long remained out of reach. Deciphering PrP's function may help to unravel the complex chain of events triggered by PrP misfolding during prion disease. In this issue of the JCB, an exciting paper (Khosravani, H., Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, M. Villemaire, Z. Ali, F.R. Jirik, and G.W. Zamponi. 2008. J. Cell Biol. 181:551-565) connects diverse observations regarding PrP into a coherent framework whereby PrP dampens the activity of an N-methyl-d-aspartate (NMDA) receptor (NMDAR) subtype and reduces excitotoxic lesions. The findings of this study suggest that understanding the normal function of proteins associated with neurodegenerative disease may elucidate the molecular pathogenesis.

  10. Adapting Information Through Tangible Augmented Reality Interfaces

    OpenAIRE

    Sinclair, Patrick; Martinez, Kirk

    2004-01-01

    Tangible augmented reality interfaces offer a hands on approach for examining objects and exploring the associated information. We describe two tangible augmented reality interfaces that can expose the adaptation of information presented to users about objects in augmented reality environments.

  11. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S;

    1998-01-01

    Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However......, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA...... receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence...

  12. Non-ionotropic signaling by the NMDA receptor: controversy and opportunity.

    Science.gov (United States)

    Gray, John A; Zito, Karen; Hell, Johannes W

    2016-01-01

    Provocative emerging evidence suggests that the N-methyl-d-aspartate (NMDA) receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD), directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction.

  13. Non-ionotropic signaling by the NMDA receptor: controversy and opportunity [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    John A. Gray

    2016-05-01

    Full Text Available Provocative emerging evidence suggests that the N-methyl-D-aspartate (NMDA receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD, directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction.

  14. Longitudinal electroencephalographic (EEG) findings in pediatric anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis: the Padua experience.

    Science.gov (United States)

    Nosadini, Margherita; Boniver, Clementina; Zuliani, Luigi; de Palma, Luca; Cainelli, Elisa; Battistella, Pier Antonio; Toldo, Irene; Suppiej, Agnese; Sartori, Stefano

    2015-02-01

    To contribute to characterize electroencephalographic (EEG) activity in pediatric anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis, we reviewed electroclinical data of 5 children with anti-NMDA receptor encephalitis diagnosed in our department. We identified 4 longitudinal electroencephalographic phases: in the early phase, background activity was normal, with intermixed nonreactive slow waves; in the florid phase, background activity deteriorated with appearance of sequences of peculiar rhythmic theta and/or delta activity unrelated to clinical changes, unresponsive to stimuli and antiepileptic medications; in the recovery phase, these sequences decreased and reactive posterior rhythm re-emerged; electroencephalogram normalized 2 to 5 months after onset. In conclusion, in the presence of evocative clinical history, recognizing a characteristic longitudinal electroencephalographic activity could provide ancillary aspects addressing the diagnosis and the overall management of children with anti-N-methyl-d-aspartate receptor encephalitis; in particular, knowing that peculiar and recurrent paroxysmal nonepileptic rhythmic theta-delta patterns can occur in these patients could help distinguish paroxysmal epileptic and nonepileptic electroencephalographic activity.

  15. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    Science.gov (United States)

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

  16. Designing Augmented Reality for the Classroom

    OpenAIRE

    Cuendet, Sébastien; Bonnard, Quentin; Do-Lenh, Son; Dillenbourg, Pierre

    2012-01-01

    Augmented reality (AR) has recently received a lot of attention in education. Multiple AR systems for learning have been developed and tested through empirical studies often conducted in lab settings. While lab studies can be insightful, they leave out the complexity of a classroom environment. We developed three AR learning environments that have been used in genuine classroom contexts, some of them being now part of classroom regular practices. These systems and the learning activities they...

  17. PSD-95 uncoupling from NMDA receptors by Tat- N-dimer ameliorates neuronal depolarization in cortical spreading depression.

    Science.gov (United States)

    Kucharz, Krzysztof; Søndergaard Rasmussen, Ida; Bach, Anders; Strømgaard, Kristian; Lauritzen, Martin

    2017-05-01

    Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat- N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat- N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat- N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat- N-dimer reduced the average amplitude of the negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO2. We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarization wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.

  18. Phenobarbital Augments Hypothermic Neuroprotection

    Science.gov (United States)

    Barks, John D.; Liu, Yi-Qing; Shangguan, Yu; Silverstein, Faye S.

    2010-01-01

    Seizures are associated with adverse outcome in infants with hypoxic-ischemic encephalopathy. We hypothesized that early administration of the anticonvulsant phenobarbital after cerebral hypoxia-ischemia could enhance the neuroprotective efficacy of delayed-onset hypothermia. We tested this hypothesis in a neonatal rodent model. Seven-day-old rats (n=104) underwent right carotid ligation, followed by 90 min 8%O2 exposure; 15 min later, they received injections of phenobarbital (40 mg/kg) or saline. One or 3h later, all were treated with hypothermia (30°C, 3h). Function and neuropathology were evaluated after 7 days (“early outcomes”) or 1 month (“late outcomes”). Early outcome assessment demonstrated better sensorimotor performance and less cortical damage in phenobarbital-treated groups; there were no differences between groups in which the hypothermia delay was shortened from 3h to 1h. Late outcome assessment confirmed sustained benefits of phenobarbital+hypothermia treatment; sensorimotor performance was better (persistent attenuation of contralateral forepaw placing deficits and absence of contralateral forepaw neglect); neuropathology scores were lower (medians, phenobarbital 2, saline 8.5, pphenobarbital may augment the neuroprotective efficacy of therapeutic hypothermia. PMID:20098339

  19. Augmented Likelihood Image Reconstruction.

    Science.gov (United States)

    Stille, Maik; Kleine, Matthias; Hägele, Julian; Barkhausen, Jörg; Buzug, Thorsten M

    2016-01-01

    The presence of high-density objects remains an open problem in medical CT imaging. Data of projections passing through objects of high density, such as metal implants, are dominated by noise and are highly affected by beam hardening and scatter. Reconstructed images become less diagnostically conclusive because of pronounced artifacts that manifest as dark and bright streaks. A new reconstruction algorithm is proposed with the aim to reduce these artifacts by incorporating information about shape and known attenuation coefficients of a metal implant. Image reconstruction is considered as a variational optimization problem. The afore-mentioned prior knowledge is introduced in terms of equality constraints. An augmented Lagrangian approach is adapted in order to minimize the associated log-likelihood function for transmission CT. During iterations, temporally appearing artifacts are reduced with a bilateral filter and new projection values are calculated, which are used later on for the reconstruction. A detailed evaluation in cooperation with radiologists is performed on software and hardware phantoms, as well as on clinically relevant patient data of subjects with various metal implants. Results show that the proposed reconstruction algorithm is able to outperform contemporary metal artifact reduction methods such as normalized metal artifact reduction.

  20. The role of NMDA receptors in human eating behavior: evidence from a case of anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Perogamvros, Lampros; Schnider, Armin; Leemann, Beatrice

    2012-06-01

    Research in animal models has implicated N-methyl-D-aspartate (NMDA) receptors (NMDARs) in the control of food intake. Until now, these findings have been not replicated in humans. Here we describe a 22-year-old woman with anti-NMDAR encephalitis and no prior neurological or psychiatric history. Her clinical course was marked by successive eating disorders: anorexia followed by hyperphagia. We propose that, much as they do in other animals, NMDARs in humans interact with the neuroendocrine, homeostatic, and reward systems controlling food intake in the central and peripheral nervous system structures related to feeding and satiety.

  1. Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    Dhawan, J.; Biegon, A.; Dhawan, J.; Benveniste, H.; Nawrocky, M.; Smith, S.D.; Biegon, A.

    2010-03-04

    Stroke is accompanied by neuroinflammation in humans and animal models. To examine the temporal and anatomical profile of neuroinflammation and NMDA receptors (NMDAR) in a stroke model, rats (N = 17) were subjected to a 90 min occlusion of the middle cerebral artery (MCAO) and compared to sham (N = 5) and intact (N = 4) controls. Striatal and parietal cortical infarction was confirmed by MRI 24 h after reperfusion. Animals were killed 14 or 30-40 days later and consecutive coronal cryostat sections were processed for quantitative autoradiography with the neuroinflammation marker [{sup 3}H]PK11195 and the NMDAR antagonist [{sup 3}H]MK801. Significantly increased specific binding of [{sup 3}H]PK11195 relative to non-ischemic controls was observed in the ipsilateral striatum (> 3 fold, p < 0.0001), substantia innominata (> 2 fold) with smaller (20%-80%) but statistically significant (p = 0.002-0.04) ipsilateral increases in other regions partially involved in the infarct such as the parietal and piriform cortex, and in the lateral septum, which was not involved in the infarct. Trends for increases in PBR density were also observed in the contralateral hemisphere. In the same animals, NMDAR specific binding was significantly decreased bilaterally in the septum, substantia innominata and ventral pallidum. Significant decreases were also seen in the ipsilateral striatum, accumbens, frontal and parietal cortex. The different anatomical distribution of the two phenomena suggests that neuroinflammation does not cause the observed reduction in NMDAR, though loss of NMDAR may be locally augmented in ipsilateral regions with intense neuroinflammation. Persistent, bilateral loss of NMDAR, probably reflecting receptor down regulation and internalization, may be responsible for some of the effects of stroke on cognitive function which cannot be explained by infarction alone.

  2. Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

    Science.gov (United States)

    Dhawan, Jasbeer; Benveniste, Helene; Nawrocky, Marta; Smith, S. David; Biegon, Anat

    2010-01-01

    Stroke is accompanied by neuroinflammation in humans and animal models. To examine the temporal and anatomical profile of neuroinflammation and NMDA receptors (NMDAR) in a stroke model, rats (N=17) were subjected to 90 minutes occlusion of the middle cerebral artery (MCAO) and compared to sham (N=5) and intact (N=4) controls. Striatal and partial cortical Infarction was confirmed by MRI 24 hr after reperfusion. Animals were killed 14 or 30–40 days later and consecutive coronal cryostat sections processed for quantitative autoradiography with the neuroinflammation marker [3H]PK11195 and the NMDAR antagonist [3H]MK801. Significantly Increased specific binding of [3H]PK11195 relative to non-ischemic controls was observed in the ipsilateral striatum (>3 fold, p2 fold) with smaller (20%–80%) but statistically significant (p=0.002–0.04) ipsilateral increases in other regions partially involved in the infarct such as the parietal and piriform cortex, and in the lateral septum, which was not involved in the infarct. Trends for increases in PBR density were also observed in the contralateral hemisphere. . In the same animals, NMDAR specific binding was significantly decreased bilaterally in the septum, substantia innominata and ventral pallidum. Significant decreases were also seen in the ipsilateral striatum, accumbens, frontal and parietal cortex. The different anatomical distribution of the two phenomena suggests that neuroinflammation does not cause the observed reduction in NMDAR, though loss of NMDAR may be locally augmented in ipsilateral regions with intense neuroinflammation. . Persistent, bilateral loss of NMDAR, probably reflecting receptor down regulation and internalization, may be responsible for some of the effects of stroke on cognitive function which can not be explained by infarction alone. PMID:20206701

  3. Understanding augmented reality concepts and applications

    CERN Document Server

    Craig, Alan B

    2013-01-01

    Augmented reality is not a technology. Augmented reality is a medium. Likewise, a book on augmented reality that only addresses the technology that is required to support the medium of augmented reality falls far short of providing the background that is needed to produce, or critically consume augmented reality applications. One reads a book. One watches a movie. One experiences augmented reality. Understanding Augmented Reality addresses the elements that are required to create compelling augmented reality experiences. The technology that supports

  4. Augmented reality som wearable technology

    DEFF Research Database (Denmark)

    Rahn, Annette

    2016-01-01

    “How Augmented reality can facilitate learning in visualizing human anatomy “ At this station I demonstrate how Augmented reality can be used to visualize the human lungs in situ and as a wearable technology which establish connection between body, image and technology in education. I will show...... the potential of Augmented reality increasing students level of understanding, interaction and engagement with the object. I will demonstrate the technology and show you the human lungs in your body and the future perspectives of the technology. Organization: developed in collaboration with Mie Buhl, Professor...

  5. Navigation in Augmented Reality, Navigation i Augmented Reality

    OpenAIRE

    Bernelind, Sarah

    2015-01-01

    The concept of augmented reality has existed since the 60’s. In this thesis it has been investigated if navigation using a mobile device would benefit, from a usability perspective, if the navigational data were presented using augmented reality instead of a standardized map. The usability principles from which the applications were evaluated are learnability, user satisfaction, efficiency and effectivity. An AR prototype was developed and tested against a standard map, in the form of Google ...

  6. Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Hitoshi Yoshiji; Masaharu Yamazaki; Masahisa Toyohara; Akira Mitoro; Hiroshi Fukui; Ryuichi Noguchi; Hideyuki Kojima; Yasuhide Ikenaka; Mitsuteru Kitade; Kosuke Kaji; Masahito Uemura; Junichi Yamao; Masao Fujimoto

    2006-01-01

    AIM:To evaluate the effect of combination treatment with the interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-I ) on several fibrotic indices in patients with refractory chronic hepatitis C (CHC).METHODS: Perindopril (an ACE-I; 4 mg/d) and/or natural IFN (3 MU/L; 3 times a week) were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed.RESULTS:ACE-Ⅰ decreased the serum fibrosis markers,whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-Ⅰ, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-β was significantly attenuated almost in parallel with suppression of the serum fibrosis markers.CONCLUSION:The combination therapy of an ACE-Ⅰand IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

  7. Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes.

    Science.gov (United States)

    Niemann, Stephan; Kanki, Hiroaki; Fukui, Yasuyuki; Takao, Keizo; Fukaya, Masahiro; Hynynen, Meri N; Churchill, Michael J; Shefner, Jeremy M; Bronson, Roderick T; Brown, Robert H; Watanabe, Masahiko; Miyakawa, Tsuyoshi; Itohara, Shigeyoshi; Hayashi, Yasunori

    2007-09-01

    NR3B is a modulatory subunit of the NMDA receptor, abundantly expressed in both cranial and spinal somatic motoneurons and at lower levels in other regions of the brain as well. Recently, we found the human NR3B gene (GRIN3B) to be highly genetically heterogeneous, and that approximately 10% of the normal European-American population lacks NR3B due to homozygous occurrence of a null allele in the gene. Therefore, it is especially important to understand the phenotypic consequences of the genetic loss of NR3B in both humans and animal models. We here provide results of behavioral analysis of mice genetically lacking NR3B, which is an ideal animal model due to homogeneity in genetic and environmental background. The NR3B(-/-) mice are viable and fertile. Consistent with the expression of NR3B in somatic motoneurons, the NR3B(-/-) mice showed a moderate but significant impairment in motor learning or coordination, and decreased activity in their home cages. Remarkably, the NR3B(-/-) mice showed a highly increased social interaction with their familiar cage mates in their home cage but moderately increased anxiety-like behaviour and decreased social interaction in a novel environment, consistent with the inhibitory role of NR3B on the functions of NMDA receptors. This work is the first reporting of the functional significance of NR3B in vivo and may give insight into the contribution of genetic variability of NR3B in the phenotypic heterogeneity among human population.

  8. Vagal afferent-dependent cholecystokinin modulation of visceral pain requires central amygdala NMDA-NR2B receptors in rats.

    Science.gov (United States)

    Wang, E M; Li, W T; Yan, X J; Chen, X; Liu, Q; Feng, C C; Cao, Z J; Fang, J Y; Chen, S L

    2015-09-01

    Cholecystokinin (CCK), a gut hormone that is released during feeding, exerts gastrointestinal effects in part through vagal pathway. It is reported to be a potential trigger for increased postprandial visceral sensitivity in healthy subjects and, especially in patients with irritable bowel syndrome. NR2B-containing N-methyl-d-aspartate (NMDA) receptors in the central amygdala (CeA) participate in pain modulation. Systemically administered CCK activates the CeA-innervating neurons. Here, we investigated whether CCK modulation of visceral sensitivity is mediated through CeA NMDA-NR2B receptors and whether this modulation involves vagal pathway. We first examined the visceromotor response (VMR) to colorectal distention (CRD) following i.p. injection of CCK octapeptide (CCK-8) in a rat model. Next, the NR2B antagonist ifenprodil and the NR2A antagonist NVP-AAM077 were microinjected into the CeA before systemic CCK injection. NR2B phosphorylation was detected by Western blot. To down-regulate NR2B gene expression, NR2B-specific small interfering RNA (siRNA) was delivered into CeA neurons by electroporation. In addition, the effects of functional deafferentation by perivagal application of capsaicin and pretreatment with the CCK1 receptor antagonist devazepide were investigated. CCK-8 increased VMR to CRD in a dose-dependent manner. This effect was blunted by intra-CeA administration of ifenprodil (but not NVP-AAM077) and was accompanied by phosphorylation of NR2B subunits in the CeA. CCK failed to increase VMR to CRD in NR2B siRNA-treated rats. Perivagal capsaicin application and pretreatment with devazepide prevented CCK-induced pronociception and CeA NR2B phosphorylation. The pronociception induced by systemic CCK, which is vagal afferent-dependent, requires activation of CeA NMDA-NR2B receptors. © 2015 John Wiley & Sons Ltd.

  9. Mersiline mesh in premaxillary augmentation.

    Science.gov (United States)

    Foda, Hossam M T

    2005-01-01

    Premaxillary retrusion may distort the aesthetic appearance of the columella, lip, and nasal tip. This defect is characteristically seen in, but not limited to, patients with cleft lip nasal deformity. This study investigated 60 patients presenting with premaxillary deficiencies in which Mersiline mesh was used to augment the premaxilla. All the cases had surgery using the external rhinoplasty technique. Two methods of augmentation with Mersiline mesh were used: the Mersiline roll technique, for the cases with central symmetric deficiencies, and the Mersiline packing technique, for the cases with asymmetric deficiencies. Premaxillary augmentation with Mersiline mesh proved to be simple technically, easy to perform, and not associated with any complications. Periodic follow-up evaluation for a mean period of 32 months (range, 12-98 months) showed that an adequate degree of premaxillary augmentation was maintained with no clinically detectable resorption of the mesh implant.

  10. Switching off LTP: mGlu and NMDA receptor-dependent novelty exploration-induced depotentiation in the rat hippocampus.

    Science.gov (United States)

    Qi, Yingjie; Hu, Neng-Wei; Rowan, Michael J

    2013-04-01

    Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3-CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory.

  11. NMDA receptor antagonism with novel indolyl, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, reduces seizures duration in a rat model of epilepsy

    Science.gov (United States)

    Rothan, Hussin A.; Amini, Elham; Faraj, Fadihl L.; Golpich, Mojtaba; Teoh, Teow Chong; Gholami, Khadijeh; Yusof, Rohana

    2017-01-01

    N-methyl-D-aspartate receptors (NMDAR) play a central role in epileptogensis and NMDAR antagonists have been shown to have antiepileptic effects in animals and humans. Despite significant progress in the development of antiepileptic therapies over the previous 3 decades, a need still exists for novel therapies. We screened an in-house library of small molecules targeting the NMDA receptor. A novel indolyl compound, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, (DDBM) showed the best binding with the NMDA receptor and computational docking data showed that DDBM antagonised the binding sites of the NMDA receptor at lower docking energies compared to other molecules. Using a rat electroconvulsive shock (ECS) model of epilepsy we showed that DDBM decreased seizure duration and improved the histological outcomes. Our data show for the first time that indolyls like DDBM have robust anticonvulsive activity and have the potential to be developed as novel anticonvulsants. PMID:28358047

  12. Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves Ca2+-dependent outward rectification

    Directory of Open Access Journals (Sweden)

    Christian Madry

    2010-03-01

    Full Text Available Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA receptors. Classical Ca2+-permeable NMDA receptors are composed of glycine-binding NR1 and glutamate-binding NR2 subunits, and hence require both glutamate and glycine for efficient activation. In contrast, recombinant receptors composed of NR1 and the glycine binding NR3A and/or NR3B subunits lack glutamate binding sites and can be activated by glycine alone. Therefore these receptors are also named excitatory glycine receptors. Co-application of antagonists of the NR1 glycine-binding site or of the divalent cation Zn2+ markedly enhances the glycine responses of these receptors. To gain further insight into the properties of these glycine-gated NMDA receptors, we investigated their current-voltage (I-V dependence. Whole-cell current-voltage relations of glycine currents recorded from NR1/NR3B and NR1/NR3A/NR3B expressing oocytes were found to be linear under our recording conditions. In contrast, NR1/NR3A receptors displayed a strong outwardly rectifying I-V relation. Interestingly, the voltage-dependent inward current block was abolished in the presence of NR1 antagonists, Zn2+ or a combination of both. Further analysis revealed that Ca2+ (1.8 mM present in our recording solutions was responsible for the voltage-dependent inhibition of ion flux through NR1/NR3A receptors. Since physiological concentrations of the divalent cation Mg2+ did not affect the I-V dependence, our data suggest that relief of the voltage-dependent Ca2+ block of NR1/NR3A receptors by Zn2+ may be important for the regulation of excitatory glycinergic transmission, according to the Mg2+-block of conventional NR1/NR2 NMDA receptors.

  13. Effects of the blood components on the AMPA and NMDA synaptic responses in brain slices in the onset of hemorrhagic stroke.

    Science.gov (United States)

    Mokrushin, Anatoly A; Pavlinova, Larisa I

    2013-12-01

    Blood-borne events play a major role in post bleeding disturbances of the neuronal network. However, very little is known about the early effects of blood plasma, leucocytes, and the red blood cells on the AMPA and NMDA-mediated synaptic responses in the onset of experimental intracranial hemorrhage (ICH). In this study, we used the technique of on-line monitoring of electrophysiological parameters referred to synaptic activity in piriform cortex of SHR rat slice. We exposed the olfactory cortex slices to diluted autologous blood or its components and compared with effects of ferric chloride. Whole blood exerted a total inhibition of synaptic activity in piriform cortex within first 5 min. Dilution of blood induced prolonged epileptic synaptic activation of NMDA receptors. Blood plasma and fraction of leucocytes induced hyperactivation of neurons transforming to epileptiform discharges. Fraction of red blood cells acted biphasic, an initial sharp activity of AMPA- and NMDA-mediated receptors replaced by a following total depression. Our slice-based models of experimental stroke revealed the mechanism of the earliest pathophysiologic events occur in brain tissue during bleeding that may be relevant to the human ICH.

  14. Wireless Augmented Reality Prototype (WARP)

    Science.gov (United States)

    Devereaux, A. S.

    1999-01-01

    Initiated in January, 1997, under NASA's Office of Life and Microgravity Sciences and Applications, the Wireless Augmented Reality Prototype (WARP) is a means to leverage recent advances in communications, displays, imaging sensors, biosensors, voice recognition and microelectronics to develop a hands-free, tetherless system capable of real-time personal display and control of computer system resources. Using WARP, an astronaut may efficiently operate and monitor any computer-controllable activity inside or outside the vehicle or station. The WARP concept is a lightweight, unobtrusive heads-up display with a wireless wearable control unit. Connectivity to the external system is achieved through a high-rate radio link from the WARP personal unit to a base station unit installed into any system PC. The radio link has been specially engineered to operate within the high- interference, high-multipath environment of a space shuttle or space station module. Through this virtual terminal, the astronaut will be able to view and manipulate imagery, text or video, using voice commands to control the terminal operations. WARP's hands-free access to computer-based instruction texts, diagrams and checklists replaces juggling manuals and clipboards, and tetherless computer system access allows free motion throughout a cabin while monitoring and operating equipment.

  15. 人肝再生增强因子CXXC活性结构的研究%Study on the CXXC Activity Motif of Human Augmenter of Liver Regeneration

    Institute of Scientific and Technical Information of China (English)

    潘艳; 佟明华; 鞠桂芝; 孔祥平

    2006-01-01

    人肝再生增强因子(human augmenter of liver regeneration,hALR)蛋白序列中有一段保守的Cys-Xaa-Xaa-Cys(CXXC)氨基酸序列,针对hALRp的CXXC结构,对hALR分别进行C65A和Q88C突变,表达、纯化突变体蛋白.体外检测hALRp和突变体的黄素腺嘌呤二核苷酸(flavin adenine dinucleotide,FAD)辅助的巯基氧化酶活性,hALR-FAD和hALRQ88C-FAD组与对照组比较有显著差异(P<0.05),hALR-FAD和hALRQ88C-FAD组之间无差异;hALRC65A-FAD组与对照组比较无差异.结果显示,通过C65A突变将CXXC结构破坏后,该突变体的巯基氧化酶活性完全丧失;通过Q88C突变增加一个CXXC序列后,该突变体的巯基氧化酶活性较hALR-FAD未见明显增加;同时,FAD不仅是hALRp发挥巯基氧化酶活性必须的辅助因子,而且有助于hALRp突变体蛋白的复性.

  16. Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush.

    Science.gov (United States)

    Rosini, Michela; Simoni, Elena; Bartolini, Manuela; Cavalli, Andrea; Ceccarini, Luisa; Pascu, Nicoleta; McClymont, David W; Tarozzi, Andrea; Bolognesi, Maria L; Minarini, Anna; Tumiatti, Vincenzo; Andrisano, Vincenza; Mellor, Ian R; Melchiorre, Carlo

    2008-08-14

    Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced Abeta aggregation and display antioxidant properties, emerging as lead candidates for treating AD.

  17. Pure Laparoscopic Augmentation Ileocystoplasty

    Directory of Open Access Journals (Sweden)

    Rafael B. Rebouças

    2014-12-01

    Full Text Available Introduction Guillain-Barre syndrome is an acute neuropathy that rarely compromises bladder function. Conservative management including clean intermittent catheterization and pharmacotherapy is the primary approach for hypocompliant contracted bladder. Surgical treatment may be used in refractory cases to improve bladder compliance and capacity in order to protect the upper urinary tract. We describe a case of pure laparoscopic augmentation ileocystoplasty in a patient affected by Guillain-Barre syndrome. Presentation A 15-year-old female, complaining of voiding dysfunction, recurrent urinary tract infection and worsening renal function for three months. A previous history of Guillain-Barre syndrome on childhood was related. A voiding cystourethrography showed a pine-cone bladder with moderate post-void residual urine. The urodynamic demonstrated a hypocompliant bladder and small bladder capacity (190mL with high detrusor pressure (54 cmH2O. Nonsurgical treatments were attempted, however unsuccessfully. The patient was placed in the exaggerated Trendelenburg position. A four-port transperitoneal technique was used. A segment of ileum approximately 15-20cm was selected and divided with its pedicle. The ileal anastomosis and creation of ileal U-shaped plate were performed laparoscopically, without staplers. Bladder mobilization and longidutinal cystotomy were performed. Enterovesical anastomosis was done with continuous running suture. A suprapubic cystostomy was placed through a 5mm trocar. Results The total operative time was 335 min. The blood loss was minimal. The patient developed ileus in the early days, diet acceptance after the fourth day and was discharged on the seventh postoperative day. The urethral catheter was removed after 2 weeks. At 6-month follow-up, a cystogram showed a significant improvement in bladder capacity. The patient adhered well to clean intermittent self-catheterization and there was no report for febrile infections

  18. GDNF and neublastin protect against NMDA-induced excitotoxicity in hippocampal slice cultures

    DEFF Research Database (Denmark)

    Bonde, C; Kristensen, B W; Blaabjerg, M;

    2000-01-01

    The potential neuroprotective effects of glial cell line-derived neurotrophic factor (GDNF) and neublastin (NBN) against NMDA-induced excitotoxicity were examined in hippocampal brain slice cultures. Recombinant human GDNF (25-100 ng/ ml) or NBN, in medium conditioned by growth of transfected, NBN......-producing HiB5 cells, were added to slice cultures I h before exposure to 10 microM NMDA for 48h. Neuronal cell death was monitored, before and during the NMDA exposure, by densitometric measurements of propidium iodide (PI) uptake and loss of Nissl staining. Both the addition of rhGDNF and NBN...

  19. EXTREME DELTA BRUSH EEG PATTERN IN A CASE WITH ANTI-NMDA RECEPTOR ENCEPHALITIS.

    Science.gov (United States)

    Söylemez, Elif; Güveli, Betül Tekin; Atakli, Dilek; Yatmazoğlu, Merve; Atay, Turan; Dayan, Cengiz

    2015-09-30

    Anti-N-methyl-D-aspartate receptor NMDA-R encephalitis is caused by antibodies against the NMDA-R and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. This disorder is often accompanied with malignancies, especially ovarian teratoma. Some patients' EEGs show a different pattern similar to the waveforms of premature infants and this pattern is specifically named as extreme delta brush (EDB). We report a 24-year-old female having anti-NMDA receptor encephalitis and EDB patern.

  20. Effects of NMDA and non-NMDA ionotropic glutamate receptors in the medial preoptic area on body temperature in awake rats.

    Science.gov (United States)

    Sengupta, Trina; Jaryal, Ashok Kumar; Mallick, Hruda Nanda

    2016-10-01

    Glutamate when microinjected at the medial preoptic area (mPOA) influences brain temperature (Tbr) and body temperature (Tb) in rats. Glutamate and its various receptors are present at the mPOA. The aim of this study was to identify the contribution of each of the ionotropic glutamatergic receptors at the mPOA on changes in Tbr and Tb in freely moving rats. Adult male Wistar rats (n=40) were implanted with bilateral guide cannula with indwelling styli above the mPOA. A telemetric transmitter was implanted at the peritoneum to record Tb and locomotor activity (LMA). A precalibrated thermocouple wire implanted near the hypothalamus was used to assess Tbr. Specific agonist for each ionotropic glutamate receptor was microinjected into the mPOA and its effects on temperature and LMA were measured in the rats. The rats were also microinjected with the respective ionotropic receptor antagonists, 15min prior to the microinjection of each agonist. Amongst amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainic acid, AMPA increased Tb and LMA when injected at the mPOA. Specific antagonists for AMPA receptors was able to attenuate this increase (ptemperature.