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Sample records for augments nmda receptor

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

    PubMed Central

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

    2015-01-01

    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. PMID:26621715

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

    PubMed

    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. PMID:26621715

  3. NMDA receptor antibodies

    PubMed Central

    Ramberger, Melanie; Bsteh, Gabriel; Schanda, Kathrin; Höftberger, Romana; Rostásy, Kevin; Baumann, Matthias; Aboulenein-Djamshidian, Fahmy; Lutterotti, Andreas; Deisenhammer, Florian; Berger, Thomas

    2015-01-01

    Objectives: To analyze the frequency of NMDA receptor (NMDAR) antibodies in patients with various inflammatory demyelinating diseases of the CNS and to determine their clinical correlates. Methods: Retrospective case-control study from 2005 to 2014 with the detection of serum IgG antibodies to NMDAR, aquaporin-4, and myelin oligodendrocyte glycoprotein by recombinant live cell-based immunofluorescence assays. Fifty-one patients with acute disseminated encephalomyelitis, 41 with neuromyelitis optica spectrum disorders, 34 with clinically isolated syndrome, and 89 with multiple sclerosis (MS) were included. Due to a known association of NMDAR antibodies with seizures and behavioral symptoms, patients with those clinical manifestations were preferentially included and are therefore overrepresented in our cohort. Nine patients with NMDAR encephalitis, 94 patients with other neurologic diseases, and 48 healthy individuals were used as controls. Results: NMDAR antibodies were found in all 9 patients with NMDAR encephalitis but in only 1 of 215 (0.5%) patients with inflammatory demyelination and in none of the controls. This patient had relapsing-remitting MS with NMDAR antibodies present at disease onset, with an increase in NMDAR antibody titer with the onset of psychiatric symptoms and cognitive deficits. Conclusion: In demyelinating disorders, NMDAR antibodies are uncommon, even in those with symptoms seen in NMDAR encephalitis. PMID:26309901

  4. NMDA receptor contributions to visual contrast coding

    PubMed Central

    Manookin, Michael B.; Weick, Michael; Stafford, Benjamin K.; Demb, Jonathan B.

    2010-01-01

    Summary In the retina, it is not well understood how visual processing depends on AMPA- and NMDA-type glutamate receptors. Here, we investigated how these receptors contribute to contrast coding in identified guinea pig ganglion cell types, in vitro. NMDA-mediated responses were negligible in ON α cells but substantial in OFF α and δ cells. OFF δ cell NMDA receptors were composed of GluN2B subunits. Using a novel deconvolution method, we determined the individual contributions of AMPA, NMDA and inhibitory currents to light responses of each cell type. OFF α and δ cells used NMDA receptors for encoding either the full contrast range (α), including near-threshold responses, or only a high range (δ). However, contrast sensitivity depended substantially on NMDA receptors only in OFF α cells. NMDA receptors contribute to visual contrast coding in a cell-type specific manner. Certain cell types generate excitatory responses using primarily AMPA receptors or disinhibition. PMID:20670835

  5. [Anti-NMDA-receptor encephalitis].

    PubMed

    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. PMID:27325034

  6. NMDA receptors and memory encoding.

    PubMed

    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

  7. Molecular determinants of NMDA receptor internalization.

    PubMed

    Roche, K W; Standley, S; McCallum, J; Dune Ly, C; Ehlers, M D; Wenthold, R J

    2001-08-01

    Although synaptic AMPA receptors have been shown to rapidly internalize, synaptic NMDA receptors are reported to be static. It is not certain whether NMDA receptor stability at synaptic sites is an inherent property of the receptor, or is due to stabilization by scaffolding proteins. In this study, we demonstrate that NMDA receptors are internalized in both heterologous cells and neurons, and we define an internalization motif, YEKL, on the distal C-terminus of NR2B. In addition, we show that the synaptic protein PSD-95 inhibits NR2B-mediated internalization, and that deletion of the PDZ-binding domain of NR2B increases internalization in neurons. This suggests an involvement for PSD-95 in NMDA receptor regulation and an explanation for NMDA receptor stability at synaptic sites. PMID:11477425

  8. Physiology and pathology of NMDA receptors.

    PubMed

    Petrović, M; Horák, M; Sedlácek, M; Vyklický, L

    2005-01-01

    Ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype are highly expressed in the central nervous system and are involved in excitatory synaptic transmission and synaptic plasticity. Prolonged activation of NMDA receptors can lead to excitotoxicity, which is implicated in the pathogenesis of neurodegeneration occurring in various acute and chronic disorders of the central nervous system. Recent advances in understanding the function, pharmacology, genetics and structure of NMDA receptors has promoted a search for new compounds that could be therapeutically used. These compounds act on agonist binding sites, either apart from them or directly within the ion channel pore. Members of the last group are called open channel blockers, and some of them, such as memantine and ketamine, are already clinically used. Kinetic modeling of NMDA receptor activity was employed to define the effects of various groups of modulators. Quantifying the action of these substances by kinetic parameters can help us to reveal the molecular mechanism of action at the receptor and to characterize the dependence of its action on the mode of NMDA receptor activation. Two modes are considered: phasic activation, induced by synaptically released glutamate, and tonic activation, which is expected to occur under pathological conditions when low, but sustained levels of glutamate activate NMDA receptors. The aim of our review is to summarize the recent data about the structural and functional properties of NMDA receptors and their role in long-term potentiation and excitotoxicity. PMID:16315761

  9. Human neuroepithelial cells express NMDA receptors.

    PubMed

    Sharp, Christopher D; Fowler, M; Jackson, T H; Houghton, J; Warren, A; Nanda, A; Chandler, I; Cappell, B; Long, A; Minagar, A; Alexander, J S

    2003-11-13

    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. PMID:14614784

  10. NMDA receptors in hyperammonemia and hepatic encephalopathy.

    PubMed

    Llansola, Marta; Rodrigo, Regina; Monfort, Pilar; Montoliu, Carmina; Kosenko, Elena; Cauli, Omar; Piedrafita, Blanca; El Mlili, Nisrin; Felipo, Vicente

    2007-12-01

    The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy. PMID:17701332

  11. Novel NMDA Receptor Modulators: An Update

    PubMed Central

    Santangelo, Rose M.; Acker, Timothy M.; Zimmerman, Sommer S.; Katzman, Brooke M.; Strong, Katie L.; Traynelis, Stephen F.; Liotta, Dennis C.

    2013-01-01

    Summary Introduction The NMDA receptor is a ligand-gated ion channel that plays a critical role in higher level brain processes and has been implicated in a range of neurological and psychiatric conditions. Although initial studies for the use of NMDA receptor antagonists in neuroprotection were unsuccessful, more recently, NMDA receptor antagonists have shown clinical promise in other indications such as Alzheimer’s disease, Parkinson’s disease, pain and depression. Based on the clinical observations and more recent insights into receptor pharmacology, new modulatory approaches are beginning to emerge, with potential therapeutic benefit. Areas Covered The article covers the known pharmacology and important features regarding NMDA receptors and their function. A discussion of pre-clinical and clinical relevance is included, as well. The subsequent patent literature review highlights the current state of the art targeting the receptor since the last review in 2010. Expert Opinion The complex nature of the NMDA receptor structure and function is becoming better understood. As knowledge about this receptor increases, it opens up new opportunities for targeting the receptor for many therapeutic indications. New strategies and advances in older technologies will need to be further developed before clinical success can be achieved. First-in-class potentiators and subunit-selective agents form the basis for most new strategies, complemented by efforts to limit off-target liability and fine-tune on-target properties. PMID:23009122

  12. New advances in NMDA receptor pharmacology

    PubMed Central

    Ogden, Kevin K.; Traynelis, Stephen F.

    2011-01-01

    N-Methyl-D-aspartate (NMDA) receptors are tetrameric ion channels containing two of four possible GluN2 subunits. These receptors have been implicated for decades in neurological diseases such as stroke, traumatic brain injury, dementia, and schizophrenia. The GluN2 subunits contribute substantially to functional diversity of NMDA receptors and are distinctly expressed in development and among brain regions. Thus, subunit-selective antagonists and modulators that differentially target the GluN2 subunit might provide an opportunity to pharmacologically modify the function of select groups of neurons for therapeutic gain. A flurry of clinical, functional, and chemical studies have together reinvigorated efforts to identify subunit-selective modulators of NMDA receptor function, resulting in a handful of new compounds that appear to act at novel sites. Here we review the properties of new emerging classes of subunit-selective NMDA receptor modulators, which we predict will mark the beginning of a productive period of progress for NMDA receptor pharmacology. PMID:21996280

  13. Crystal structure of a heterotetrameric NMDA receptor ion channel

    PubMed Central

    Karakas, Erkan; Furukawa, Hiro

    2014-01-01

    N -methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors, which mediate most excitatory synaptic transmission in mammalian brains. Calcium permeation triggered by activation of NMDA receptors is the pivotal event for initiation of neuronal plasticity. Here we show the crystal structure of the intact heterotetrameric GluN1/GluN2B NMDA receptor ion channel at 4 Å. The NMDA receptors are arranged as a dimer of GluN1-GluN2B heterodimers with the two-fold symmetry axis running through the entire molecule composed of an amino terminal domain (ATD), a ligand-binding domain (LBD), and a transmembrane domain (TMD). The ATD and LBD are much more highly packed in the NMDA receptors than non-NMDA receptors, which may explain why ATD regulates ion channel activity in NMDA receptors but not in non-NMDA receptors. PMID:24876489

  14. NMDA Receptor Activity in Neuropsychiatric Disorders

    PubMed Central

    Lakhan, Shaheen E.; Caro, Mario; Hadzimichalis, Norell

    2013-01-01

    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. PMID:23772215

  15. NMDA Receptors Mediate Synaptic Competition in Culture

    PubMed Central

    She, Kevin; Craig, Ann Marie

    2011-01-01

    Background Activity through NMDA type glutamate receptors sculpts connectivity in the developing nervous system. This topic is typically studied in the visual system in vivo, where activity of inputs can be differentially regulated, but in which individual synapses are difficult to visualize and mechanisms governing synaptic competition can be difficult to ascertain. Here, we develop a model of NMDA-receptor dependent synaptic competition in dissociated cultured hippocampal neurons. Methodology/Principal Findings GluN1 -/- (KO) mouse hippocampal neurons lacking the essential NMDA receptor subunit were cultured alone or cultured in defined ratios with wild type (WT) neurons. The absence of functional NMDA receptors did not alter neuron survival. Synapse development was assessed by immunofluorescence for postsynaptic PSD-95 family scaffold and apposed presynaptic vesicular glutamate transporter VGlut1. Synapse density was specifically enhanced onto minority wild type neurons co-cultured with a majority of GluN1 -/- neighbour neurons, both relative to the GluN1 -/- neighbours and relative to sister pure wild type cultures. This form of synaptic competition was dependent on NMDA receptor activity and not conferred by the mere physical presence of GluN1. In contrast to these results in 10% WT and 90% KO co-cultures, synapse density did not differ by genotype in 50% WT and 50% KO co-cultures or in 90% WT and 10% KO co-cultures. Conclusions/Significance The enhanced synaptic density onto NMDA receptor-competent neurons in minority coculture with GluN1 -/- neurons represents a cell culture paradigm for studying synaptic competition. Mechanisms involved may include a retrograde ‘reward’ signal generated by WT neurons, although in this paradigm there was no ‘punishment’ signal against GluN1 -/- neurons. Cell culture assays involving such defined circuits may help uncover the rules and mechanisms of activity-dependent synaptic competition in the developing nervous

  16. NMDA Receptors: Power Switches for Oligodendrocytes.

    PubMed

    Krasnow, Anna M; Attwell, David

    2016-07-01

    The role of NMDA receptors in oligodendrocytes has been controversial. A new paper (Saab et al., 2016) suggests they play a key role in regulating glucose uptake in response to axonal glutamate release, thus controlling metabolic cooperation between oligodendrocytes and axons. PMID:27387644

  17. Subunit Arrangement and Function in NMDA Receptors

    SciTech Connect

    Furukawa,H.; Singh, S.; Mancusso, R.; Gouaux, E.

    2005-01-01

    Excitatory neurotransmission mediated by NMDA (N-methyl-D-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions including learning and memory. Here we report crystal structures of the ligand-binding core of NR2A with glutamate and that of the NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defines the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggests a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiological experiments, confirms that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.

  18. Modulation of the NMDA receptor by polyamines

    SciTech Connect

    Williams, K.; Romano, C.; Dichter, M.A.; Molinoff, P.B. )

    1991-01-01

    Results of recent biochemical and electrophysiological studies have suggested that a recognition site for polyamines exists as part of the NMDA receptor complex. The endogenous polyamines spermine and spermidine increase the binding of open-channel blockers and increase NMDA-elicited currents in cultured neutrons. These polyamines have been termed agonists at the polyamine recognition site. Studies of the effects of natural and synthetic polyamines on the binding of ({sup 3}H)MK-801 and on NMDA-elicited currents in cultured neurons have led to the identification of compounds classified as partial agonists, antagonists, and inverse agonists at the polyamine recognition site. Polyamines have also been found to affect the binding of ligands to the recognition sites for glutamate and glycine. However, these effects may be mediated at a site distinct from that at which polyamines act to modulate the binding of open-channel blockers. Endogenous polyamines may modulate excitatory synaptic transmission by acting at the polyamine recognition site of the NMDA receptor. This site could represent a novel therapeutic target for the treatment of ischemia-induced neurotoxicity, epilepsy, and neurodegenerative diseases.

  19. The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes

    PubMed Central

    Burzomato, Valeria; Frugier, Guillaume; Pérez-Otaño, Isabel; Kittler, Josef T; Attwell, David

    2010-01-01

    NMDA receptors have been shown to contribute to glutamate-evoked currents in oligodendrocytes. Activation of these receptors damages myelin in ischaemia, in part because they are more weakly blocked by Mg2+ than are most neuronal NMDA receptors. This weak Mg2+ block was suggested to reflect an unusual subunit composition including the NR2C and NR3A subunits. Here we expressed NR1/NR2C and triplet NR1/NR2C/NR3A recombinant receptors in HEK cells and compared their currents with those of NMDA-evoked currents in rat cerebellar oligodendrocytes. NR1/NR2C/3A receptors were less blocked by 2 mm Mg2+ than were NR1/NR2C receptors (the remaining current was 30% and 18%, respectively, of that seen without added Mg2+) and showed less channel noise, suggesting a smaller single channel conductance. NMDA-evoked currents in oligodendrocytes showed a Mg2+ block (to 32%) similar to that observed for NR1/NR2C/NR3A and significantly different from that for NR1/NR2C receptors. Co-immunoprecipitation revealed interactions between NR1, NR2C and NR3A subunits in a purified myelin preparation from rat brain. These data are consistent with NMDA-evoked currents in oligodendrocytes reflecting the activation of receptors containing NR1, NR2C and NR3A subunits. PMID:20660562

  20. A family of photoswitchable NMDA receptors

    PubMed Central

    Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Tauner, Dirk; Isacoff, Ehud Y

    2016-01-01

    NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991

  1. A family of photoswitchable NMDA receptors.

    PubMed

    Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Tauner, Dirk; Isacoff, Ehud Y

    2016-01-01

    NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. PMID:26929991

  2. Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

    PubMed Central

    RON, DORIT

    2005-01-01

    One of the major targets for ethanol (alcohol) in the brain is the N-methyl-d-aspartate (NMDA) receptor, a glutamate-gated ion channel. Intriguingly, the effects of ethanol on the NMDA receptor are not homogeneous throughout the brain. This review focuses on recent studies revealing molecular mechanisms that mediate the actions of ethanol on the NMDA receptor in different brain regions via changes in NMDA receptor phosphorylation and compartmentalization. Specifically, the role of the scaffolding protein RACK1 and the regulatory protein DARPP-32 in mediating the distinct effects of ethanol is presented. PMID:15271260

  3. NMDA receptor binding in focal epilepsies

    PubMed Central

    McGinnity, C J; Koepp, M J; Hammers, A; Riaño Barros, D A; Pressler, R M; Luthra, S; Jones, P A; Trigg, W; Micallef, C; Symms, M R; Brooks, D J; Duncan, J S

    2015-01-01

    Objective To demonstrate altered N-methyl-d-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [18F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy. Methods Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [18F]GE-179 PET scan, in a cross-sectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [18F]GE-179 volume-of-distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping. Results Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [18F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [18F]GE-179 VT (−29%; p<0.002). There were no focal abnormalities common to the epilepsy group. Conclusions In patients with focal epilepsies, we detected primarily global increases of [18F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [18F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy. PMID:25991402

  4. NAAG, NMDA receptor and psychosis.

    PubMed

    Bergeron, Richard; Coyle, Joseph T

    2012-01-01

    At central synapses, glutamate is the main excitatory neurotransmitter. Once released from presynaptic terminals, glutamate activates a number of different glutamatergic receptors one of which is the ligand gated ionophore glutamatergic subtype N-methyl-D-aspartate receptors (NMDARs). NMDARs play a crucial role in controlling various determinants of synaptic function. N-acetylaspartylglutamate (NAAG) is the most prevalent peptide transmitter in the mammalian central nervous system. NAAG is released upon neuronal depolarization by a calcium-dependent process from glutamatergic and GABAergic neurons. It is cleaved by a specific peptidase located on astrocytes, glutamate carboxypeptidase type II (GCP-II), to N-acetylaspartate (NAA) and glutamate. Current evidence supports the hypothesis that NAAG is an endogenous agonist at G protein coupled mGluR3 receptors and an antagonist at NMDAR. In several disorders and animal models of human diseases, the levels of NAAG and the activity of GCP-II are altered in ways that are consistent with NAAG's role in regulation of glutamatergic neurotransmission. Several lines of evidence suggest that a dysfunction in glutamatergic via the NMDAR might be involved in schizophrenia. This hypothesis has evolved from findings that NMDAR antagonists such as phencyclidine (PCP or "angel dust"), produces a syndrome in normal individuals that closely resembles schizophrenia and exacerbates psychotic symptoms in patients with chronic schizophrenia. Recent postmortem, metabolic and genetic studies have provided evidence that hypofunction of discrete populations of NMDAR can contribute to the symptoms of schizophrenia, at least in some patients. The review outlines the role of endogenous NAAG at NMDAR neurotransmission and its putative role in the pathophysiology of schizophrenia. PMID:22304714

  5. Serotonin and NMDA receptors in respiratory long-term facilitation

    PubMed Central

    Ling, Liming

    2008-01-01

    Some have postulated that long-term facilitation (LTF), a persistent augmentation of respiratory activity after episodic hypoxia, may play a beneficial role in helping stabilize upper airway patency in obstructive sleep apnea (OSA) patients. However, the neuronal and cellular mechanisms underlying this plasticity of respiratory motor behavior are still poorly understood. The main purpose of this review is to summarize recent findings about serotonin and NMDA receptors involved in both LTF and its enhancement after chronic intermittent hypoxia (CIH). The potential roles of these receptors in the initiation, formation and/or maintenance of LTF, as well as the CIH effect on LTF, will be discussed. As background, different paradigms for the stimulus protocol, different patterns of LTF expression and their mechanistic implications in LTF will also be discussed. PMID:18606575

  6. NMDA Receptor Modulators in the Treatment of Drug Addiction

    PubMed Central

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

    2013-01-01

    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. PMID:24275950

  7. NMDA Receptor Function During Senescence: Implication on Cognitive Performance

    PubMed Central

    Kumar, Ashok

    2015-01-01

    N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function. PMID:26732087

  8. Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism.

    PubMed

    Saab, Aiman S; Tzvetavona, Iva D; Trevisiol, Andrea; Baltan, Selva; Dibaj, Payam; Kusch, Kathrin; Möbius, Wiebke; Goetze, Bianka; Jahn, Hannah M; Huang, Wenhui; Steffens, Heinz; Schomburg, Eike D; Pérez-Samartín, Alberto; Pérez-Cerdá, Fernando; Bakhtiari, Davood; Matute, Carlos; Löwel, Siegrid; Griesinger, Christian; Hirrlinger, Johannes; Kirchhoff, Frank; Nave, Klaus-Armin

    2016-07-01

    Oligodendrocytes make myelin and support axons metabolically with lactate. However, it is unknown how glucose utilization and glycolysis are adapted to the different axonal energy demands. Spiking axons release glutamate and oligodendrocytes express NMDA receptors of unknown function. Here we show that the stimulation of oligodendroglial NMDA receptors mobilizes glucose transporter GLUT1, leading to its incorporation into the myelin compartment in vivo. When myelinated optic nerves from conditional NMDA receptor mutants are challenged with transient oxygen-glucose deprivation, they show a reduced functional recovery when returned to oxygen-glucose but are indistinguishable from wild-type when provided with oxygen-lactate. Moreover, the functional integrity of isolated optic nerves, which are electrically silent, is extended by preincubation with NMDA, mimicking axonal activity, and shortened by NMDA receptor blockers. This reveals a novel aspect of neuronal energy metabolism in which activity-dependent glutamate release enhances oligodendroglial glucose uptake and glycolytic support of fast spiking axons. PMID:27292539

  9. Treadmill exercise enhances NMDA receptor expression in schizophrenia mice

    PubMed Central

    Park, Joon-Ki; Lee, Sam-Jun; Kim, Tae-Won

    2014-01-01

    Schizophrenia is a serious psychiatric disorder with several symptoms including cognitive dysfunction. Although the causes of schizophrenia are still unclear, there is a strong suspicion that the abnormality in N-methyl-D-aspartate (NMDA) receptor may contribute to schizophrenia symptoms. In the present study, the effect of treadmill exercise on the NMDA receptor expression was evaluated using MK-801-induced schizophrenia mice. Immunohistochemistry for expressions of NMDA receptor tyrosine hydroxylase (TH) was conducted. Western blot for brain-derived neurotrophic factor (BDNF) was also performed. In the present results, the mice in the MK-801-treated group displayed reduced NMDA receptor expression. Enhanced TH expression and suppressed BDNF expression were also observed in the MK-801-treated mice. Treadmill exercise improved NMDA receptor expression in the MK-801-induced schizophrenia mice. Treadmill exercise also suppressed TH expression and enhanced BDNF expression in the MK-801-induced schizophrenia mice. The present study showed that down-regulation of NMDA receptor demonstrated schizophrenia-like parameters, meanwhile treadmill running improved schizophrenia-related parameters through enhancing NMDA receptor expression. PMID:24678500

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

    PubMed

    Oswald, Manfred J; Schulz, Jan M; Kelsch, Wolfgang; Oorschot, Dorothy E; Reynolds, John N J

    2015-01-01

    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 afterhyperpolarization (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 Mg(2+)-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 Mg(2+)-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. PMID:25914618

  11. NMDA and non-NMDA glutamate receptors in auditory transmission in the barn owl inferior colliculus.

    PubMed

    Feldman, D E; Knudsen, E I

    1994-10-01

    The pharmacology of auditory responses in the inferior colliculus (IC) of the barn owl was investigated by iontophoresis of excitatory amino acid receptor antagonists into two different functional subdivisions of the IC, the external nucleus (ICx) and the lateral shell of the central nucleus (lateral shell), both of which carry out important computations in the processing of auditory spatial information. Combined application of the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP5) and the non-NMDA receptor antagonist 6-cyano-5-nitroquinoxaline-2,3-dione (CNQX) significantly reduced auditory-evoked spikes at all sites in these two subdivisions, and completely eliminated responses at many locations. This suggests that excitatory amino acid receptors mediate the bulk, if not all, of auditory responses in the ICx and lateral shell. NMDA and non-NMDA receptors contributed differently to auditory responses in the two subdivisions. In the ICx, AP5 significantly reduced the number of auditory-evoked spikes at every site tested. On average, AP5 eliminated 55% of auditory-evoked spikes at multiunit sites and 64% at single-unit sites in this structure. In contrast, in the lateral shell, AP5 significantly reduced responses at less than half the sites tested, and, on average, AP5 eliminated only 19% of spikes at multiunit sites and 25% at single-unit sites. When the magnitude of response blockade produced by AP5 at individual multiunit sites was normalized to adjust for site-to-site differences in the efficacy of iontophoresed AP5 and CNQX, AP5 blockade was still significantly greater in the ICx than the lateral shell. CNQX application strongly reduced responses in both subdivisions. These data suggest that NMDA receptor currents make a major contribution to auditory responses in the ICx, while they make only a small contribution to auditory responses in the lateral shell. Non-NMDA receptor currents, on the other hand, contribute to auditory responses in both

  12. Non-NMDA receptor antagonist-induced drinking in rat

    NASA Technical Reports Server (NTRS)

    Xu, Z.; Johnson, A. K.

    1998-01-01

    Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

  13. Anti-NMDA-receptor antibody encephalitis in infants

    PubMed Central

    Matoq, Amr A.; Rappoport, Adam S.; Yang, Yiting; O'Babatunde, Jessica; Bakerywala, Rubina; Sheth, Raj D.

    2015-01-01

    Purpose Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is an autoimmune disorder manifesting subacutely with prominent aberrant movements and psychiatric symptoms. The clinical course is one of progressive clinical deterioration that can be halted and often reversed by early diagnosis and treatment. Patterns of presentation and etiology of anti-NMDA-receptor antibody encephalitis are dependent on age and can be challenging to recognize in very young children. Reports Sequential clinical case observations of anti-NMDA-receptor antibody encephalitis presenting in very young children were examined over a year at a single tertiary pediatric institution. Cerebrospinal fluid confirmed anti-NMDA-receptor antibodies in two cases (a 21-month-old boy and a 29-month-old girl) that demonstrated either bizarre behavioral patterns or status epilepticus both associated with progressive deterioration. Once recognized, the clinical course was arrested and reversed by aggressive treatment with plasma exchange, immunoglobulin, and high dose IV steroids. 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. PMID:26744696

  14. Amyloid β peptide oligomers directly activate NMDA receptors.

    PubMed

    Texidó, Laura; Martín-Satué, Mireia; Alberdi, Elena; Solsona, Carles; Matute, Carlos

    2011-03-01

    Amyloid beta (Aβ) oligomers accumulate in the brain tissue of Alzheimer disease patients and are related to disease pathogenesis. The precise mechanisms by which Aβ oligomers cause neurotoxicity remain unknown. We recently reported that Aβ oligomers cause intracellular Ca(2+) overload and neuronal death that can be prevented by NMDA receptor antagonists. This study investigated whether Aβ oligomers directly activated NMDA receptors (NMDARs) using NR1/NR2A and NR1/NR2B receptors that were heterologously expressed in Xenopus laevis oocytes. Indeed, Aβ oligomers induced inward non-desensitizing currents that were blocked in the presence of the NMDA receptor antagonists memantine, APV, and MK-801. Intriguingly, the amplitude of the responses to Aβ oligomers was greater for NR1/NR2A heteromers than for NR1/NR2B heteromers expressed in oocytes. Consistent with these findings, we observed that the increase in the cytosolic concentration of Ca(2+) induced by Aβ oligomers in cortical neurons is prevented by AP5, a broad spectrum NMDA receptor antagonist, but slightly attenuated by ifenprodil which blocks receptors with the NR2B subunit. Together, these results indicate that Aβ oligomers directly activate NMDA receptors, particularly those with the NR2A subunit, and further suggest that drugs that attenuate the activity of such receptors may prevent Aβ damage to neurons in Alzheimeŕs disease. PMID:21349580

  15. Dendritic NMDA receptors activate axonal calcium channels

    PubMed Central

    Christie, Jason M.; Jahr, Craig E.

    2008-01-01

    Summary NMDA receptor (NMDAR) activation can alter synaptic strength by regulating transmitter release from a variety of neurons in the CNS. As NMDARs are permeable to Ca2+ and monovalent cations, they could alter release directly by increasing presynaptic Ca2+ or indirectly by axonal depolarization sufficient to activate voltage-sensitive Ca2+ channels (VSCCs). Using two-photon microscopy to measure Ca2+ excursions, we found that somatic depolarization or focal activation of dendritic NMDARs elicited small Ca2+ transients in axon varicosities of cerebellar stellate cell interneurons. These axonal transients resulted from Ca2+ entry through VSCCs that were opened by the electrotonic spread of the NMDAR-mediated depolarization elicited in the dendrites. In contrast, we were unable to detect direct activation of NMDARs on axons indicating an exclusive somatodendritic expression of functional NMDARs. In cerebellar stellate cells, dendritic NMDAR activation masquerades as a presynaptic phenomenon and may influence Ca2+-dependent forms of presynaptic plasticity and release. PMID:18957221

  16. Developmental changes in NMDA receptor expression in the platyfish brain

    NASA Technical Reports Server (NTRS)

    Flynn, K. M.; Schreibman, M. P.; Magliulo-Cepriano, L.

    1997-01-01

    We have examined the distribution of the N-methyl-D-aspartate (NMDA) receptor in the brain of a freshwater teleost using an antibody against the R1 subunit of the receptor (NMDAR1). The primary site of localization was the nucleus olfactoretinalis (NOR), a significant gonadotropin releasing hormone (GnRH)-containing brain nucleus. The number of cells expressing NMDAR1 in this nucleus was dependent upon developmental stage, with pubescent and mature animals displaying significantly more stained cells than immature and senescent animals. This is the first reported observation of age- and maturity-related NMDA receptor association with GnRH-containing brain areas.

  17. Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum.

    PubMed

    ElMlili, Nisrin; Boix, Jordi; Ahabrach, Hanan; Rodrigo, Regina; Errami, Mohammed; Felipo, Vicente

    2010-02-01

    Reduced function of the glutamate--nitric oxide (NO)--cGMP pathway is responsible for some cognitive alterations in rats with hyperammonemia and hepatic encephalopathy. Hyperammonemia impairs the pathway in cerebellum by increasing neuronal nitric oxide synthase (nNOS) phosphorylation in Ser847 by calcium-calmodulin-dependent protein kinase II (CaMKII), reducing nNOS activity, and by reducing nNOS amount in synaptic membranes, which reduces its activation following NMDA receptors activation. The reason for increased CaMKII activity in hyperammonemia remains unknown. We hypothesized that it would be as a result of increased tonic activation of NMDA receptors. The aims of this work were to assess: (i) whether tonic NMDA activation receptors is increased in cerebellum in chronic hyperammonemia in vivo; and (ii) whether this tonic activation is responsible for increased CaMKII activity and reduced activity of nNOS and of the glutamate--NO--cGMP pathway. Blocking NMDA receptors with MK-801 increases cGMP and NO metabolites in cerebellum in vivo and in slices from hyperammonemic rats. This is because of reduced phosphorylation and activity of CaMKII, leading to normalization of nNOS phosphorylation and activity. MK-801 also increases nNOS in synaptic membranes and reduces it in cytosol. This indicates that hyperammonemia increases tonic activation of NMDA receptors leading to reduced activity of nNOS and of the glutamate--NO--cGMP pathway. PMID:20002515

  18. Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium.

    PubMed

    Betzen, Christian; White, Robin; Zehendner, Christoph M; Pietrowski, Eweline; Bender, Bianca; Luhmann, Heiko J; Kuhlmann, Christoph R W

    2009-10-15

    N-methyl-d-aspartate receptor (NMDA-R)-mediated oxidative stress has been implicated in blood-brain barrier (BBB) disruption in a variety of neuropathological diseases. Although some interactions between both phenomena have been elucidated, possible influences of reactive oxygen species (ROS) on the NMDA-R itself have so far been neglected. The objective of this study was to examine how the cerebroendothelial NMDA-R is affected by exposure to oxidative stress and to assess possible influences on BBB integrity. RT-PCR confirmed several NMDA-R subunits (NR1, NR2B-D) expressed in the bEnd3 cell line (murine cerebrovascular endothelial cells). NR1 protein expression after exposure to ROS was observed via in-cell Western. The functionality of the expressed NMDA-R was determined by measuring DiBAC fluorescence in ROS-preexposed cells upon stimulation with the specific agonist NMDA. Finally, the effects on barrier integrity were evaluated using the ECIS system to detect changes in monolayer impedance upon NMDA-R stimulation after exposure to ROS. The expression of NR1 significantly (p<0.001) increased 72 h after 30 min exposure to superoxide (+33.8+/-7.5%), peroxynitrite (+84.9+/-10.7%), or hydrogen peroxide (+92.8+/-7.6%), resulting in increased cellular response to NMDA-R stimulation and diminished monolayer impedance. We conclude that oxidative stress upregulates NMDA-R on cerebrovascular endothelium and thus heightens susceptibility to glutamate-induced BBB disruption. PMID:19660541

  19. Access of inhibitory neurosteroids to the NMDA receptor

    PubMed Central

    Borovska, Jirina; Vyklicky, Vojtech; Stastna, Eva; Kapras, Vojtech; Slavikova, Barbora; Horak, Martin; Chodounska, Hana; Vyklicky Jr, Ladislav

    2012-01-01

    BACKGROUND AND PURPOSE NMDA receptors are glutamatergic ionotropic receptors involved in excitatory neurotransmission, synaptic plasticity and excitotoxic cell death. Many allosteric modulators can influence the activity of these receptors positively or negatively, with behavioural consequences. 20-Oxo-5β-pregnan-3α-yl sulphate (pregnanolone sulphate; PA-6) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective. We tested the hypothesis that the interaction of PA-6 with the plasma membrane is critical for its inhibitory effect at NMDA receptors. EXPERIMENTAL APPROACH Electrophysiological recordings and live microscopy were performed on heterologous HEK293 cells expressing GluN1/GluN2B receptors and cultured rat hippocampal neurons. KEY RESULTS Our experiments showed that the kinetics of the steroid inhibition were slow and not typical of drug-receptor interaction in an aqueous solution. In addition, the recovery from steroid inhibition was accelerated by β- and γ-cyclodextrin. Values of IC50 assessed for novel synthetic C3 analogues of PA-6 differed by more than 30-fold and were positively correlated with the lipophilicity of the PA-6 analogues. Finally, the onset of inhibition induced by C3 analogues of PA-6 ranged from use-dependent to use-independent. The onset and offset of cell staining by fluorescent analogues of PA-6 were slower than those of steroid-induced inhibition of current responses mediated by NMDA receptors. CONCLUSION AND IMPLICATIONS We conclude that steroid accumulation in the plasma membrane is the route by which it accesses a binding site on the NMDA receptor. Thus, our results provide a possible structural framework for pharmacologically targeting the transmembrane domains of the receptor. PMID:22188257

  20. EVALUATING THE NMDA-GLUTAMATE RECEPTOR AS A SITE OF ACTION FOR TOLUENE, IN VIVO

    EPA Science Inventory

    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...

  1. NMDA receptor structures reveal subunit arrangement and pore architecture

    PubMed Central

    Lee, Chia-Hsueh; Lü, Wei; Michel, Jennifer Carlisle; Goehring, April; Du, Juan; Song, Xianqiang; Gouaux, Eric

    2014-01-01

    Summary N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present x-ray crystal structures of the GluN1/GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino terminal and ligand binding domains. The transmembrane domains harbor a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ~2-fold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors. PMID:25008524

  2. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.

    PubMed

    Farber, N B; Kim, S H; Dikranian, K; Jiang, X P; Heinkel, C

    2002-01-01

    NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated. PMID:11803444

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

    PubMed

    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. PMID:21763704

  4. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    PubMed

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic. PMID:11554551

  5. FROM MOLECULAR PHYLOGENY TOWARDS DIFFERENTIATING PHARMACOLOGY FOR NMDA RECEPTOR SUBTYPES

    PubMed Central

    Platt, Randall J.; Curtice, Kigen J.; Twede, Vernon D.; Watkins, Maren; Gruszczyński, Paweł; Bulaj, Grzegorz; Horvath, Martin P.; Olivera, Baldomero M.

    2014-01-01

    In order to decode the roles that N-methyl-D-aspartate (NMDA) receptors play in excitatory neurotransmission, synaptic plasticity, and neuropathologies, there is need for ligands that differ in their subtype selectivity. The conantokin family of Conus peptides is the only group of peptidic natural products known to target NMDA receptors. Using a search that was guided by phylogeny, we identified new conantokins from the marine snail Conus bocki that complement the current repertoire of NMDA receptor pharmacology. Channel currents measured in Xenopus oocytes demonstrate conantokins conBk-A, conBk-B, and conBk-C have highest potencies for NR2D containing receptors, in contrast to previously characterized conantokins that preferentially block NR2B containing NMDA receptors. Conantokins are rich in γ-carboxyglutamate, typically 17–34 residues, and adopt helical structure in a calcium-dependent manner. As judged by CD spectroscopy, conBk-C adopts significant helical structure in a calcium ion-dependent manner, while calcium, on its own, appears insufficient to stabilize helical conformations of conBk-A or conBk-B. Molecular dynamics simulations help explain the differences in calcium-stabilized structures. Two-dimensional NMR spectroscopy shows that the 9-residue conBk-B is relatively unstructured but forms a helix in the presence of TFE and calcium ions that is similar to other conantokin structures. These newly discovered conantokins hold promise that further exploration of small peptidic antagonists will lead to a set of pharmacological tools that can be used to characterize the role of NMDA receptors in nervous system function and disease. PMID:24508768

  6. Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats

    PubMed Central

    McGuire, Michelle; Zhang, Yi; White, David P; Ling, Liming

    2005-01-01

    Exposure to episodic hypoxia induces a persistent augmentation of respiratory activity, known as long-term facilitation (LTF). LTF of phrenic nerve activity has been reported to require serotonin receptor activation and protein syntheses. However, the underlying cellular mechanism still remains poorly understood. NMDA receptors play key roles in synaptic plasticity (e.g. some forms of hippocampal long-term potentiation). The present study was designed to examine the role of NMDA receptors in phrenic LTF and test if the relevant receptors are located in the phrenic motonucleus. Integrated phrenic nerve activity was measured in anaesthetized, vagotomized, neuromuscularly blocked and artificially ventilated rats before, during and after three episodes of 5 min isocapnic hypoxia (Pa,O2= 30–45 mmHg), separated by 5 min hyperoxia (50% O2). Either saline (as control) or the NMDA receptor antagonist MK-801 (0.2 mg kg−1, i.p.) was systemically injected ∼1 h before hypoxia. Phrenic LTF was eliminated by the MK-801 injection (vehicle, 32.8 ± 3.7% above baseline in phrenic amplitude at 60 min post-hypoxia; MK-801, −0.5 ± 4.1%, means ± s.e.m.), with little change in both the CO2-apnoeic threshold and the hypoxic phrenic response (HPR). Vehicle (saline, 5 × 100 nl) or MK-801 (10 μm; 5 × 100 nl) was also microinjected into the phrenic motonucleus region in other groups. Phrenic LTF was eliminated by the MK-801 microinjection (vehicle, 34.2 ± 3.4%; MK-801, −2.5 ± 2.8%), with minimal change in HPR. Collectively, these results suggest that the activation of NMDA receptors in the phrenic motonucleus is required for the episodic hypoxia-induced phrenic LTF. PMID:15932891

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

    PubMed

    Maheshwari, Atul; Nahm, Walter K; Noebels, Jeffrey L

    2013-01-01

    Paradoxical seizure exacerbation by anti-epileptic 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 (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid) 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 twofold decrease in the dendrite:soma GluA4 expression ratio compared to wild-type (WT) littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg (2) (+)-induced network discharges in WT 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. PMID:24065886

  8. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.

    PubMed

    Micu, I; Jiang, Q; Coderre, E; Ridsdale, A; Zhang, L; Woulfe, J; Yin, X; Trapp, B D; McRory, J E; Rehak, R; Zamponi, G W; Wang, W; Stys, P K

    2006-02-23

    Central nervous system myelin is a specialized structure produced by oligodendrocytes that ensheaths axons, allowing rapid and efficient saltatory conduction of action potentials. Many disorders promote damage to and eventual loss of the myelin sheath, which often results in significant neurological morbidity. However, little is known about the fundamental mechanisms that initiate myelin damage, with the assumption being that its fate follows that of the parent oligodendrocyte. Here we show that NMDA (N-methyl-d-aspartate) glutamate receptors mediate Ca2+ accumulation in central myelin in response to chemical ischaemia in vitro. Using two-photon microscopy, we imaged fluorescence of the Ca2+ indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor antagonist NBQX completely blocked the ischaemic Ca2+ increase in oligodendroglial cell bodies, but only modestly reduced the Ca2+ increase in myelin. In contrast, the Ca2+ increase in myelin was abolished by broad-spectrum NMDA receptor antagonists (MK-801, 7-chlorokynurenic acid, d-AP5), but not by more selective blockers of NR2A and NR2B subunit-containing receptors (NVP-AAM077 and ifenprodil). In vitro ischaemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2 and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits are present for the formation of functional NMDA receptors. Our data show that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, our finding that the Ca2+ increase was mediated in large part by activation of myelinic NMDA receptors suggests a new mechanism of axo-myelinic signalling. Such a mechanism may represent a

  9. Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer's disease.

    PubMed

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

    2011-01-01

    A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β, contributing to the initiation of Alzheimer's disease. Among the different routes of Ca(2+) entry, N-methyl-d-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca(2+) influx. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer's disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia. PMID:21568789

  10. Catatonic Syndrome in Anti-NMDA Receptor Encephalitis.

    PubMed

    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

  11. Catatonic Syndrome in Anti-NMDA Receptor Encephalitis

    PubMed Central

    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

  12. Alcohol and NMDA receptor: current research and future direction

    PubMed Central

    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. PMID:23754976

  13. NMDA receptor antagonist ketamine impairs feature integration in visual perception.

    PubMed

    Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F

    2013-01-01

    Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans. PMID:24223927

  14. NMDA Receptor Antagonist Ketamine Impairs Feature Integration in Visual Perception

    PubMed Central

    Meuwese, Julia D. I.; van Loon, Anouk M.; Scholte, H. Steven; Lirk, Philipp B.; Vulink, Nienke C. C.; Hollmann, Markus W.; Lamme, Victor A. F.

    2013-01-01

    Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans. PMID:24223927

  15. Interplay between non-NMDA and NMDA receptor activation during oscillatory wave propagation: Analyses of caffeine-induced oscillations in the visual cortex of rats.

    PubMed

    Yoshimura, Hiroshi; Sugai, Tokio; Kato, Nobuo; Tominaga, Takashi; Tominaga, Yoko; Hasegawa, Takahiro; Yao, Chenjuan; Akamatsu, Tetsuya

    2016-07-01

    Generation and propagation of oscillatory activities in cortical networks are important features of the brain. However, many issues related to oscillatory phenomena are unclear. We previously reported neocortical oscillation following caffeine treatment of rat brain slices. Input to the primary visual cortex (Oc1) generates N-methyl-d-aspartate (NMDA) receptor-dependent oscillations, and we proposed that the oscillatory signals originate in the secondary visual cortex (Oc2). Because non-NMDA and NMDA receptors cooperate in synaptic transmission, non-NMDA receptors may also play an important role in oscillatory activities. Here we investigated how non-NMDA receptor activities contribute to NMDA receptor-dependent oscillations by using optical recording methods. After induction of stable oscillations with caffeine application, blockade of NMDA receptors abolished the late stable oscillatory phase, but elicited 'hidden' non-NMDA receptor-dependent oscillation during the early depolarizing phase. An interesting finding is that the origin of the non-NMDA receptor-dependent oscillation moved from the Oc1, during the early phase, toward the origin of the NMDA receptor-dependent oscillation that is fixed in the Oc2. In addition, the frequency of the non-NMDA receptor-dependent oscillation was higher than that of the NMDA receptor-dependent oscillation. Thus, in one course of spatiotemporal oscillatory activities, the relative balance in receptor activities between non-NMDA and NMDA receptors gradually changes, and this may be due to the different kinetics of the two receptor types. These results suggest that interplay between the two receptor types in the areas of Oc1 and Oc2 may play an important role in oscillatory signal communication. PMID:27136667

  16. Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

    NASA Astrophysics Data System (ADS)

    Trujillo, Keith A.; Akil, Huda

    1991-01-01

    The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

  17. NMDA receptors and fear extinction: implications for cognitive behavioral therapy.

    PubMed

    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. PMID:22275851

  18. Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter.

    PubMed

    Bakiri, Yamina; Hamilton, Nicola B; Káradóttir, Ragnhildur; Attwell, David

    2008-01-15

    Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors. PMID:18046734

  19. ER to synapse trafficking of NMDA receptors

    PubMed Central

    Horak, Martin; Petralia, Ronald S.; Kaniakova, Martina; Sans, Nathalie

    2014-01-01

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. There are three distinct subtypes of ionotropic glutamate receptors (GluRs) that have been identified including 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs) and kainate receptors. The most common GluRs in mature synapses are AMPARs that mediate the fast excitatory neurotransmission and NMDARs that mediate the slow excitatory neurotransmission. There have been large numbers of recent reports studying how a single neuron regulates synaptic numbers and types of AMPARs and NMDARs. Our current research is centered primarily on NMDARs and, therefore, we will focus in this review on recent knowledge of molecular mechanisms occurring (1) early in the biosynthetic pathway of NMDARs, (2) in the transport of NMDARs after their release from the endoplasmic reticulum (ER); and (3) at the plasma membrane including excitatory synapses. Because a growing body of evidence also indicates that abnormalities in NMDAR functioning are associated with a number of human psychiatric and neurological diseases, this review together with other chapters in this issue may help to enhance research and to gain further knowledge of normal synaptic physiology as well as of the etiology of many human brain diseases. PMID:25505872

  20. ER to synapse trafficking of NMDA receptors.

    PubMed

    Horak, Martin; Petralia, Ronald S; Kaniakova, Martina; Sans, Nathalie

    2014-01-01

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. There are three distinct subtypes of ionotropic glutamate receptors (GluRs) that have been identified including 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs) and kainate receptors. The most common GluRs in mature synapses are AMPARs that mediate the fast excitatory neurotransmission and NMDARs that mediate the slow excitatory neurotransmission. There have been large numbers of recent reports studying how a single neuron regulates synaptic numbers and types of AMPARs and NMDARs. Our current research is centered primarily on NMDARs and, therefore, we will focus in this review on recent knowledge of molecular mechanisms occurring (1) early in the biosynthetic pathway of NMDARs, (2) in the transport of NMDARs after their release from the endoplasmic reticulum (ER); and (3) at the plasma membrane including excitatory synapses. Because a growing body of evidence also indicates that abnormalities in NMDAR functioning are associated with a number of human psychiatric and neurological diseases, this review together with other chapters in this issue may help to enhance research and to gain further knowledge of normal synaptic physiology as well as of the etiology of many human brain diseases. PMID:25505872

  1. Non-ionotropic signaling by the NMDA receptor: controversy and opportunity.

    PubMed

    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. PMID:27303637

  2. Non-ionotropic signaling by the NMDA receptor: controversy and opportunity

    PubMed Central

    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. PMID:27303637

  3. Cholesterol modulates open probability and desensitization of NMDA receptors

    PubMed Central

    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

  4. Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

    PubMed

    Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

    2016-08-01

    Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. PMID:26769920

  5. Cell-type Specific Development of NMDA Receptors in the Interneurons of Rat Prefrontal Cortex

    PubMed Central

    Wang, Huai-Xing; Gao, Wen-Jun

    2009-01-01

    In the prefrontal cortex, N-methyl-D-aspartic acid (NMDA) receptors are critical not only for normal prefrontal functions but also for the pathological processes of schizophrenia. Little is known, however, about the developmental properties of NMDA receptors in the functionally diverse subpopulations of interneurons. We investigated the developmental changes of NMDA receptors in rat prefrontal interneurons using patch clamp recording in cortical slices. We found that fast-spiking (FS) interneurons exhibited properties of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA currents distinct from those in regular spiking (RS) and low-threshold spiking (LTS) interneurons, particularly during the adolescent period. In juvenile animals, most (73%) of the FS cells demonstrated both AMPA and NMDA currents. The NMDA currents, however, gradually became undetectable during cortical development, with most (74%) of the FS cells exhibiting no NMDA current in adults. In contrast, AMPA and NMDA currents in RS and LTS interneurons were relatively stable, without significant changes from juveniles to adults. Moreover, even in FS cells with NMDA currents, the NMDA/AMPA ratio dramatically decreased during the adolescent period but returned to juvenile level in adults, compared to the relatively stable ratios in RS and LTS interneurons. These data suggest that FS interneurons in the PFC undergo dramatic changes in glutamatergic receptors during the adolescent period. These properties may make FS cells particularly sensitive and vulnerable to epigenetic stimulation, thus contributing to the onset of many psychiatric disorders, including schizophrenia. PMID:19242405

  6. Noncompetitive, Voltage-Dependent NMDA Receptor Antagonism by Hydrophobic Anions

    PubMed Central

    Linsenbardt, Andrew J.; Chisari, Mariangela; Yu, Andrew; Shu, Hong-Jin; Zorumski, Charles F.

    2013-01-01

    NMDA receptor (NMDAR) antagonists are dissociative anesthetics, drugs of abuse, and are of therapeutic interest in neurodegeneration and neuropsychiatric disease. Many well-known NMDAR antagonists are positively charged, voltage-dependent channel blockers. We recently showed that the hydrophobic anion dipicrylamine (DPA) negatively regulates GABAA receptor function by a mechanism indistinguishable from that of sulfated neurosteroids. Because sulfated neurosteroids also modulate NMDARs, here we examined the effects of DPA on NMDAR function. In rat hippocampal neurons DPA inhibited currents gated by 300 µM NMDA with an IC50 of 2.3 µM. Neither onset nor offset of antagonism exhibited dependence on channel activation but exhibited a noncompetitive profile. DPA antagonism was independent of NMDAR subunit composition and was similar at extrasynaptic and total receptor populations. Surprisingly, similar to cationic channel blockers but unlike sulfated neurosteroids, DPA antagonism was voltage dependent. Onset and offset of DPA antagonism were nearly 10-fold faster than DPA-induced increases in membrane capacitance, suggesting that membrane interactions do not directly explain antagonism. Furthermore, voltage dependence did not derive from association of DPA with a site on NMDARs directly accessible to the outer membrane leaflet, assessed by DPA translocation experiments. Consistent with the expected lack of channel block, DPA antagonism did not interact with permeant ions. Therefore, we speculate that voltage dependence may arise from interactions of DPA with the inherent voltage dependence of channel gating. Overall, we conclude that DPA noncompetitively inhibits NMDA-induced current by a novel voltage-dependent mechanism and represents a new class of anionic NMDAR antagonists. PMID:23144238

  7. Anti-NMDA Receptor Encephalitis During Pregnancy

    PubMed Central

    Mathis, Stéphane; Pin, Jean-Christophe; Pierre, Fabrice; Ciron, Jonathan; Iljicsov, Anna; Lamy, Matthias; Neau, Jean-Philippe

    2015-01-01

    Abstract Anti-N-methyl-D-aspartate receptor (anti-MMDAR) encephalitis is an immune-mediated encephalitis mainly affecting young women. We describe the case of a 21-year-old woman who developed a classical form of anti-NMDAR encephalitis during the 10th week of gestation. The patient had been treated with methylpredinsolone and intravenous immunoglobulins. Birth history of the child was normal, with normal APGAR score. The clinical symptoms of the patient have improved after a few months. This rare occurrence during pregnancy (only 9 other cases described) presents an opportunity to highlight the importance of making the earliest possible diagnosis of this treatable and potentially reversible encephalitis, and to educate gynecologists, psychiatrists, anesthetists, and neurologists on this potential cause of psychiatric and neurological manifestations during pregnancy. PMID:26131809

  8. Alcohol Related Changes in Regulation of NMDA Receptor Functions

    PubMed Central

    Nagy, József

    2008-01-01

    Long-term alcohol exposure may lead to development of alcohol dependence in consequence of altered neurotransmitter functions. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol’s action. Several studies showed that ethanol potently inhibits NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory “up-regulation” of NMDAR mediated functions. Therefore, alterations in NMDAR function are supposed to contribute to the development of ethanol tolerance, dependence as well as to the acute and late signs of ethanol withdrawal. A number of publications report alterations in the expression and phosphorylation states of NMDAR subunits, in their interaction with scaffolding proteins or other receptors in consequence of chronic ethanol treatment. Our knowledge on the regulatory processes, which modulate NMDAR functions including factors altering transcription, protein expression and post-translational modifications of NMDAR subunits, as well as those influencing their interactions with different regulatory proteins or other downstream signaling elements are incessantly increasing. The aim of this review is to summarize the complex chain of events supposedly playing a role in the up-regulation of NMDAR functions in consequence of chronic ethanol exposure. PMID:19305787

  9. Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors

    PubMed Central

    Terunuma, Miho; Vargas, Karina J.; Wilkins, Megan E.; Ramírez, Omar A.; Jaureguiberry-Bravo, Matías; Pangalos, Menelas N.; Smart, Trevor G.; Moss, Stephen J.; Couve, Andrés

    2010-01-01

    Slow and persistent synaptic inhibition is mediated by metabotropic GABAB receptors (GABABRs). GABABRs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABABRs are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial. Here, we explore the role of glutamate receptor activation in regulating the function and surface availability of GABABRs in central neurons. We demonstrate that prolonged activation of NMDA receptors (NMDA-Rs) leads to endocytosis, a diversion from a recycling route, and subsequent lysosomal degradation of GABABRs. These sorting events are paralleled by a reduction in GABABR-dependent activation of inwardly rectifying K+ channel currents. Postendocytic sorting is critically dependent on phosphorylation of serine 783 (S783) within the GABABR2 subunit, an established substrate of AMP-dependent protein kinase (AMPK). NMDA-R activation leads to a rapid increase in phosphorylation of S783, followed by a slower dephosphorylation, which results from the activity of AMPK and protein phosphatase 2A, respectively. Agonist activation of GABABRs counters the effects of NMDA. Thus, NMDA-R activation alters the phosphorylation state of S783 and acts as a molecular switch to decrease the abundance of GABABRs at the neuronal plasma membrane. Such a mechanism may be of significance during synaptic plasticity or pathological conditions, such as ischemia or epilepsy, which lead to prolonged activation of glutamate receptors. PMID:20643948

  10. PSD-95 Uncouples Dopamine-Glutamate Interaction in the D1/PSD-95/NMDA Receptor Complex

    PubMed Central

    Zhang, Jingping; Xu, Tai-Xiang; Hallett, Penelope J.; Watanabe, Masahiko; Grant, Seth G. N.; Isacson, Ole; Yao, Wei-Dong

    2008-01-01

    Classical dopaminergic signaling paradigms and emerging studies on direct physical interactions between the D1 dopamine (DA) receptor and the N-Methyl-D-Aspartate (NMDA) glutamate receptor predict a reciprocally facilitating, positive feedback loop. This loop, if not controlled, may cause concomitant overactivation of both D1 and NMDA receptors, triggering neurotoxicity. Endogenous protective mechanisms must exist. Here we show that PSD-95, a prototypical structural and signaling scaffold in the postsynaptic density, inhibits D1-NMDA receptor association and uncouples NMDA receptor-dependent enhancement of D1 signaling. This uncoupling is achieved, at least in part, via a disinhibition mechanism by which PSD-95 abolishes NMDA receptor-dependent inhibition of D1 internalization. Knockdown of PSD-95 immobilizes D1 receptors on the cell surface and escalates NMDA receptor-dependent D1 cAMP signaling in neurons. Thus, in addition to its role in receptor stabilization and synaptic plasticity, PSD-95 acts as a brake on the D1-NMDA receptor complex and dampens the interaction between them. PMID:19261890

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

    PubMed

    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. PMID:24611998

  12. Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.

    PubMed

    Provencio, Jose Javier; Swank, Valerie; Lu, Haiyan; Brunet, Sylvain; Baltan, Selva; Khapre, Rohini V; Seerapu, Himabindu; Kokiko-Cochran, Olga N; Lamb, Bruce T; Ransohoff, Richard M

    2016-05-01

    Cognitive deficits after aneurysmal subarachnoid hemorrhage (SAH) are common and disabling. Patients who experience delayed deterioration associated with vasospasm are likely to have cognitive deficits, particularly problems with executive function, verbal and spatial memory. Here, we report neurophysiological and pathological mechanisms underlying behavioral deficits in a murine model of SAH. On tests of spatial memory, animals with SAH performed worse than sham animals in the first week and one month after SAH suggesting a prolonged injury. Between three and six days after experimental hemorrhage, mice demonstrated loss of late long-term potentiation (L-LTP) due to dysfunction of the NMDA receptor. Suppression of innate immune cell activation prevents delayed vasospasm after murine SAH. We therefore explored the role of neutrophil-mediated innate inflammation on memory deficits after SAH. Depletion of neutrophils three days after SAH mitigates tissue inflammation, reverses cerebral vasoconstriction in the middle cerebral artery, and rescues L-LTP dysfunction at day 6. Spatial memory deficits in both the short and long-term are improved and associated with a shift of NMDA receptor subunit composition toward a memory sparing phenotype. This work supports further investigating suppression of innate immunity after SAH as a target for preventative therapies in SAH. PMID:26872422

  13. The Emergence of NMDA Receptor Metabotropic Function: Insights from Imaging.

    PubMed

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2016-01-01

    The NMDA receptor (R) participates in many important physiological and pathological processes. For example, its activation is required for both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. Furthermore, it may play a role in the actions of amyloid-beta on synapses as well as in the signaling leading to cell death following stroke. Until recently, these processes were thought to be mediated by ion-flux through the receptor. Using a combination of imaging and electrophysiological approaches, ion-flux independent functions of the NMDAR were recently examined. In this review, we will discuss the role of metabotropic NMDAR function in LTD and synaptic dysfunction. PMID:27516738

  14. The Emergence of NMDA Receptor Metabotropic Function: Insights from Imaging

    PubMed Central

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2016-01-01

    The NMDA receptor (R) participates in many important physiological and pathological processes. For example, its activation is required for both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. Furthermore, it may play a role in the actions of amyloid-beta on synapses as well as in the signaling leading to cell death following stroke. Until recently, these processes were thought to be mediated by ion-flux through the receptor. Using a combination of imaging and electrophysiological approaches, ion-flux independent functions of the NMDAR were recently examined. In this review, we will discuss the role of metabotropic NMDAR function in LTD and synaptic dysfunction. PMID:27516738

  15. An NMDA receptor-dependent mechanism underlies inhibitory synapse development

    PubMed Central

    Gu, Xinglong; Zhou, Liang; Lu, Wei

    2016-01-01

    Summary In the mammalian brain GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here we report that NMDA-type ionotropic glutamate receptors (NMDARs) in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, while GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain. PMID:26774487

  16. Multiple effects of copper on NMDA receptor currents.

    PubMed

    Marchetti, Carla; Baranowska-Bosiacka, Irena; Gavazzo, Paola

    2014-01-13

    Copper (Cu) is an essential metal present in the human brain and released from synaptic vesicles following neuronal depolarization. Cu is known to reduce the NMDA receptor (NR) current with IC50≈20 µM. We have studied the effect of Cu on the NR current in cultured neonatal rat cerebellum granule cells (CGC) and in transiently transfected HEK293 cells (HEK), expressing either GluN1/GLUN2A or GluN1/GluN2B receptors. In CGCs, Cu causes a potentiation of the NR current at concentrations <30 µM (EC50=4.6 µM) and a block at higher concentrations (IC50=24 µM). In Fura2 loaded CGCs, Cu (≤30 µM) caused an increase of NMDA-driven calcium influx. This facilitating effect was prevented by pre-treatment with the reducing agent DTT. Cu also caused an increase of the NR current in GluN1/GluN2A receptors (EC50=2 µM) and a block at higher concentrations (IC50=26 µM). Both facilitation and inhibition were independent of voltage. The effect of Cu was quantitatively similar in GluN1/GluN2B receptors, which were potentiated by 10 µM and inhibited by 100 µM Cu. Potentiation was absent in mutants deleted of their entire amino terminal domain (ATD) of the protein, suggesting an involvement of this region in the interaction. These results indicate that Cu can facilitate the NR current at lower concentrations than those required for blocking it; this effect can have consequences on the activity of the metal at synaptic and extrasynaptic sites. PMID:24161827

  17. Effects of NMDA receptor inhibition by phencyclidine on the neuronal differentiation of PC12 cells.

    PubMed

    Lee, Eunsook; Williams, Zakia; Goodman, Carl B; Oriaku, Ebenezer T; Harris, Cynthia; Thomas, Mathews; Soliman, Karam F A

    2006-07-01

    Phencyclidine (PCP) is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist and exposing the developing brain to PCP has been shown to cause deficits in neurobehavioral functions. In the present study we tested the effects of PCP, as an NMDA receptor inhibitor, on the neuronal differentiation and biogenic amines levels including norepinephrine (NE), epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) in the rat pheochromocytoma (PC12) cells. After PC12 cells were differentiated with nerve growth factor (NGF) in the presence of PCP, NMDA binding kinetics, biogenic amines analysis and NMDA receptor protein expression assay were conducted. The results showed that NMDA receptor binding activities were significantly increased after differentiated with NGF in PC12 cells. B(max) values were increased in differentiated cells by four-folds, whereas K(d) values were not changed. All of biogenic amines were significantly increased in differentiated cells. On the other hand, PCP at 50 and 100 microM inhibited neuronal differentiation in a dose-dependent manner in NGF-stimulated PC12 cells without affecting cell viability. PCP treatment during differentiation significantly reduced NMDA binding activity and biogenic amine levels. Western blotting analysis revealed that NMDA receptor protein expression was significantly higher in NGF-differentiated cells and PCP treatment decreased the expression of NMDA receptor proteins. These results indicate that NMDA receptor functions and monoaminergic nervous systems are significantly stimulated during NGF-induced differentiation. PCP suppresses neuronal outgrowth and hampers neuronal functions possibly by inhibiting NMDA receptor functions and biogenic amine production, implying the suppressive effects of PCP exposure on neuronal developments. PMID:16580729

  18. Kinetic contributions to gating by interactions unique to N-methyl-D-aspartate (NMDA) receptors.

    PubMed

    Borschel, William F; Cummings, Kirstie A; Tindell, LeeAnn K; Popescu, Gabriela K

    2015-10-30

    Among glutamate-gated channels, NMDA receptors produce currents that subside with unusually slow kinetics, and this feature is essential to the physiology of central excitatory synapses. Relative to the homologous AMPA and kainate receptors, NMDA receptors have additional intersubunit contacts in the ligand binding domain that occur at both conserved and non-conserved sites. We examined GluN1/GluN2A single-channel currents with kinetic analyses and modeling to probe these class-specific intersubunit interactions for their role in glutamate binding and receptor gating. We found that substitutions that eliminate such interactions at non-conserved sites reduced stationary gating, accelerated deactivation, and imparted sensitivity to aniracetam, an AMPA receptor-selective positive modulator. Abolishing unique contacts at conserved sites also reduced stationary gating and accelerated deactivation. These results show that contacts specific to NMDA receptors, which brace the heterodimer interface within the ligand binding domain, stabilize actively gating receptor conformations and result in longer bursts and slower deactivations. They support the view that the strength of the heterodimer interface modulates gating in both NMDA and non-NMDA receptors and that unique interactions at this interface are responsible in part for basic differences between the kinetics of NMDA and non-NMDA currents at glutamatergic synapses. PMID:26370091

  19. The role of non-receptor protein tyrosine kinases in the excitotoxicity induced by the overactivation of NMDA receptors.

    PubMed

    Sun, Yongjun; Chen, You; Zhan, Liying; Zhang, Linan; Hu, Jie; Gao, Zibin

    2016-04-01

    Protein tyrosine phosphorylation is one of the primary modes of regulation of N-methyl-d-aspartate (NMDA) receptors. The non-receptor tyrosine kinases are one of the two types of protein tyrosine kinases that are involved in this process. The overactivation of NMDA receptors is a primary reason for neuron death following cerebral ischemia. Many studies have illustrated the important role of non-receptor tyrosine kinases in ischemia insults. This review introduces the roles of Src, Fyn, focal adhesion kinase, and proline-rich tyrosine kinase 2 in the excitotoxicity induced by the overactivation of NMDA receptors following cerebral ischemia. PMID:26540220

  20. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons.

    PubMed

    Losi, G; Vicini, S; Neale, J

    2004-03-01

    The peptide transmitter N-acetylaspartylglutamate (NAAG) selectively activates the group II metabotropic glutamate receptors. Several reports also suggest that this peptide acts as a partial agonist at N-methyl-D-aspartate (NMDA) receptors but its putative antagonist effects have not been directly tested. To do this, we used whole cell recordings from cerebellar granule cells (CGC) in culture that allow the highest possible resolution of NMDA channel activation. When CGC were activated with equimolar concentrations of NMDA and NAAG, the peptide failed to alter the peak current elicited by NMDA. Very high concentrations of NAAG (100-200 microM) did not significantly reduce the current elicited by 10 microM NMDA or 0.1 microM glutamate, while 400 microM NAAG produced only a very small (less than 15%) reduction in these whole cell currents. Similarly, NAAG (400 microM) failed to significantly alter the average decay time constant or the peak amplitude of NMDA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs). We conclude that high concentrations of the peptide do not exert physiologically relevant antagonist actions on synaptic NMDA receptor activation following vesicular release of glutamate. As an agonist, purified NAAG was found to be at least 10,000-fold less potent than glutamate in increasing "background" current via NMDA receptors on CGC. Inasmuch as it is difficult to confirm that NAAG preparations are completely free from contamination with glutamate at the 0.01% level, the peptide itself appears unlikely to have a direct agonist activity at the NMDA receptor subtypes found in CGC. Recent reports indicate that enhancing the activity of endogenous NAAG may be an important therapeutic approach to excitotoxicity and chronic pain perception. These effects are likely mediated by group II mGluRs, not NMDA receptors. PMID:14975672

  1. Functional Interaction Between Na/K-ATPase and NMDA Receptor in Cerebellar Neurons.

    PubMed

    Akkuratov, Evgeny E; Lopacheva, Olga M; Kruusmägi, Markus; Lopachev, Alexandr V; Shah, Zahoor A; Boldyrev, Alexander A; Liu, Lijun

    2015-12-01

    NMDA receptors play a crucial role in regulating synaptic plasticity and memory. Activation of NMDA receptors changes intracellular concentrations of Na(+) and K(+), which are subsequently restored by Na/K-ATPase. We used immunochemical and biochemical methods to elucidate the potential mechanisms of interaction between these two proteins. We observed that NMDA receptor and Na/K-ATPase interact with each other and this interaction was shown for both isoforms of α subunit (α1 and α3) of Na/K-ATPase expressed in neurons. Using Western blotting, we showed that long-term exposure of the primary culture of cerebellar neurons to nanomolar concentrations of ouabain (a cardiotonic steroid, a specific ligand of Na/K-ATPase) leads to a decrease in the levels of NMDA receptors which is likely mediated by the α3 subunit of Na/K-ATPase. We also observed a decrease in enzymatic activity of the α1 subunit of Na/K-ATPase caused by NMDA receptor activation. This effect is mediated by an increase in intracellular Ca(2+). Thus, Na/K-ATPase and NMDA receptor can interact functionally by forming a macromolecular complex which can be important for restoring ionic balance after neuronal excitation. Furthermore, this interaction suggests that NMDA receptor function can be regulated by endogenous cardiotonic steroids which recently have been found in cerebrospinal fluid or by pharmacological drugs affecting Na/K-ATPase function. PMID:25381029

  2. Hippocampus NMDA receptors selectively mediate latent extinction of place learning.

    PubMed

    Goodman, Jarid; Gabriele, Amanda; Packard, Mark G

    2016-09-01

    Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical "response extinction," animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In "latent extinction," animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)-dependent response learning and hippocampus-dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long-Evans rats were trained in a response learning task in a water plus-maze, in which animals were reinforced to make a consistent body-turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra-hippocampal infusions of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were

  3. A dual mechanism for impairment of GABAA receptor activity by NMDA receptor activation in rat cerebellum granule cells.

    PubMed

    Robello, M; Amico, C; Cupello, A

    1997-01-01

    The function of the GABAA receptor has been studied using the whole cell voltage clamp recording technique in rat cerebellum granule cells in culture. Activation of NMDA-type glutamate receptors causes a reduction in the effect of GABA. Full GABAA receptor activity was recovered after washing out NMDA and NMDA action was prevented in a Mg+2 containing medium. The NMDA effect was also absent when extracellular Ca+2 was replaced by Ba+2 and when 10 mM Bapta was present in the intracellular solution. Charge accumulations via voltage activated Ca+2 channels greater than the ones via NMDA receptors do not cause any reduction in GABAA receptor function, suggesting that Ca+2 influx through NMDA receptor channels is critical for the effect. The NMDA effect was reduced by including adenosine-5'-O-3-thiophosphate (ATP-gamma-S) in the internal solution and there was a reduction in the NMDA effect caused by deltamethrin, a calcineurin inhibitor. Part of the NMDA induced GABAA receptor impairment was prevented by prior treatment with L-arginine. Analogously, part of the NMDA effect was prevented by blockage of NO-synthase activity by N omega-nitro-L-arginine. A combination of NO-synthase and calcineurin inhibitors completely eliminated the NMDA action. An analogous result was obtained by combining the NO-synthase inhibitor with the addition of ATP-gamma-S to the pipette medium. The additivity of the prevention of the NMDA impairment of GABAA receptor by blocking the L-arginine/NO pathway and inhibiting calcineurin activity suggests an independent involvement of these two pathways in the interaction between NMDA and the GABAA receptor. On the one hand Ca+2 influx across NMDA channels activates calcineurin and dephosphorylates the GABAA receptor complex directly or dephosphorylates proteins critical for the function of the receptor. On the other hand, Ca+2 influx activates NO-synthase and induces nitric oxide production, which regulates such receptors via protein kinase G

  4. Defining the role of NMDA receptors in anesthesia: are we there yet?

    PubMed

    Petrenko, Andrey B; Yamakura, Tomohiro; Sakimura, Kenji; Baba, Hiroshi

    2014-01-15

    N-methyl-d-aspartate (NMDA) receptors are important in mediating excitatory neurotransmission in the nervous system. They are preferentially inhibited by some general anesthetics and have, therefore, been implied in the mediation of their effects. This review summarizes the main research findings available related to NMDA receptors and their role in anesthesia. The contribution of NMDA receptors to the anesthetized state is discussed separately for each of its components: amnesia, analgesia, unconsciousness and immobility. Anesthetic-induced unconsciousness and immobility have received the most attention in the research community and are the main focus of this review. In the overall perspective, however, studies using pharmacological or electrophysiological approaches have failed to reach definitive conclusions regarding the contribution of NMDA receptors to these anesthetic endpoints. None of the studies have specifically addressed the role of NMDA receptors in the amnestic effect of general anesthetics, and the few available data are (at best) only indirect. NMDA receptor antagonism by general anesthetics may have a preventive anti-hyperalgesic effect. The only and most extensively used genetic tool to examine the role of NMDA receptors in anesthesia is global knockout of the GluN2A subunit of the NMDA receptor. These animals are resistant to many intravenous and inhalational anesthetics, but the interpretation of their phenotype is hindered by the secondary changes occurring in these animals after GluN2A knockout, which are themselves capable of altering anesthetic sensitivity. Generation of more sophisticated conditional knockout models targeting NMDA receptors is required to finally define their role in the mechanisms of anesthesia. PMID:24333550

  5. The Rac1 Inhibitor NSC23766 Suppresses CREB Signaling by Targeting NMDA Receptor Function

    PubMed Central

    Hou, Hailong; Chávez, Andrés E.; Wang, Chih-Chieh; Yang, Hongtian; Gu, Hua; Siddoway, Benjamin A.; Hall, Benjamin J.; Castillo, Pablo E.

    2014-01-01

    NMDA receptor signaling plays a complex role in CREB activation and CREB-mediated gene transcription, depending on the subcellular location of NMDA receptors, as well as how strongly they are activated. However, it is not known whether Rac1, the prototype of Rac GTPase, plays a role in neuronal CREB activation induced by NMDA receptor signaling. Here, we report that NSC23766, a widely used specific Rac1 inhibitor, inhibits basal CREB phosphorylation at S133 (pCREB) and antagonizes changes in pCREB levels induced by NMDA bath application in rat cortical neurons. Unexpectedly, we found that NSC23766 affects the levels of neuronal pCREB in a Rac1-independent manner. Instead, our results indicate that NSC23766 can directly regulate NMDA receptors as indicated by their strong effects on both exogenous and synaptically evoked NMDA receptor-mediated currents in mouse and rat neurons, respectively. Our findings strongly suggest that Rac1 does not affect pCREB signaling in cortical neurons and reveal that NSC23766 could be a novel NMDA receptor antagonist. PMID:25319697

  6. The involvement of NMDA receptors in acute and chronic effects of ethanol.

    PubMed

    Danysz, W; Dyr, W; Jankowska, E; Glazewski, S; Kostowski, W

    1992-06-01

    Recent evidence indicates involvement of excitatory amino acid receptors sensitive to N-methyl-d-aspartate (NMDA) in the action of ethanol (EtOH). Pronounced inhibition of NMDA receptor function is seen in vitro with concentrations of EtOH corresponding to those present during alcohol intoxication in humans. The present study was devoted to investigate the role of NMDA receptors in the action of EtOH in rats. Acute experiments showed antagonism by EtOH of convulsions induced by intracerebroventricular injection of NMDA. A similar effect was seen with a high dose of diazepam. Convulsions induced by an agonist of another excitatory amino acid receptor subtype, kainate, were also inhibited by EtOH. An uncompetitive antagonist of NMDA receptors, 5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801), potentiated EtOH-induced loss of righting, but attenuated the hypothermic action of EtOH. Moreover, MK-801 inhibited audiogenic convulsions in EtOH withdrawn rats. At the same time the effect of a proconvulsive dose of NMDA was not enhanced. Tolerance to the myorelaxant action of both EtOH and MK-801 upon repetitive administration was seen. Also some degree of cross-tolerance was observed. Moreover, MK-801 failed to modify EtOH preference in rats. The present results support involvement of NMDA receptors in expression of some acute and subchronic actions of EtOH and in expression of EtOH withdrawal. PMID:1385679

  7. Three-dimensional models of non-NMDA glutamate receptors.

    PubMed Central

    Sutcliffe, M J; Wo, Z G; Oswald, R E

    1996-01-01

    Structural models have been produced for three types of non-NMDA inotropic glutamate receptors: an AMPA receptor, GluR1, a kainate receptor, GluR6; and a low-molecular-weight kainate receptor from goldfish, GFKAR alpha. Modeling was restricted to the domains of the proteins that bind the neurotransmitter glutamate and that form the ion channel. Model building combined homology modeling, distance geometry, molecular mechanics, interactive modeling, and known constraints. The models indicate new potential interactions in the extracellular domain between protein and agonists, and suggest that the transition from the "closed" to the "open" state involves the movement of a conserved positive residue away from, and two conserved negative residues into, the extracellular entrance to the pore upon binding. As a first approximation, the ion channel domain was modeled with a structure comprising a central antiparallel beta-barrel that partially crosses the membrane, and against which alpha-helices from each subunit are packed; a third alpha-helix packs against these two helices in each subunit. Much, but not all, of the available data were consistent with this structure. Modifying the beta-barrel to a loop-like topology produced a model consistent with available data. Images FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 7 PMID:8785317

  8. NMDA receptor properties in rat supraoptic magnocellular neurons: characterization and postnatal development.

    PubMed

    Hussy, N; Boissin-Agasse, L; Richard, P; Desarménien, M G

    1997-07-01

    Hypothalamo-neurohypophysial magnocellular neurons display specific electrical activities in relation to the mode of release of their hormonal content (vasopressin or oxytocin). These activities are under strong glutamatergic excitatory control. The implication of NMDA receptors in the control of vasopressinergic and oxytocinergic neurons is still a matter of debate. We here report the first detailed characterization of functional properties of NMDA receptors in voltage-clamped magnocellular neurons acutely dissociated from the supraoptic nucleus. All cells responded to NMDA with currents that reversed polarity around 0 mV and were inhibited by D-2-amino-5-phosphonovalerate (D-APV) and by 100 microM extracellular Mg2+ (at -80 mV). Sensitivity to the co-agonist glycine (EC50, 2 microM) was low compared with most other neuronal preparations. The receptors displayed low sensitivity to ifenprodil, were insensitive to glycine-independent potentiation by spermine, and had a unitary conductance of 50 pS. No evidence was found for two distinct cell populations, suggesting that oxytocinergic and vasopressinergic neurons express similar NMDA receptors. Characterization of NMDA receptors at different postnatal ages revealed a transient increase in density of NMDA currents during the second postnatal week. This was accompanied by a specific decrease in sensitivity to D-APV, with no change in NMDA sensitivity or any other properties studied. Supraoptic NMDA receptors thus present characteristics that strikingly resemble those of reconstituted receptors composed of NR1 and NR2A subunits. Understanding the functional significance of the development of NMDA receptors in the supraoptic nucleus will require further knowledge about the maturation of neuronal excitability, synaptic connections and neurohormone release mechanisms. PMID:9240401

  9. Discriminative stimulus effects of NMDA, AMPA and mGluR5 glutamate receptor ligands in methamphetamine-trained rats

    PubMed Central

    Wooters, Thomas E.; Dwoskin, Linda P.; Bardo, Michael T.

    2011-01-01

    Glutamate contributes to the reinforcing and stimulant effects of methamphetamine, yet its potential role in the interoceptive stimulus properties of methamphetamine is unknown. In the current study, adult male Sprague-Dawley rats were trained to discriminate methamphetamine (1.0 mg/kg, i.p.) from saline in a standard operant discrimination task. The effects of methamphetamine (0.1-1.0 mg/kg, i.p.), the N-methyl-D-aspartate (NMDA) receptor channel blockers MK-801 (0.03-0.3 mg/kg, i.p.) and ketamine (1.0-10.0 mg/kg, i.p.), the low-affinity NMDA antagonist memantine (1.0-10 mg/kg, i.p.), the polyamine site NMDA receptor antagonist ifenprodil (1-10 mg/kg), the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1-10 mg/kg, i.p.), and the metabotropic 5 (mGluR5) receptor antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP; 1-10 mg/kg) given alone were determined in substitution tests. The effects of MK-801 (0.03 and 0.1 mg/kg), ketamine (1.0 and 3.0 mg/kg), ifenprodil (5.6 mg/kg), CNQX (5.6 mg/kg) and MPEP (5.6 mg/kg) were also tested in combination with methamphetamine to assess for alterations in the methamphetamine cue. In substitution tests, none of the test drugs generalized to the methamphetamine cue. However, ketamine and ifenprodil produced significant leftward shifts in the methamphetamine dose-response curve; pretreatment with 3 mg/kg of ketamine, for example, decreased the ED50 value for methamphetamine by half. These results suggest that blockade of the NMDA receptor augments the interoceptive stimulus properties of methamphetamine. PMID:21836462

  10. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke

    PubMed Central

    Tu, Weihong; Xu, Xin; Peng, Lisheng; Zhong, Xiaofen; Zhang, Wenfeng; Soundarapandian, Mangala M.; Balel, Cherine; Wang, Manqi; Jia, Nali; Zhang, Wen; Lew, Frank; Chan, Sic Lung; Chen, Yanfang; Lu, Youming

    2010-01-01

    SUMMARY N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extra-synaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292–1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. PMID:20141836

  11. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil.

    PubMed

    Tajima, Nami; Karakas, Erkan; Grant, Timothy; Simorowski, Noriko; Diaz-Avalos, Ruben; Grigorieff, Nikolaus; Furukawa, Hiro

    2016-06-01

    The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1-GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1-GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel. PMID:27135925

  12. Effects of pharmacological manipulations of NMDA-receptors on deliberation in the Multiple-T task

    PubMed Central

    Blumenthal, Anna; Steiner, Adam; Seeland, Kelsey

    2011-01-01

    Both humans and non-human animals have the ability to navigate and make decisions within complex environments. This ability is largely dependent upon learning and memory processes, many of which are known to depend on NMDA-sensitive receptors. When humans come to difficult decisions they often pause to deliberate over their choices. Similarly, rats pause at difficult choice points. This behavior, known as vicarious trial and error (VTE), is hippocampally dependent and entails neurophysiological representations of expectations of future outcomes in hippocampus and downstream structures. In order to determine the dependence of VTE behaviors on NMDA-sensitive receptors, we tested rats on a Multiple-T choice task with a reward-delivery reversal known to elicit VTE. Rats under the influence of NMDA-receptor antagonists (CPP) showed a significant reduction in VTE, particularly at the reward reversal, implying a role for NMDA-sensitive receptors in the generation of vicarious trial and error behaviors. PMID:21296174

  13. Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut

    PubMed Central

    Prüss, H.; Leubner, J.; Wenke, N. K.; Czirják, G. Á.; Szentiks, C. A.; Greenwood, A. D.

    2015-01-01

    Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut’s encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut’s cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed. PMID:26313569

  14. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, István; Kolok, Sándor; Galgóczy, Kornél; Gere, Anikó; Horváth, Csilla; Farkas, Sándor; Greiner, István; Domány, György

    2007-01-15

    A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. PMID:17074483

  15. Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut.

    PubMed

    Prüss, H; Leubner, J; Wenke, N K; Czirják, G Á; Szentiks, C A; Greenwood, A D

    2015-01-01

    Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut's encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut's cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed. PMID:26313569

  16. Discrimination reversal conditioning of an eyeblink response is impaired by NMDA receptor blockade.

    PubMed

    Churchill, J D; Green, J T; Voss, S E; Manley, E; Steinmetz, J E; Garraghty, P E

    2001-01-01

    In the present study we examined the effects of the specific NMDA receptor antagonist CPP on discrimination reversal learning in rabbits. We report two primary findings. First, the institution of NMDA receptor blockade had no effect on a learned discrimination. Second, after stimulus reversal, CPP treatment impaired acquisition of the discrimination reversal. This impairment manifested itself early in training as a retardation in acquisition of a CR to the new CS+ and late in training as an inability to suppress responsiveness to the new CS-. Given the comparability of the present results with previously published results for phenytoin-treated rabbits, we suggest that the effects of phenytoin on learning in this paradigm is at least in part mediated by its effects on NMDA receptors. We further suggest that these findings emphasize the need to better define the role of NMDA receptor activation and hippocampally-mediated circuits in a variety of associative learning paradigms. PMID:11484997

  17. Dopamine D1 receptor inhibition of NMDA receptor currents mediated by tyrosine kinase-dependent receptor trafficking in neonatal rat striatum

    PubMed Central

    Tong, Huaxia; Gibb, Alasdair J

    2008-01-01

    NMDA receptors are of particular importance in the control of synaptic strength and integration of synaptic activity. Dopamine receptor modulation of NMDA receptors in neonatal striatum may influence the efficacy of synaptic transmission in the cortico-striatal pathway and if so, this modulation will affect the behaviour of the basal ganglia network. Here, we show that in acute brain slices of neonatal (P7) rat striatum the dopamine D1 receptor agonist SKF-82958 significantly decreases NMDA receptor currents in patch-clamp whole-cell recordings. This inhibition is not abolished by application of a G protein inhibitor (GDP-β-S) or irreversible G protein activator (GTP-γ-S) suggesting a G protein-independent mechanism. In addition, intracellular application of protein tyrosine kinase inhibitors (lavendustin A or PP2) abolished D1 inhibition of NMDA currents. In contrast, in older animals (P28) D1 receptor activation produces a potentiation of the NMDA response which suggests there is a developmental switch in D1 modulation of striatal NMDA receptors. Single-channel recordings show that direct D1 receptor inhibition of NMDA receptors cannot be observed in isolated membrane patches. We hypothesize that D1 inhibition in whole-cell recordings from neonatal rats may be mediated by a change in NMDA receptor trafficking. Consistent with this hypothesis, intracellular application of a dynamin inhibitory peptide (QVPSRPNRAP) abolished D1 inhibition of NMDA receptor currents. We therefore conclude that a tyrosine kinase-dependent alteration of NMDA receptor trafficking underlies D1 dopamine receptor-mediated down-regulation of NMDA receptor currents in medium spiny neurons of neonatal rat striatum. PMID:18703578

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

    PubMed

    Hasan, Mazahir T; 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, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking NMDA receptors in the [corrected] primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning. PMID:23978820

  19. In vitro neuronal network activity in NMDA receptor encephalitis

    PubMed Central

    2013-01-01

    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. PMID:23379293

  20. Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.

    PubMed

    Piguel, Nicolas H; Fievre, Sabine; Blanc, Jean-Michel; Carta, Mario; Moreau, Maïté M; Moutin, Enora; Pinheiro, Vera L; Medina, Chantal; Ezan, Jerome; Lasvaux, Léa; Loll, François; Durand, Christelle M; Chang, Kai; Petralia, Ronald S; Wenthold, Robert J; Stephenson, F Anne; Vuillard, Laurent; Darbon, Hervé; Perroy, Julie; Mulle, Christophe; Montcouquiol, Mireille; Racca, Claudia; Sans, Nathalie

    2014-10-23

    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. PMID:25310985

  1. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex

    PubMed Central

    Jackson, Mark E.; Homayoun, Houman; Moghaddam, Bita

    2004-01-01

    Cognitive deficits associated with frontal lobe dysfunction are a determinant of long-term disability in schizophrenia and are not effectively treated with available medications. Clinical studies show that many aspects of these deficits are transiently induced in healthy individuals treated with N-methyl-d-aspartate (NMDA) antagonists. These findings and recent genetic linkage studies strongly implicate NMDA receptor deficiency in schizophrenia and suggest that reversing this deficiency is pertinent to treating the cognitive symptoms of schizophrenia. Despite the wealth of behavioral data on the effects of NMDA antagonist treatment in humans and laboratory animals, there is a fundamental lack of understanding about the mechanisms by which a general state of NMDA deficiency influences the function of cortical neurons. Using ensemble recording in freely moving rats, we found that NMDA antagonist treatment, at doses that impaired working memory, potentiated the firing rate of most prefrontal cortex neurons. This potentiation, which correlated with expression of behavioral stereotypy, resulted from an increased number of irregularly discharged single spikes. Concurrent with the increase in spike activity, there was a significant reduction in organized bursting activity. These results identify two distinct mechanisms by which NMDA receptor deficiency may disrupt frontal lobe function: an increase in disorganized spike activity, which may enhance cortical noise and transmission of disinformation; and a decrease in burst activity, which reduces transmission efficacy of cortical neurons. These findings provide a physiological basis for the NMDA receptor deficiency model of schizophrenia and may clarify the nature of cortical dysfunction in this disease. PMID:15159546

  2. Rat intra-hippocampal NMDA infusion induces cell-specific damage and changes in expression of NMDA and GABAA receptor subunits.

    PubMed

    Rambousek, Lukas; Kleteckova, Lenka; Kubesova, Anna; Jirak, Daniel; Vales, Karel; Fritschy, Jean-Marc

    2016-06-01

    Excessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABAA α5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABAA receptors. PMID:26930443

  3. Integrative role for serotonergic and glutamatergic receptor mechanisms in the action of NMDA antagonists: potential relationships to antipsychotic drug actions on NMDA antagonist responsiveness.

    PubMed

    Breese, George R; Knapp, Darin J; Moy, Sheryl S

    2002-06-01

    NMDA receptor antagonists worsen symptoms in schizophrenia and induce schizophrenic-like symptoms in normal individuals. In animals, NMDA antagonist-induced behavioral responses include increased activity, head weaving, deficits in paired pulse inhibition and social interaction, and increased forced swim immobility. Repeated exposure to NMDA antagonists in animals results in behavioral sensitization-a phenomenon accentuated in rats with dopaminergic neurons lesioned during development. In keeping with an involvement of serotonin and glutamate release in NMDA antagonist action, selected behaviors induced by NMDA antagonists are minimized by 5-HT(2A) receptor antagonists and mGLU2 receptor agonists. These observations provide promising new approaches for treating acute NMDA antagonist-induced psychosis. Further, acute atypical antipsychotic drugs also minimize NMDA antagonist actions to a greater degree than typical antipsychotics. However, because knowledge concerning acute versus chronic effectiveness of various antipsychotic drugs against NMDA antagonist neuropathology is limited, future studies to define more fully the basis of their differences in efficacy after chronic treatment could provide an understanding of their actions on neural mechanisms responsible for the core pathogenesis of schizophrenia. PMID:12204191

  4. Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel

    PubMed Central

    Emnett, Christine M; Eisenman, Lawrence N; Mohan, Jayaram; Taylor, Amanda A; Doherty, James J; Paul, Steven M; Zorumski, Charles F; Mennerick, Steven

    2015-01-01

    Background and Purpose Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. Experimental Approach We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. Key Results SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks – measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. Conclusions and Implications Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour. PMID:25377730

  5. Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain.

    PubMed

    Cauli, Omar; Rodrigo, Regina; Boix, Jordi; Piedrafita, Blanca; Agusti, Ana; Felipo, Vicente

    2008-09-01

    Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF. PMID:18599589

  6. Neonatal NMDA Receptor Blockade Disrupts Spike Timing and Glutamatergic Synapses in Fast Spiking Interneurons in a NMDA Receptor Hypofunction Model of Schizophrenia

    PubMed Central

    Jones, Kevin S.; Corbin, Joshua G.; Huntsman, Molly M.

    2014-01-01

    The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI) is considered a primary contributor to the pathophysiology of schizophrenia (SZ), but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model. PMID:25290690

  7. Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade

    PubMed Central

    Stefani, Mark R.; Moghaddam, Bita

    2010-01-01

    Metabotropic glutamate (mGlu) receptors provide a mechanism by which the function of NMDA glutamate receptors can be modulated. As NMDA receptor hypofunction is implicated in the etiology of psychiatric disorders, including schizophrenia, the pharmacological regulation of mGlu receptor activity represents a promising therapeutic approach. We examined the effects of the positive allosteric mGlu5 receptor modulator 3- cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), alone and in combination with the NMDA receptor antagonist MK-801, on a task measuring cognitive set-shifting ability. This task measures NMDA receptor-dependent cognitive abilities analogous to those impaired in schizophrenia. Systemic administration of CDPPB (10 & 30 mg/kg i.p) blocked MK-801 (0.1 mg/kg, i.p.)-induced impairments in set-shifting ability. The effect on learning was dose-dependent, with the 30 mg/kg dose having a greater effect than the 10 mg/kg dose across all trials. This ameliorative effect of CDPPB reflected a reduction in MK-801-induced perseverative responding. These results add to the evidence that mGlu5 receptors interact functionally with NMDA receptors to regulate behavior, and suggest that positive modulators of mGlu5 receptors may have therapeutic potential in the treatment of disorders, like schizophrenia, characterized by impairments in cognitive flexibility and memory. PMID:20371234

  8. NMDA Receptor Involvement in Spatial Delayed Alternation in Developing Rats

    PubMed Central

    Watson, Deborah J.; Herbert, Mariel R.; Stanton, Mark E.

    2014-01-01

    Two experiments examined the effect of the non-competitive NMDA receptor antagonist, dizocilpine maleate (MK-801), on spatial working memory during development. Rats were trained on spatial delayed alternation (SDA) in a T-maze following i.p. administration of 0.06 mg/kg MK-801, 0.1 mg/kg MK-801, or saline on postnatal days (P) P23 and P33 (Experiment 1), or following bilateral intrahippocampal administration of 2.5 or 5.0 micro-g per side MK-801 or saline on P26 (Experiment 2). In Experiment 1, MK-801 dose-dependently impaired SDA learning at both ages. Because the same doses of systemic MK-801 have no effect on T-maze position discrimination learning, impairment of SDA by MK-801 likely reflects disruption of spatial working memory. Both doses of MK-801 abolished acquisition of SDA performance in Experiment 2. Disruption of hippocampal plasticity may account for the effects produced by systemic MK-801 administration. These results confirm and extend earlier lesion studies by implicating plasticity of hippocampal neurons in the ontogeny of spatial delayed alternation. PMID:19170429

  9. NMDA receptor antibodies associated with distinct white matter syndromes

    PubMed Central

    Hacohen, Yael; Absoud, Michael; Hemingway, Cheryl; Jacobson, Leslie; Lin, Jean-Pierre; Pike, Mike; Pullaperuma, Sunil; Siddiqui, Ata; Wassmer, Evangeline; Waters, Patrick; Irani, Sarosh R.; Buckley, Camilla

    2014-01-01

    Objective: To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders. Method: Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody–positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated. Results: Three distinct clinicoradiologic phenotypes were recognized: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved following immunotherapy with steroids, IV immunoglobulin, and plasma exchange, either individually or in combination. Two patients had escalation of immunotherapy at relapse resulting in clinical improvement. The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers. Conclusion: Clinicoradiologic evidence of white matter involvement, often distinct, was identified in 22% of children with NMDAR antibodies and appears immunotherapy responsive, particularly when treated in the acute phase of neurologic presentation. When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease. PMID:25340058

  10. Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release

    PubMed Central

    Nisticò, Robert; Florenzano, Fulvio; Mango, Dalila; Ferraina, Caterina; Grilli, Massimo; Di Prisco, Silvia; Nobili, Annalisa; Saccucci, Stefania; D'Amelio, Marcello; Morbin, Michela; Marchi, Mario; Mercuri, Nicola B.; Davis, Roger J.; Pittaluga, Anna; Feligioni, Marco

    2015-01-01

    Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for single JNK isoforms, we proved that JNK2 is the essential isoform in mediating this presynaptic event. Overall the present findings unveil a novel JNK2 localization and function, which is likely to play a role in different physiological and pathological conditions. PMID:25762148

  11. Cell type-specific pharmacology of NMDA receptors using masked MK801

    PubMed Central

    Yang, Yunlei; Lee, Peter; Sternson, Scott M

    2015-01-01

    N-Methyl-D-aspartate receptors (NMDA-Rs) are ion channels that are important for synaptic plasticity, which is involved in learning and drug addiction. We show enzymatic targeting of an NMDA-R antagonist, MK801, to a molecularly defined neuronal population with the cell-type-selectivity of genetic methods and the temporal control of pharmacology. We find that NMDA-Rs on dopamine neurons are necessary for cocaine-induced synaptic potentiation, demonstrating that cell type-specific pharmacology can be used to dissect signaling pathways within complex brain circuits. DOI: http://dx.doi.org/10.7554/eLife.10206.001 PMID:26359633

  12. NR2C and NR2D subunits of NMDA receptors in frog and turtle retina.

    PubMed

    Vitanova, Lily Alexandrova

    2012-12-01

    Glutamate NMDA (N-methyl-D-aspartate) receptors are widely distributed in the central nervous system where they are involved in cognitive processes, motor control and many other functions. They are also well studied in the retina, which may be regarded as a biological model of the nervous system. However, little is known about NR2C and NR2D subunits of NMDA receptors, which have some specific features as compared to other subunits. Consequently the aim of the present study was to investigate their distribution in frog (Rana ridibunda) and turtle (Emys orbicularis) retinas which possess mixed and cone types of retina respectively. The experiments were performed using an indirect immunofluorescence method. Four antibodies directed to NR2C and NR2D subunits of NMDA receptor, as well as three antibodies directed to different splice variants of NR1 subunit, which is known to be obligatory for proper functioning of the receptor, were applied. All antibodies caused well expressed labeling in frog and turtle retinas. The NR2C and NR2D subunits were localized in glial Müller cells, while the NR1 subunit had both neuronal and glial localization. Our results show that glial NMDA receptors differ from neuronal ones in their subunit composition. The functional significance of the NMDA receptors and their NR2C and NR2D subunits, in particular for the neuron-glia interactions, is discussed. PMID:22386206

  13. Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes

    PubMed Central

    Ryan, Tomás J; Emes, Richard D; Grant, Seth GN; Komiyama, Noboru H

    2008-01-01

    Background Glutamate gated postsynaptic receptors in the central nervous system (CNS) are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied in vitro and in vivo, their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the N-methyl-D-aspartate (NMDA) receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticity Results The vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent divergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure. Conclusion We highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using in silico methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of the NR2 C-terminus and its

  14. Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

    PubMed Central

    Zeiler, F. A.

    2015-01-01

    Refractory status epilepticus (RSE) and superrefractory status epilepticus (SRSE) pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA) receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE. PMID:25649724

  15. The function of the NMDA-receptor during normal brain aging.

    PubMed

    Müller, W E; Stoll, S; Scheuer, K; Meichelböck, A

    1994-01-01

    Age-related changes of N-methyl-D-aspartate (NMDA) receptors have been found in cortical areas and in the hippocampus of many species. On the basis of a variety of experimental observations it has been suggested that the decrease of NMDA-receptor density might be one of the causative factors of the cognitive decline with aging. Based on these findings several strategies have been developed to improve cognition by compensating the NMDA-receptor deficits in aging. The most promising approaches are the indirect activation of glutamatergic neurotransmission by agonists of the glycine site or the restoration of the age-related deficit of receptor density by several nootropics. PMID:7897387

  16. Pharmacological characterization of NMDA-like receptors in the single-celled organism Paramecium primaurelia.

    PubMed

    Ramoino, Paola; Candiani, Simona; Pittaluga, Anna Maria; Usai, Cesare; Gallus, Lorenzo; Ferrando, Sara; Milanese, Marco; Faimali, Marco; Bonanno, Giambattista

    2014-02-01

    Paramecium primaurelia is a unicellular eukaryote that moves in freshwater by ciliary beating and responds to environmental stimuli by altering motile behaviour. The movements of the cilia are controlled by the electrical changes of the cell membrane: when the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, the ciliary beating reverses its direction, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. Here, we evaluated the effects due to the activation or blockade of N-methyl-d-aspartic acid (NMDA) receptors on swimming behaviour in Paramecium. Paramecia normally swim forward, drawing almost linear tracks. We observed that the simultaneous administration of NMDA and glycine induced a partial ciliary reversal (PaCR) leading to a continuous spiral-like swim. Furthermore, the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, was longer in NMDA+glycine-treated cells. NMDA action required the presence of Ca(2+), as the normal forward swimming was restored when the ion was omitted from the extracellular milieu. The PaCR and the enhancement of CCR duration significantly decreased when the antagonists of the glutamate site D-AP5 or CGS19755, the NMDA channel blocker MK-801 or the glycine site antagonist DCKA was added. The action of NMDA+glycine was also abolished by Zn(2+) or ifenprodil, the GluN2A and the GluN2B NMDA-containing subunit blockers, respectively. Searches of the Paramecium genome database currently available indicate that the NMDA-like receptor with ligand-binding characteristics of an NMDA receptor-like complex, purified from rat brain synaptic membranes and found in some metazoan genomes, is also present in Paramecium. These results provide evidence that functional NMDA receptors similar to those typical of mammalian neuronal cells are present in the single-celled organism Paramecium and thus

  17. Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists.

    PubMed

    Pereira, Nuno A L; Sureda, Francesc X; Pérez, Maria; Amat, Mercedes; Santos, Maria M M

    2016-01-01

    Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors. PMID:27509489

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

    PubMed Central

    Hasan, Mazahir T.; 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, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning. PMID:23978820

  19. Actions of Bupivacaine, a Widely Used Local Anesthetic, on NMDA Receptor Responses

    PubMed Central

    Paganelli, Meaghan A.

    2015-01-01

    NMDA receptors mediate excitatory neurotransmission in brain and spinal cord and play a pivotal role in the neurological disease state of chronic pain, which is caused by central sensitization. Bupivacaine is the indicated local anesthetic in caudal, epidural, and spinal anesthesia and is widely used clinically to manage acute and chronic pain. In addition to blocking Na+ channels, bupivacaine affects the activity of many other channels, including NMDA receptors. Importantly, bupivacaine inhibits NMDA receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization. We used recombinant NMDA receptors expressed in HEK293 cells and found that increasing concentrations of bupivacaine decreased channel open probability in GluN2 subunit- and pH-independent manner by increasing the mean duration of closures and decreasing the mean duration of openings. Using kinetic modeling of one-channel currents, we attributed the observed current decrease to two main mechanisms: a voltage-dependent “foot-in-the-door” pore block and an allosteric gating effect. Further, the inhibition was state-independent because it occurred to the same degree whether the drug was applied before or after glutamate stimulation and was mediated by extracellular and intracellular inhibitory sites, via hydrophilic and hydrophobic pathways. These results predict that clinical doses of bupivacaine would decrease the peak and accelerate the decay of synaptic NMDA receptor currents during normal synaptic transmission. These quantitative predictions inform possible applications of bupivacaine as preventative and therapeutic approaches in chronic pain. PMID:25589775

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

    PubMed Central

    Liang, Willmann; Lam, Wai Ping; Tang, Hong Chai; Leung, Ping Chung; Yew, David T.

    2013-01-01

    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. PMID:24276380

  1. NMDA receptor antagonists attenuate the proconvulsant effect of juvenile social isolation in male mice.

    PubMed

    Amiri, Shayan; Haj-Mirzaian, Arya; Amini-Khoei, Hossein; Momeny, Majid; Shirzadian, Armin; Balaei, Maryam Rahimi; Zarrinrad, Ghazaleh; Ghazi-Khansari, Mahmoud; Azizi, Romina; Dehpour, Ahmad Reza; Mehr, Shahram Ejtemaei

    2016-03-01

    Experiencing psychosocial stress in early life, such as social isolation stress (SIS), is known to have negative enduring effects on the development of the brain and behavior. In addition to anxiety and depressive-like behaviors, we previously showed that juvenile SIS increases susceptibility to pentylenetetrazole (PTZ)-induced seizures in mice through enhancing the nitrergic system activity in the hippocampus. In this study, we investigated the possible involvement of N-methyl-d-aspartate (NMDA) receptors in proconvulsant effects of juvenile SIS. Applying 4 weeks of SIS to juvenile male mice at postnatal day 21-23, we observed an increased susceptibility to PTZ as well as anxiety and depressive-like behaviors in adult mice. Intraperitoneal (i.p.) administration of NMDA receptor antagonists, MK-801 (0.05mg/kg) and ketamine (0.5mg/kg), reversed the proconvulsant effects of SIS in Isolated (and not social) housed animals. Co-administration of non-effective doses of nitric oxide synthase (NOS) inhibitors, 7NI (25mg/kg) and L-NAME (10mg/kg), with NMDA receptor antagonists, MK-801 (0.01mg/kg) and ketamine (0.1mg/kg) attenuated the proconvulsant effects of juvenile SIS only in isolated housed mice. Also, using real time RT-PCR, we showed that hippocampal upregulation of NR2B subunit of NMDA receptor may play a critical role in proconvulsant effects of juvenile SIS by dysregulation of NMDA/NO pathway. In conclusion, results of present study revealed that experiencing SIS during adolescence predisposes the co-occurrence of seizure disorders with psychiatric comorbidities and also, alteration of NMDA receptor structure and function in hippocampus plays a role in proconvulsant effects of juvenile SIS through enhancing the NMDA/NO pathway. PMID:26836272

  2. Synthesis of 4-(aminoalkyl) substituted 1,3-dioxanes as potent NMDA and σ receptor antagonists.

    PubMed

    Utech, Tina; Köhler, Jens; Wünsch, Bernhard

    2011-06-01

    Elongation of the distance between the oxygen heterocycle and the basic amino moiety or ring expansion of the oxygen heterocycle of the NMDA receptor antagonists dexoxadrol and etoxadrol led to compounds with promising NMDA receptor affinity. Herein the combination of both structural features, i.e. elongation of the O-heterocycle--amine distance with a 1,3-dioxane ring is envisaged. The synthesis of aminoethyl-1,3-dioxanes 13, 22, 23 and 29 was performed by transacetalization of various acetals with pentane-1,3,5-triol, activation of the remaining free OH moiety with tosyl chloride and subsequent nucleophilic substitution. The corresponding 3-aminopropyl derivatives 33-35 were prepared by substitution of the tosylates with KCN and LiAlH4 reduction. The highest NMDA receptor affinity was found for 1,3-dioxanes with a phenyl and an ethyl residue at the acetalic position (23) followed by diphenyl (22) and monophenyl derivatives (13). Generally the NMDA affinity of primary amines is higher than the NMDA affinity of secondary and tertiary amines. Altogether the primary amine 23a (Ki=24 nM) represents the most promising NMDA receptor antagonist of this series exceeding the NMDA affinity of the mono-homologues (2-aminoethyl)-1,3-dioxolanes (3,4) and (aminomethyl)-1,3-dioxanes (5,6). Whereas the primary amine 23a turned out to be selective against σ1 and σ2 receptors the benzylamine 13d was identified as potent (Ki=19 nM) and selective σ1 antagonist, which showed extraordinarily high antiallodynic activity in the capsaicin assay. PMID:21444132

  3. ROLE OF NMDA, NICOTINIC, AND GABA RECEPTORS IN THE STEADY STATE VISUAL EVOKED POTENTIAL IN RATS.

    EPA Science Inventory

    This manuscript characterizes the receptor pathways involved in pattern-evoked potential generation in rats

    " NMDA and nicotinic acetylcholine receptors appear to be involved in the generation of the steady-state pattern evoked response in vivo.

    " The pattern evok...

  4. Structure of the Zinc-Bound Amino-Terminal Domain of the NMDA Receptor NR2B Subunit

    SciTech Connect

    Karakas, E.; Simorowski, N; Furukawa, H

    2009-01-01

    N-methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors (iGluRs) that mediate the majority of fast excitatory synaptic transmission in the mammalian brain. One of the hallmarks for the function of NMDA receptors is that their ion channel activity is allosterically regulated by binding of modulator compounds to the extracellular amino-terminal domain (ATD) distinct from the L-glutamate-binding domain. The molecular basis for the ATD-mediated allosteric regulation has been enigmatic because of a complete lack of structural information on NMDA receptor ATDs. Here, we report the crystal structures of ATD from the NR2B NMDA receptor subunit in the zinc-free and zinc-bound states. The structures reveal the overall clamshell-like architecture distinct from the non-NMDA receptor ATDs and molecular determinants for the zinc-binding site, ion-binding sites, and the architecture of the putative phenylethanolamine-binding site.

  5. Nitric oxide modulates blood pressure through NMDA receptors in the rostral ventrolateral medulla of conscious rats.

    PubMed

    Machado, Natalia L S; Silva, Fernanda C S; Chianca, Deoclecio A; de Menezes, Rodrigo C

    2016-07-15

    The rostral ventrolateral medulla (RVLM) is an important site of cardiovascular control related to the tonic excitation and regulating the sympathetic vasomotor tone through local presympathetic neurons. Nitric oxide (NO) has been implicated in the modulation of neurotransmission by several areas of the central nervous system including the RVLM. However the pathways driving NO affects and the correlation between NO and glutamate-induced mechanisms are not well established. Here, we investigate the influence of NO on the cardiovascular response evoked by the activation of NMDA and non-NMDA glutamatergic receptors in the RVLM in conscious rats. For that, we examined the influence of acute inhibition of the NO production within the RVLM, by injecting the nonselective constitutive NOS inhibitor, l-NAME, on responses evoked by the microinjection of excitatory amino acids l-glutamate, NMDA or AMPA agonists into RVLM. Our results show that the injection of l-glutamate, NMDA or AMPA agonists into RVLM, unilaterally, induced a marked increase in the mean arterial pressure (MAP). Pretreatment with l-NAME reduced the hypertensive response evoked by the glutamate injection, and also abolished the pressor response induced by the injection of NMDA into the RVLM. However, blocking the NO synthesis did not alter the response produced by the injection of AMPA agonist. These data provide evidence that the glutamatergic neurotransmission within the RVLM depends on excitatory effects exerted by NO on NMDA receptors, and that this mechanism might be essential to regulate systemic blood pressure. PMID:27150817

  6. The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration.

    PubMed

    Mantuano, Elisabetta; Lam, Michael S; Shibayama, Masataka; Campana, W Marie; Gonias, Steven L

    2015-09-15

    NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury. PMID:26272917

  7. IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders.

    PubMed

    Kang, Jaeseung; Park, Haram; Kim, Eunjoon

    2016-01-01

    IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. PMID:26275848

  8. Differential involvement of amygdala and cortical NMDA receptors activation upon encoding in odor fear memory.

    PubMed

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

    2014-12-01

    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 BLA and olfactory cortex at discrete moments of an odor fear conditioning session. We showed that NMDA receptors in BLA are critically involved in odor fear acquisition during the first association but not during the next ones. In the cortex, NMDA receptor activation at encoding is not necessary for recent odor fear memory while its role in remote memory storage needs further investigation. PMID:25403452

  9. The opioid peptide dynorphin directly blocks NMDA receptor channels in the rat.

    PubMed Central

    Chen, L; Gu, Y; Huang, L Y

    1995-01-01

    1. The actions of dynorphin on N-methyl-D-aspartate (NMDA) responses were examined in acutely dissociated trigeminal neurons in rat. Whole-cell and single-channel currents were recorded using the patch clamp technique. 2. Dynorphins reduced NMDA-activated currents (INMDA). The IC50 was 0.25 microM for dynorphin (1-32), 1.65 microM for dynorphin (1-17) and 1.8 microM for dynorphin (1-13). 3. The blocking action of dynorphin is voltage independent. 4. The inhibitory action of dynorphin cannot be blocked by high concentration of the non-selective opioid receptor antagonist naloxone, nor by the specific kappa-opioid receptor antagonist nor-Binaltorphimine (nor-BNI). 5. Single-channel analyses indicate that dynorphin reduces the fraction of time the channel is open without altering the channel conductance. 6. We propose that dynorphin acts directly on NMDA receptors. PMID:7537820

  10. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95.

    PubMed

    Kornau, H C; Schenker, L T; Kennedy, M B; Seeburg, P H

    1995-09-22

    The N-methyl-D-aspartate (NMDA) receptor subserves synaptic glutamate-induced transmission and plasticity in central neurons. The yeast two-hybrid system was used to show that the cytoplasmic tails of NMDA receptor subunits interact with a prominent postsynaptic density protein PSD-95. The second PDZ domain in PSD-95 binds to the seven-amino acid, COOH-terminal domain containing the terminal tSXV motif (where S is serine, X is any amino acid, and V is valine) common to NR2 subunits and certain NR1 splice forms. Transcripts encoding PSD-95 are expressed in a pattern similar to that of NMDA receptors, and the NR2B subunit co-localizes with PSD-95 in cultured rat hippocampal neurons. The interaction of these proteins may affect the plasticity of excitatory synapses. PMID:7569905

  11. Anti-NMDA receptor encephalitis presenting as atypical anorexia nervosa: an adolescent case report.

    PubMed

    Mechelhoff, David; van Noort, Betteke Maria; Weschke, Bernhard; Bachmann, Christian J; Wagner, Christiane; Pfeiffer, Ernst; Winter, Sibylle

    2015-11-01

    Since 2007, more than 600 patients have been diagnosed with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, with almost 40 % of those affected being children or adolescents. In early phases of the illness, this life-threatening disease is characterized by psychiatric symptoms, such as depression, anxiety, obsessions, hallucinations or delusions. Consequently, a high percentage of patients receive psychiatric diagnoses at first, hindering the crucial early diagnosis and treatment of the anti-NMDA receptor encephalitis. We report on a 15-year-old girl initially presenting with pathological eating behaviour and significant weight loss resulting in an (atypical) anorexia nervosa (AN) diagnosis. Her early course of illness, diagnostic process, treatment and short-term outcome are described. This case report aims to raise awareness about the association between anorectic behaviour and anti-NMDA receptor encephalitis and highlight the importance of multidisciplinary teams in child and adolescent services. PMID:25663428

  12. A conserved structural mechanism of NMDA receptor inhibition: A comparison of ifenprodil and zinc

    PubMed Central

    Sirrieh, Rita E.; MacLean, David M.

    2015-01-01

    N-methyl-d-aspartate (NMDA) receptors, one of the three main types of ionotropic glutamate receptors (iGluRs), are involved in excitatory synaptic transmission, and their dysfunction is implicated in various neurological disorders. NMDA receptors, heterotetramers typically composed of GluN1 and GluN2 subunits, are the only members of the iGluR family that bind allosteric modulators at their amino-terminal domains (ATDs). We used luminescence resonance energy transfer to characterize the conformational changes the receptor undergoes upon binding ifenprodil, a synthetic compound that specifically inhibits activation of NMDA receptors containing GluN2B. We found that ifenprodil induced an overall closure of the GluN2B ATD without affecting conformation of the GluN1 ATD or the upper lobes of the ATDs, the same mechanism whereby zinc inhibits GluN2A. These data demonstrate that the conformational changes induced by zinc and ifenprodil represent a conserved mechanism of NMDA receptor inhibition. Additionally, we compared the structural mechanism of zinc inhibition of GluN1–GluN2A receptors to that of ifenprodil inhibition of GluN1–GluN2B. The similarities in the conformational changes induced by inhibitor binding suggest a conserved structural mechanism of inhibition independent of the binding site of the modulator. PMID:26170175

  13. EVALUATING THE NMDA-GLUTAMATE RECEPTOR AS A SITE OF ACTION FOR TOLUENE USING PATTERN ELICITED VISUAL EVOKED POTENTIALS.

    EPA Science Inventory

    In vitro studies have demonstrated that toluene disrupts the function of NMDA-glutamate receptors, as well as other channels. This has led to the hypothesis that effects on NMDA receptor function may contribute to toluene neurotoxicity, CNS depression, and altered visual evoked ...

  14. NMDA-Receptor Activation but Not Ion Flux Is Required for Amyloid-Beta Induced Synaptic Depression

    PubMed Central

    Tamburri, Albert; Dudilot, Anthony; Licea, Sara; Bourgeois, Catherine; Boehm, Jannic

    2013-01-01

    Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer’s disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor. PMID:23750255

  15. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis in a young Lebanese girl.

    PubMed

    Safadieh, Layal; Dabbagh, Omar

    2013-10-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a recently recognized autoimmune neurologic disorder that presents with severe neuropsychiatric symptoms in previously healthy children. A 4-year-old Lebanese girl presented with new-onset behavioral changes, orofacial dyskinesias, fluctuation in consciousness, inability to walk, and mutism. Antibodies directed against NMDA receptors were detected in the patient's serum and cerebrospinal fluid. Prompt treatment with a single course of intravenous immunoglobulin resulted in early complete recovery. This is the first case report of a Middle Eastern child affected with this condition. PMID:22992990

  16. Effects of N-methyl-D-aspartate (NMDA) receptor blockade on breathing pattern in newborn cat.

    PubMed

    Schweitzer, P; Pierrefiche, O; Foutz, A S; Denavit-Saubié, M

    1990-11-01

    We gave newborn kittens the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 systemically while recording their breathing patterns by the barometric method. Unlike pentobarbital, MK-801 at an anaesthetic dose increased the relative length of inspiration within the respiratory cycle. The section of both vagus nerves under MK-801 produced apneustic breathing, whereas vagotomy under pentobarbital had no such effect. We conclude that the central inspiratory-termination mechanism mediated through NMDA receptors and the vagally-mediated mechanism that independently 'switches off' inspiration are both functional at birth. PMID:2148125

  17. Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

    PubMed Central

    Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

    2012-01-01

    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 Ca2+ increase, but does not require PKA and extracellular Ca2+ 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. PMID:23284812

  18. State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons.

    PubMed

    Fleming, Tiffany M; Scott, Victoria; Naskar, Krishna; Joe, Natalie; Brown, Colin H; Stern, Javier E

    2011-08-15

    Despite the long-established presence of glutamate NMDA receptors at extrasynaptic sites (eNMDARs), their functional roles remain poorly understood. Factors influencing the concentration and time course of glutamate in the extrasynaptic space, such as the topography of the neuronal–glial microenvironment, as well as glial glutamate transporters, are expected to affect eNMDAR-mediated signalling strength. In this study, we used in vitro and in vivo electrophysiological recordings to assess the properties, functional relevance and modulation of a persistent excitatory current mediated by activation of eNMDARs in hypothalamic supraoptic nucleus (SON) neurons. We found that ambient glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic I(NMDA)), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin α-aminodadipic acid, enhanced tonic I(NMDA) and neuronal activity, supporting an astrocyte regulation of tonic I(NMDA) strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodelling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic I(NMDA) strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic I(NMDA) activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge. PMID:21690192

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

    PubMed Central

    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

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

    NASA Technical Reports Server (NTRS)

    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.

  1. Synergy of AMPA and NMDA Receptor Currents in Dopaminergic Neurons: A Modeling Study.

    PubMed

    Zakharov, Denis; Lapish, Christopher; Gutkin, Boris; Kuznetsov, Alexey

    2016-01-01

    Dopaminergic (DA) neurons display two modes of firing: low-frequency tonic and high-frequency bursts. The high frequency firing within the bursts is attributed to NMDA, but not AMPA receptor activation. In our models of the DA neuron, both biophysical and abstract, the NMDA receptor current can significantly increase their firing frequency, whereas the AMPA receptor current is not able to evoke high-frequency activity and usually suppresses firing. However, both currents are produced by glutamate receptors and, consequently, are often co-activated. Here we consider combined influence of AMPA and NMDA synaptic input in the models of the DA neuron. Different types of neuronal activity (resting state, low frequency, or high frequency firing) are observed depending on the conductance of the AMPAR and NMDAR currents. In two models, biophysical and reduced, we show that the firing frequency increases more effectively if both receptors are co-activated for certain parameter values. In particular, in the more quantitative biophysical model, the maximal frequency is 40% greater than that with NMDAR alone. The dynamical mechanism of such frequency growth is explained in the framework of phase space evolution using the reduced model. In short, both the AMPAR and NMDAR currents flatten the voltage nullcline, providing the frequency increase, whereas only NMDA prevents complete unfolding of the nullcline, providing robust firing. Thus, we confirm a major role of the NMDAR in generating high-frequency firing and conclude that AMPAR activation further significantly increases the frequency. PMID:27252643

  2. Synergy of AMPA and NMDA Receptor Currents in Dopaminergic Neurons: A Modeling Study

    PubMed Central

    Zakharov, Denis; Lapish, Christopher; Gutkin, Boris; Kuznetsov, Alexey

    2016-01-01

    Dopaminergic (DA) neurons display two modes of firing: low-frequency tonic and high-frequency bursts. The high frequency firing within the bursts is attributed to NMDA, but not AMPA receptor activation. In our models of the DA neuron, both biophysical and abstract, the NMDA receptor current can significantly increase their firing frequency, whereas the AMPA receptor current is not able to evoke high-frequency activity and usually suppresses firing. However, both currents are produced by glutamate receptors and, consequently, are often co-activated. Here we consider combined influence of AMPA and NMDA synaptic input in the models of the DA neuron. Different types of neuronal activity (resting state, low frequency, or high frequency firing) are observed depending on the conductance of the AMPAR and NMDAR currents. In two models, biophysical and reduced, we show that the firing frequency increases more effectively if both receptors are co-activated for certain parameter values. In particular, in the more quantitative biophysical model, the maximal frequency is 40% greater than that with NMDAR alone. The dynamical mechanism of such frequency growth is explained in the framework of phase space evolution using the reduced model. In short, both the AMPAR and NMDAR currents flatten the voltage nullcline, providing the frequency increase, whereas only NMDA prevents complete unfolding of the nullcline, providing robust firing. Thus, we confirm a major role of the NMDAR in generating high-frequency firing and conclude that AMPAR activation further significantly increases the frequency. PMID:27252643

  3. Brain-derived neurotrophic factor rapidly increases NMDA receptor channel activity through Fyn-mediated phosphorylation.

    PubMed

    Xu, Fei; Plummer, Mark R; Len, Guo-Wei; Nakazawa, Takanobu; Yamamoto, Tadashi; Black, Ira B; Wu, Kuo

    2006-11-22

    Brain-derived neurotrophic factor (BDNF) is a potent modulator of hippocampal synaptic plasticity. Previously, we found that one of the targets of BDNF modulation is NR2B-containing NMDA receptors. Furthermore, exposure to the trophin rapidly increases NMDA receptor activity and enhances tyrosine phosphorylation of NR2B in cortical and hippocampal postsynaptic densities (PSDs), potentially linking receptor phosphorylation to synaptic plasticity. To define the specific NR2B residue(s) regulated by BDNF, we focused on tyrosine 1472, phosphorylation of which increases after LTP. BDNF rapidly increased phosphorylation in cortical PSDs. The tyrosine kinase Fyn is critical since BDNF-dependent phosphorylation was abolished in Fyn knockout mice. Single-channel patch clamp recordings showed that Fyn is required for the increase in NMDA receptor activity elicited by BDNF. Collectively, our results suggest that BDNF enhances phosphorylation of NR2B tyrosine 1472 through activation of Fyn, leading to alteration of NMDA receptor activity and increased synaptic transmission. PMID:17045972

  4. PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat

    PubMed Central

    Losi, Gabriele; Prybylowski, Kate; Fu, Zhanyan; Luo, Jianhong; Wenthold, Robert J; Vicini, Stefano

    2003-01-01

    We transfected a green fluorescent protein-tagged PSD-95 (PSD-95gfp) into cultured rat cerebellar granule cells (CGCs) to investigate the role of PSD-95 in excitatory synapse maturation. Cells were grown in low potassium to favour functional synapse formation in vitro. Transfected cells displayed clear clusters of PSD-95gfp, often at the extremities of the short dendritic trees. We recorded NMDA and AMPA miniature excitatory postsynaptic currents (NMDA- and AMPA-mESPCs) in the presence of TTX and bicuculline. At days in vitro (DIV) 7–8 PSD-95gfp-transfected cells had NMDA-mEPSCs with faster decay and smaller amplitudes than matching controls. In contrast, AMPA-mEPSC frequencies and amplitudes were increased. Whole-cell current density and ifenprodil sensitivity were reduced in PSD-95gfp cells, indicating a reduction of NR2B subunits containing NMDA receptors. No changes were observed compared to control when cells were transfected with cDNA for PSD-95gfp with palmitoylation site mutations that prevent targeting to the synapse. Overexpression of the NMDA receptor NR2A subunit, but not the NR2B subunit, prevented NMDA-mEPSC amplitude reduction when cotransfected with PSD-95gfp. PSD-95gfp overexpression produced faster NMDA-mEPSC decay when transfected alone or with either NR2 subunit. Surface staining of the epitope-tagged NR2 subunits revealed that colocalization with PSD-95gfp was higher for flag-tagged NR2A subunit clusters than for flag-tagged NR2B subunit clusters. These data suggest that PSD-95 overexpression in CGCs favours synaptic maturation by allowing synaptic insertion of NR2A and depressing expression of NR2B subunits. PMID:12576494

  5. The HIV coat protein gp120 promotes forward trafficking and surface clustering of NMDA receptors in membrane microdomains

    PubMed Central

    Xu, Hangxiu; Bae, Mihyun; Tovar-y-Romo, Luis B.; Patel, Neha; Bandaru, Veera Venkata Ratnam; Pomerantz, Daniel; Steiner, Joseph; Haughey, Norman J.

    2011-01-01

    Infection by the Human immunodeficiency virus (HIV) can result in debilitating neurological syndromes collectively known as HIV associated neurocognitive disorders (HAND). While the HIV coat protein gp120 has been identified as a potent neurotoxin that enhances NMDA receptor function, the exact mechanisms for effect are not known. Here we provide evidence that gp120 activates two separate signaling pathways that converge to enhance NMDA-evoked calcium flux by clustering NMDA receptors in modified membrane microdomains. HIV gp120 enlarged, and stabilized the structure of lipid rafts on neuronal dendrites by mechanisms that involved a redox-regulated translocation of a sphingomyelin hydrolase (neutral sphingomyelinase-2; nSMase2) to the plasma membrane. A concurrent pathway was activated that enhanced the forward traffic of NMDA receptors by promoting a PKA-dependent phopshorylation of the NR1 C-terminal serine 897 (that masks an ER retention signal), followed by a PKC-dependent phosphorylation of serine 896 (important for surface expression). NMDA receptors were preferentially targeted to synapses, and clustered in modified membrane microdomains. In these conditions, NMDA receptors were unable to laterally disperse, and did not internalize, even in response to strong agonist induction. Focal NMDA-evoked calcium bursts were enhanced three-fold in these regions. Inhibiting membrane modification or NR1 phosphorylation prevented gp120 from enhancing the surface localization and clustering of NMDA receptors, while disrupting the structure of membrane microdomains restored the ability of NMDA receptors to disperse and internalize following gp120. These findings demonstrate that gp120 contributes to synaptic dysfunction in the setting of HIV-infection by interfering with the traffic of NMDA receptors. PMID:22114277

  6. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications.

    PubMed

    Rodrigo, Regina; Cauli, Omar; Boix, Jordi; ElMlili, Nisrin; Agusti, Ana; Felipo, Vicente

    2009-01-01

    Acute liver failure (ALF) may lead to rapid death unless the patients receive a liver for transplantation. However, the number of livers available is not enough and a number of patients die before a suitable liver is available for transplantation. The liver has a high capacity for regeneration which may allow complete recovery even in patients with severe liver failure. It would be therefore very useful to have procedures to prevent or delay the mechanisms by which ALF leads to death. These mechanisms are no well understood. Progression of ALF leads to multi-organ failure, systemic inflammatory response, hepatic encephalopathy, cerebral oedema and increased intracranial pressure, which seem the most important immediate causes of mortality in patients with ALF. A main contributor to these events is hyperammonemia, due to impaired ammonia detoxification in the liver. Acute hyperammonemia per se leads to death, which is mediated by activation of the NMDA type of glutamate receptors in brain and may be prevented by antagonists blocking these receptors. Acute liver failure also leads to hyperammonemia and excessive activation of NMDA receptors in brain which contributes to ALF-induced death. Sustained blocking of NMDA receptors by continuous administration of the antagonists MK-801 or memantine increases about twice the survival time of rats with severe ALF due to injection of 2.5g/kg of galactosamine. In rats with milder ALF due to injection of 1.5g/kg of galactosamine, blocking NMDA receptors increases the percentage of surviving rats from 23% to 62% and increases about twice the survival time of the rats which die. These data strongly support that blocking NMDA receptors would improve survival of patients with ALF, either by allowing more time for liver regeneration or to get a liver suitable for transplantation. PMID:19428814

  7. Differential Modulation of Reinforcement Learning by D2 Dopamine and NMDA Glutamate Receptor Antagonism

    PubMed Central

    Klein, Tilmann A.; Ullsperger, Markus

    2014-01-01

    The firing pattern of midbrain dopamine (DA) neurons is well known to reflect reward prediction errors (PEs), the difference between obtained and expected rewards. The PE is thought to be a crucial signal for instrumental learning, and interference with DA transmission impairs learning. Phasic increases of DA neuron firing during positive PEs are driven by activation of NMDA receptors, whereas phasic suppression of firing during negative PEs is likely mediated by inputs from the lateral habenula. We aimed to determine the contribution of DA D2-class and NMDA receptors to appetitively and aversively motivated reinforcement learning. Healthy human volunteers were scanned with functional magnetic resonance imaging while they performed an instrumental learning task under the influence of either the DA D2 receptor antagonist amisulpride (400 mg), the NMDA receptor antagonist memantine (20 mg), or placebo. Participants quickly learned to select (“approach”) rewarding and to reject (“avoid”) punishing options. Amisulpride impaired both approach and avoidance learning, while memantine mildly attenuated approach learning but had no effect on avoidance learning. These behavioral effects of the antagonists were paralleled by their modulation of striatal PEs. Amisulpride reduced both appetitive and aversive PEs, while memantine diminished appetitive, but not aversive PEs. These data suggest that striatal D2-class receptors contribute to both approach and avoidance learning by detecting both the phasic DA increases and decreases during appetitive and aversive PEs. NMDA receptors on the contrary appear to be required only for approach learning because phasic DA increases during positive PEs are NMDA dependent, whereas phasic decreases during negative PEs are not. PMID:25253860

  8. Differential modulation of reinforcement learning by D2 dopamine and NMDA glutamate receptor antagonism.

    PubMed

    Jocham, Gerhard; Klein, Tilmann A; Ullsperger, Markus

    2014-09-24

    The firing pattern of midbrain dopamine (DA) neurons is well known to reflect reward prediction errors (PEs), the difference between obtained and expected rewards. The PE is thought to be a crucial signal for instrumental learning, and interference with DA transmission impairs learning. Phasic increases of DA neuron firing during positive PEs are driven by activation of NMDA receptors, whereas phasic suppression of firing during negative PEs is likely mediated by inputs from the lateral habenula. We aimed to determine the contribution of DA D2-class and NMDA receptors to appetitively and aversively motivated reinforcement learning. Healthy human volunteers were scanned with functional magnetic resonance imaging while they performed an instrumental learning task under the influence of either the DA D2 receptor antagonist amisulpride (400 mg), the NMDA receptor antagonist memantine (20 mg), or placebo. Participants quickly learned to select ("approach") rewarding and to reject ("avoid") punishing options. Amisulpride impaired both approach and avoidance learning, while memantine mildly attenuated approach learning but had no effect on avoidance learning. These behavioral effects of the antagonists were paralleled by their modulation of striatal PEs. Amisulpride reduced both appetitive and aversive PEs, while memantine diminished appetitive, but not aversive PEs. These data suggest that striatal D2-class receptors contribute to both approach and avoidance learning by detecting both the phasic DA increases and decreases during appetitive and aversive PEs. NMDA receptors on the contrary appear to be required only for approach learning because phasic DA increases during positive PEs are NMDA dependent, whereas phasic decreases during negative PEs are not. PMID:25253860

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

    ERIC Educational Resources Information Center

    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. Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

    PubMed Central

    Bendix, Ivo; Serdar, Meray; Herz, Josephine; von Haefen, Clarissa; Nasser, Fatme; Rohrer, Benjamin; Endesfelder, Stefanie; Felderhoff-Mueser, Ursula; Spies, Claudia D.; Sifringer, Marco

    2014-01-01

    Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. PMID:24595240

  11. New benzoyl urea derivatives as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, I; Greiner, I; Kolok, S; Galgóczy, K; Ignácz-Szendrei, Gy; Horváth, Cs; Farkas, S; Gáti, T; Háda, V; Domány, Gy

    2006-09-01

    A novel series of benzoyl urea derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substitution of the piperidine ring on the biological activity of the compounds was studied. Compound 9 was active in the formalin test in mice. PMID:17020160

  12. Reconsolidation after Remembering an Odor-Reward Association Requires NMDA Receptors

    ERIC Educational Resources Information Center

    Torras-Garcia, Meritxell; Tronel, Sophie; Sara, Susan J.; Lelong, Julien

    2005-01-01

    A rapidly learned odor discrimination task based on spontaneous foraging behavior of the rat was used to evaluate the role of N-methyl-D-aspartate (NMDA) receptors (NMDARs) in ongoing memory consolidation. Rats were trained in a single session to discriminate among three odors, one of which was associated with palatable food reward. Previous…

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

    SciTech Connect

    Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki; Kume, Toshiaki; Fukushima, Nobuyuki; Akaike, Akinori; Kawabata, Atsufumi

    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.

  14. NMDA and non-NMDA glutamate receptors in the paraventricular nucleus of the hypothalamus modulate different stages of hemorrhage-evoked cardiovascular responses in rats.

    PubMed

    Busnardo, C; Crestani, C C; Fassini, A; Resstel, L B M; Corrêa, F M A

    2016-04-21

    Here we report the involvement of N-Methyl-d-Aspartate (NMDA) and non-NMDA glutamate receptors from the paraventricular nucleus of the hypothalamus (PVN) in the mediation of cardiovascular changes observed during hemorrhage and post-bleeding periods. In addition, the present study provides further evidence of the involvement of circulating vasopressin and cardiac sympathetic activity in cardiovascular responses to hemorrhage. Systemic treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP (50 μg/kg, i.v.) increased the latency to the onset of hypotension during hemorrhage and slowed post-bleeding recovery of blood pressure. Systemic treatment with the β1-adrenergic receptor antagonist atenolol (1 mg/kg, i.v.) also increased the latency to the onset of hypotension during hemorrhage. Moreover, atenolol reversed the hemorrhage-induced tachycardia into bradycardia. Bilateral microinjection of the selective NMDA glutamate receptor antagonist LY235959 (2 nmol/100 nL) into the PVN blocked the hypotensive response to hemorrhage and reduced the tachycardia during the post-hemorrhage period. Systemic treatment with dTyr(CH2)5(Me)AVP inhibited the effect of LY235959 on hemorrhage-induced hypotension, without affecting the post-bleeding tachycardia. PVN treatment with the selective non-NMDA receptor antagonist NBQX (2 nmol/100 nL) reduced the recovery of blood pressure to normal levels in the post-bleeding phase and reduced hemorrhage-induced tachycardia. Combined blockade of both NMDA and non-NMDA glutamate receptors in the PVN completely abolished the hypotensive response in the hemorrhage period and reduced the tachycardiac response in the post-hemorrhage period. These results indicate that local PVN glutamate neurotransmission is involved in the neural pathway mediating cardiovascular responses to hemorrhage, via an integrated control involving autonomic nervous system activity and vasopressin release into the circulation. PMID:26861418

  15. Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

    SciTech Connect

    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.

  16. Recent Progress in Understanding Subtype Specific Regulation of NMDA Receptors by G Protein Coupled Receptors (GPCRs)

    PubMed Central

    Yang, Kai; Jackson, Michael F.; MacDonald, John F.

    2014-01-01

    G Protein Coupled Receptors (GPCRs) are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs), which belong to the ionotropic glutamate receptor family, are likewise ubiquitously expressed in the central nervous system (CNS) and play a pivotal role in learning and memory. Despite its critical contribution to physiological and pathophysiological processes, few pharmacological interventions aimed directly at regulating NMDAR function have been developed to date. However, it is well established that NMDAR function is precisely regulated by cellular signalling cascades recruited downstream of G protein coupled receptor (GPCR) stimulation. Accordingly, the downstream regulation of NMDARs likely represents an important determinant of outcome following treatment with neuropsychiatric agents that target selected GPCRs. Importantly, the functional consequence of such regulation on NMDAR function varies, based not only on the identity of the GPCR, but also on the cell type in which relevant receptors are expressed. Indeed, the mechanisms responsible for regulating NMDARs by GPCRs involve numerous intracellular signalling molecules and regulatory proteins that vary from one cell type to another. In the present article, we highlight recent findings from studies that have uncovered novel mechanisms by which selected GPCRs regulate NMDAR function and consequently NMDAR-dependent plasticity. PMID:24562329

  17. Overexpression of α-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity.

    PubMed

    Yang, Junfeng; Hertz, Ellen; Zhang, Xiaoqun; Leinartaité, Lina; Lundius, Ebba Gregorsson; Li, Jie; Svenningsson, Per

    2016-01-12

    Progressive accumulation of α-synuclein (α-syn)-containing protein aggregates throughout the nervous system is a pathological hallmark of Parkinson's disease (PD). The mechanisms whereby α-syn exerts neurodegeneration remain to be fully understood. Here we show that overexpression of α-syn in transgenic mice leads to increased phosphorylation of glutamate NMDA receptor (NMDAR) subunits NR1 and NR2B in substantia nigra and striatum as well as reduced glucocerebrosidase (GCase) levels. Similarly, molecular studies performed in mouse N2A cells stably overexpressing human α-syn ((α-syn)N2A) showed that phosphorylation states of the same NMDAR subunits were increased, whereas GCase levels and lysosomal GCase activity were reduced. (α-syn)N2A cells showed an increased sensitivity to neurotoxicity towards 6-hydroxydopamine and NMDA. However, wildtype N2A, but not (α-syn)N2A cells, showed a further reduction in viability when co-incubated with 6-hydroxydopamine and the lysosomal inhibitors NH4Cl and leupeptin, suggesting that α-syn per se perturbs lysosomal functions. NMDA treatment reduced lysosomal GCase activity to the same extent in (α-syn)N2A cells as in wildtype N2A cells, indicating that the α-syn-dependent difference in NMDA neurotoxicity is unrelated to an altered GCase activity. Nevertheless, these data provide molecular evidence that overexpression of α-syn simultaneously induces two potential neurotoxic hits by increasing glutamate NMDA receptor phosphorylation, consistent with increased NMDA receptors functionality, and reducing GCase activity. PMID:26610904

  18. Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat

    PubMed Central

    Shin, AH; Kim, HJ; Thayer, SA

    2012-01-01

    BACKGROUND AND PURPOSE Neurocognitive disorders afflict approximately 20% of HIV-infected patients. HIV-1-infected cells in the brain shed viral proteins such as transactivator of transcription (Tat). Tat elicits cell death and synapse loss via processes initiated by NMDA receptor activation but mediated by separate downstream signalling pathways. Subunit selective NMDA receptor antagonists may differentially modulate survival relative to synaptic changes. EXPERIMENTAL APPROACH Tat-evoked cell death was quantified by measuring propidium iodide uptake into rat hippocampal neurons in culture. The effects of Tat on synaptic changes were measured using an imaging-based assay that quantified clusters of the scaffolding protein postsynaptic density 95 fused to green fluorescent protein. KEY RESULTS Dizocilpine, a non-competitive NMDA receptor antagonist, inhibited Tat-induced synapse loss, subsequent synapse recovery and Tat-induced cell death with comparable potencies. Memantine (10 µM) and ifenprodil (10 µM), which preferentially inhibit GluN2B-containing NMDA receptors, protected from Tat-induced cell death with no effect on synapse loss. Surprisingly, memantine and ifenprodil induced synapse recovery in the presence of Tat. In contrast, the GluN2A-prefering antagonist TCN201 prevented synapse loss and recovery with no effect on cell death. CONCLUSIONS AND IMPLICATIONS Synapse loss is a protective mechanism that enables the cell to cope with excess excitatory input. Thus, memantine and ifenprodil are promising neuroprotective drugs because they spare synaptic changes and promote survival. These GluN2B-preferring drugs induced recovery from Tat-evoked synapse loss, suggesting that synaptic pharmacology changed during the neurotoxic process. NMDA receptor subtypes differentially participate in the adaptation and death induced by excitotoxic insult. PMID:22142193

  19. NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus.

    PubMed

    Swanger, Sharon A; Vance, Katie M; Pare, Jean-François; Sotty, Florence; Fog, Karina; Smith, Yoland; Traynelis, Stephen F

    2015-12-01

    The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease. PMID:26631477

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

    PubMed Central

    Favero, Morgana

    2015-01-01

    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. PMID:25878152

  1. Heterogeneity of clinical features and corresponding antibodies in seven patients with anti-NMDA receptor encephalitis

    PubMed Central

    SÜHS, KURT-WOLFRAM; WEGNER, FLORIAN; SKRIPULETZ, THOMAS; TREBST, CORINNA; TAYEB, SAID BEN; RAAB, PETER; STANGEL, MARTIN

    2015-01-01

    Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is the most common type of encephalitis in the spectrum of autoimmune encephalitis defined by antibodies targeting neuronal surface antigens. In the present study, the clinical spectrum of this disease is presented using instructive cases in correlation with the anti-NMDA receptor antibody titers in the cerebrospinal fluid (CSF) and serum. A total of 7 female patients admitted to the hospital of Hannover Medical School (Hannover, Germany) between 2008 and 2014 were diagnosed with anti-NMDA receptor encephalitis. Among these patients, 3 cases were selected to illustrate the range of similar and distinct clinical features across the spectrum of the disease and to compare anti-NMDA antibody levels throughout the disease course. All patients received immunosuppressive treatment with methylprednisolone, intravenous immunoglobulin and/or plasmapheresis, followed in the majority of patients by second-line therapy with rituximab and cyclophosphamide. The disease course correlated with NMDA receptor antibody titers, and to a greater extent with the ratio between antibody titer and protein concentration. A favorable clinical outcome with a modified Rankin Scale (mRS) score of ≤1 was achieved in 4 patients, 1 patient had an mRS score of 2 after 3 months of observation only, whereas 2 patients remained severely impaired (mRS score 4). Early and aggressive immunosuppressive treatment appears to support a good clinical outcome; however, the clinical signs and symptoms differ distinctively and treatment decisions have to be made on an individual basis. PMID:26622479

  2. Involvement of the NMDA receptor, NO-cyclic GMP and nuclear factor K-beta in an animal model of repeated trauma.

    PubMed

    Harvey, Brian H; Bothma, Tanya; Nel, Ané; Wegener, Gregers; Stein, Dan J

    2005-07-01

    Post-traumatic stress disorder (PTSD) may be associated with shrinkage of the hippocampus, with glutamate release causally related to these events. Recent animal studies strongly implicate activation of the nitric oxide (NO)-cascade in anxiety and stress. Using an animal model of repeated trauma, the effect of stress was investigated on the hippocampal NO-cGMP signalling pathway, specifically the release of nitrogen oxides (NOx) and its modulation by NMDA receptor-, NO-, cGMP- and nuclear factor K-beta (NFK-beta)-selective drugs. Immediately after stress, rats received the glutamate NMDA receptor antagonist, memantine (MEM; 5 mg/kg i.p./d), the NO synthase inhibitor, 7-nitroindazole sodium salt (7-NINA; 20 mg/kg i.p./d), the cGMP-specific PDE inhibitor, sildenafil (SIL; 10 mg/kg i.p./d) or the NFkappa-beta antagonist, pyrollidine dithiocarbamate (PDTC; 70 mg/kg i.p./d), for 7 days. Stress significantly increased hippocampal NOx on day 7 post-stress, which was blocked by either 7-NINA or PDTC, while MEM was without effect. SIL, however, significantly augmented stress-induced NOx accumulation. Increased cGMP therefore acts as a protagonist in driving stress-related events, while both nNOS (neuronal NOS) and iNOS (inducible/immunological NOS) may represent a therapeutic target in preventing the effects of severe stress. The value of NMDA receptor antagonism, however, appears limited in this model. PMID:15912566

  3. Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract.

    PubMed

    Zhao, Huan; Peters, James H; Zhu, Mingyan; Page, Stephen J; Ritter, Robert C; Appleyard, Suzanne M

    2015-01-01

    Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation. NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear. In this study we used whole cell patch-clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses. Results show that NMDA receptors contribute up to 70% of the charge transferred across the synapse at high (>5 Hz) firing rates, but have little contribution at lower firing frequencies. Results also show that NMDA receptors critically contribute to the fidelity of transmission across these synapses during high frequency (>5 Hz) afferent discharge rates. This novel role of NMDA receptors may explain in part how primary visceral afferents, including vagal afferents, can maintain fidelity of transmission across a broad range of firing frequencies. Neurons within the nucleus of the solitary tract (NTS) receive vagal afferent innervations that initiate gastrointestinal and cardiovascular reflexes. Glutamate is the fast excitatory neurotransmitter released in the NTS by vagal afferents, which arrive there via the solitary tract (ST). ST stimulation elicits excitatory postsynaptic currents (EPSCs) in NTS neurons mediated by both AMPA- and NMDA-type glutamate receptors (-Rs). Vagal afferents exhibit a high probability of vesicle release and exhibit robust frequency-dependent depression due to presynaptic vesicle depletion. Nonetheless, synaptic throughput is maintained even at high frequencies of afferent activation. Here we test the hypothesis that postsynaptic NMDA-Rs are essential in maintaining throughput across ST-NTS synapses. Using patch clamp electrophysiology in horizontal brainstem slices, we found that NMDA-Rs, including NR2B subtypes, carry up to 70% of the charge transferred

  4. NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus

    PubMed Central

    Swanger, Sharon A.; Vance, Katie M.; Pare, Jean-François; Sotty, Florence; Fog, Karina; Smith, Yoland

    2015-01-01

    The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)–P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease. SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a key component of the basal ganglia, a group of subcortical nuclei that control movement and are dysregulated in movement disorders such as Parkinson's disease. Subthalamic neurons receive direct excitatory input, but the pharmacology of excitatory

  5. The NMDA receptor NR2A subunit regulates proliferation of MKN45 human gastric cancer cells

    SciTech Connect

    Watanabe, Kanako; Kanno, Takeshi; Oshima, Tadayuki; Miwa, Hiroto; Tashiro, Chikara; Nishizaki, Tomoyuki

    2008-03-07

    The present study investigated proliferation of MKN28 and MKN45 human gastric cancer cells regulated by the N-methyl-D-aspartate (NMDA) receptor subunit. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5) inhibited proliferation of MKN45 cells, but not MKN28 cells. Of the NMDA subunits such as NR1, NR2 (2A, 2B, 2C, and 2D), and NR3 (3A and 3B), all the NMDA subunit mRNAs except for the NR2B subunit mRNA were expressed in both MKN28 and MKN45 cells. MKN45 cells were characterized by higher expression of the NR2A subunit mRNA and lower expression of the NR1 subunit mRNA, but MKN28 otherwise by higher expression of the NR1 subunit mRNA and lower expression of the NR2A subunit mRNA. MKN45 cell proliferation was also inhibited by silencing the NR2A subunit-targeted gene. For MKN45 cells, AP5 or knocking-down the NR2A subunit increased the proportion of cells in the G{sub 1} phase of cell cycling and decreased the proportion in the S/G{sub 2} phase. The results of the present study, thus, suggest that blockage of NMDA receptors including the NR2A subunit suppresses MKN45 cell proliferation due to cell cycle arrest at the G{sub 1} phase; in other words, the NR2A subunit promotes MKN45 cell proliferation by accelerating cell cycling.

  6. Genetic NMDA receptor deficiency disrupts acute and chronic effects of cocaine but not amphetamine.

    PubMed

    Ramsey, Amy J; Laakso, Aki; Cyr, Michel; Sotnikova, Tatyana D; Salahpour, Ali; Medvedev, Ivan O; Dykstra, Linda A; Gainetdinov, Raul R; Caron, Marc G

    2008-10-01

    NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre- and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways. PMID:18185498

  7. Abnormal dephosphorylation effect on NMDA receptor regulation in ALS spinal cord.

    PubMed

    Wagey, R; Krieger, C; Shaw, C A

    1997-01-01

    Previous studies have demonstrated a significant reduction of N-methyl-D-aspartate (NMDA) receptor binding in spinal cord sections from patients who died with amyotrophic lateral sclerosis (ALS) compared to that in control patients. The reduction in NMDA receptor binding in ALS could be increased toward control values by treatment with phorbol ester, suggesting a role for receptor protein phosphorylation in this disorder. In the present study we have evaluated the time course of recovery of [3H]MK-801 binding following phorbol ester treatment to assess protein phosphatase activity in spinal cord sections from ALS and control subjects. Phorbol ester-stimulated changes in [3H]MK-801 binding returned to untreated values significantly faster in ALS tissue compared to control and could not be blocked by the coapplication of the protein phosphatase inhibitors sodium vanadate or sodium beta-D-glycerol phosphate. Okadaic acid coapplication blocked recovery in both ALS and control tissue at a concentration range at which phosphatase 2B (calcineurin) would likely be inhibited. The results suggest that abnormal levels or activity of protein phosphatases, including calcineurin, may be involved in the abnormal levels of NMDA receptors in ALS and may play some role in the pathogenesis of the disease. PMID:9440123

  8. NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference123

    PubMed Central

    Tokarski, Krzysztof; Bobula, Bartosz; Zygmunt, Magdalena; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Hess, Grzegorz; Przewlocki, Ryszard

    2016-01-01

    Abstract Plasticity of the brain’s dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1D1CreERT2 mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1D1CreERT2 mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general. PMID:27294197

  9. NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference.

    PubMed

    Sikora, Magdalena; Tokarski, Krzysztof; Bobula, Bartosz; Zajdel, Joanna; Jastrzębska, Kamila; Cieślak, Przemysław Eligiusz; Zygmunt, Magdalena; Sowa, Joanna; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Engblom, David; Hess, Grzegorz; Przewlocki, Ryszard; Rodriguez Parkitna, Jan

    2016-01-01

    Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general. PMID:27294197

  10. Ethanol withdrawal hyper-responsiveness mediated by NMDA receptors in spinal cord motor neurons

    PubMed Central

    Li, Hui-Fang; Kendig, Joan J

    2003-01-01

    is necessary for withdrawal hyper-responsiveness. Both tyrosine kinase and PKC, but not PKA, appear to be essential for EtOH withdrawal hyper-responsiveness mediated by postsynaptic NMDA receptors in spinal cord motor neurons. PMID:12746225

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

    PubMed

    Fedder, Karlie N; Sabo, Shasta L

    2015-01-01

    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. PMID:26694480

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

    PubMed Central

    Fedder, Karlie N.; Sabo, Shasta L.

    2015-01-01

    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. PMID:26694480

  13. NMDA Receptor-Dependent Synaptic Reinforcement as a Crucial Process for Memory Consolidation

    NASA Astrophysics Data System (ADS)

    Shimizu, Eiji; Tang, Ya-Ping; Rampon, Claire; Tsien, Joe Z.

    2000-11-01

    The hippocampal CA1 region is crucial for converting new memories into long-term memories, a process believed to continue for week(s) after initial learning. By developing an inducible, reversible, and CA1-specific knockout technique, we could switch N-methyl-D-aspartate (NMDA) receptor function off or on in CA1 during the consolidation period. Our data indicate that memory consolidation depends on the reactivation of the NMDA receptor, possibly to reinforce site-specific synaptic modifications to consolidate memory traces. Such a synaptic reinforcement process may also serve as a cellular means by which the new memory is transferred from the hippocampus to the cortex for permanent storage.

  14. The effect of the NMDA receptor blocker, dextromethorphan, on cribbing in horses.

    PubMed

    Rendon, R A; Shuster, L; Dodman, N H

    2001-01-01

    Stereotypic cribbing in horses is thought to involve excess dopaminergic activity within the striatum. Various models of stress-induced stereotypies including cribbing in horses postulate that stress stimulates the release of endorphins, triggering the release of striatal dopamine. Dopamine in turn activates basal ganglia motor programs, reinforcing behavior via a reward mechanism. Furthermore, the release of dopamine by endorphins has been shown to depend on activation of NMDA receptors. In the present study, horses identified as cribbers and volunteered by their owners were treated with the NMDA receptor antagonist dextromethorphan (DM). When DM was administered via jugular injection (1 mg/kg), eight of nine horses responded with reductions in cribbing rate (CR) compared to baseline, and cribbing was suppressed completely for a period of time in almost half of the horses tested. PMID:11274707

  15. Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model.

    PubMed

    Heusler, Peter; Tourette, Amélie; Cussac, Didier

    2015-05-01

    N-methyl-D-aspartate (NMDA) receptor channels are implicated in a wide range of physiological and pathophysiological processes, and a large number of pharmacological agents have been introduced that target the receptor via diverse mechanisms of action. Amongst others, subunit selectivity (in particular for the NR2B receptor subunit) and rapid unblocking kinetics have been put forward as favourable pharmacological properties of NMDA receptor-targeting drugs. Here, we describe a pharmacological characterization of human recombinant NMDA receptors expressed in Xenopus oocytes in an electrophysiological set-up. Using this approach, we compare inhibitor potencies of several known NMDA receptor ligands as well as unblocking kinetic properties of selected compounds. All compounds tested had similar potencies at receptors containing NR2A or NR2B receptors with the exception of traxoprodil, which was selective for NR2B. The rank order of potency was (+)MK-801 > phencyclidine (PCP) ≈ traxoprodil > memantine ≈ ketamine > duloxetine. In line with its proposed rapid dissociation properties, the relatively well-tolerated drug memantine exhibits markedly faster unblocking than ketamine and PCP, similar to the low-affinity compound, duloxetine. Electrophysiological recording in Xenopus oocytes thus allows a relatively convenient comparison of key pharmacological parameters at recombinant human NMDA receptors. PMID:25604077

  16. NMDA Receptor-Mediated Activation of NADPH Oxidase and Glomerulosclerosis in Hyperhomocysteinemic Rats

    PubMed Central

    Zhang, Chun; Yi, Fan; Xia, Min; Boini, Krishna M.; Zhu, Qing; Laperle, Laura A.; Abais, Justine M.; Brimson, Christopher A.

    2010-01-01

    Abstract This study investigated the role of NMDA receptor in hyperhomocyteinemia (hHcys)-induced NADPH oxidase (Nox) activation and glomerulosclerosis. Sprague–Dawley rats were fed a folate-free (FF) diet to produce hHcys, and a NMDA receptor antagonist, MK-801, was administrated. Rats fed the FF diet exhibited significantly increased plasma homocysteine levels, upregulated NMDA receptor expression, enhanced Nox activity and Nox-dependent O2.− production in the glomeruli, which were accompanied by remarkable glomerulosclerosis. MK-801 treatment significantly inhibited Nox-dependent O2.− production induced by hHcys and reduced glomerular damage index as compared with vehicle-treated hHcys rats. Correspondingly, glomerular deposition of extracellular matrix components in hHcys rats was ameliorated by the administration of MK-801. Additionally, hHcys induced an increase in tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and a decrease in matrix metalloproteinase (MMP)-1 and MMP-9 activities, all of which were abolished by MK-801 treatment. In vitro studies showed that homocysteine increased Nox-dependent O2.− generation in rat mesangial cells, which was blocked by MK-801. Pretreatment with MK-801 also reversed homocysteine-induced decrease in MMP-1 activity and increase in TIMP-1 expression. These results support the view that the NMDA receptor may mediate Nox activation in the kidney during hHcys and thereby play a critical role in the development of hHcys-induced glomerulosclerosis. Antioxid. Redox Signal. 13, 975–986. PMID:20406136

  17. Mobility of NMDA autoreceptors but not postsynaptic receptors at glutamate synapses in the rat entorhinal cortex

    PubMed Central

    Yang, Jian; Chamberlain, Sophie E L; Woodhall, Gavin L; Jones, Roland S G

    2008-01-01

    NMDA receptors (NMDAr) are known to undergo recycling and lateral diffusion in postsynaptic spines and dendrites. However, NMDAr are also present as autoreceptors on glutamate terminals, where they act to facilitate glutamate release, but it is not known whether these receptors are also mobile. We have used functional pharmacological approaches to examine whether NMDA receptors at excitatory synapses in the rat entorhinal cortex are mobile at either postsynaptic sites or in presynaptic terminals. When NMDAr-mediated evoked EPSCs (eEPSCs) were blocked by MK-801, they showed no evidence of recovery when the irreversible blocker was removed, suggesting that postsynaptic NMDAr were relatively stably anchored at these synapses. However, using frequency-dependent facilitation of AMPA receptor (AMPAr)-mediated eEPSCs as a reporter of presynaptic NMDAr activity, we found that when facilitation was blocked with MK-801 there was a rapid (∼30–40 min) anomalous recovery upon removal of the antagonist. This was not observed when global NMDAr blockade was induced by combined perfusion with MK-801 and NMDA. Anomalous recovery was accompanied by an increase in frequency of spontaneous EPSCs, and a variable increase in frequency-facilitation. Following recovery from blockade of presynaptic NMDAr with a competitive antagonist, frequency-dependent facilitation of AMPAr-mediated eEPSCs was also transiently enhanced. Finally, an increase in frequency of miniature EPSCs induced by NMDA was succeeded by a persistent decrease. Our data provide the first evidence for mobility of NMDAr in the presynaptic terminals, and may point to a role of this process in activity-dependent control of glutamate release. PMID:18718983

  18. Benzimidazole-2-carboxamides as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, István; Kolok, Sándor; Gere, Anikó; Nagy, József; Fodor, László; Galgóczy, Kornél; Fetter, József; Bertha, Ferenc; Agai, Béla; Horváth, Csilla; Farkas, Sándor; Domány, György

    2006-09-01

    A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration. PMID:16782335

  19. The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity

    PubMed Central

    Driesen, Naomi R; McCarthy, Gregory; Bhagwagar, Zubin; Bloch, Michael H; Calhoun, Vincent D; D'Souza, Deepak C; Gueorguieva, Ralitza; He, George; Leung, Hoi-Chung; Ramani, Ramachandran; Anticevic, Alan; Suckow, Raymond F; Morgan, Peter T; Krystal, John H

    2013-01-01

    Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments. PMID:23856634

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

    PubMed Central

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

    2015-01-01

    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. PMID:26032883

  1. Opposite effects of GABAA and NMDA receptor antagonists on ethanol-induced behavioral sleep in rats.

    PubMed

    Beleslin, D B; Djokanović, N; Jovanović Mićić, D; Samardzić, R

    1997-01-01

    The effects of the GABAA receptor antagonists, pentylenetetrazol, bicuculline, and picrotoxin, the glycine antagonist, strychnine, and the NMDA receptor antagonist, memantine, on ethanol-induced behavioral sleep and body temperature were investigated. Pentylenetetrazol, bicuculline, and picrotoxin given prior and following ethanol reduced the behavioral sleep and potentiated the hypothermia caused by ethanol. However, convulsions appeared when bicuculline, but not pentylenetetrazol and picrotoxin, were given following ethanol. After the reversal of unconsciousness in rats without convulsions the animals remained awake throughout the experiments without motor incoordination, hyperexcitability, and sedation, but they were in hypothermia within 12 h. The glycine antagonist, strychnine, given prior or after ethanol had virtually no effect on ethanol-induced behavioral sleep and hypothermia. Ethanol given prior or following strychnine failed to antagonize strychnine-induced convulsions. The NMDA receptor antagonist, memantine, given following ethanol potentiated the behavioral sleep and had virtually no effect on hypothermia induced by ethanol. It is suggested that the ethanol-induced behavioral sleep may be attributed to its ability to enhance the GABAergic mechanisms and to inhibit NMDA-mediated excitatory responses. However, the ethanol-induced hypothermia may be ascribed solely to the facilitation of GABAergic transmission. Further, it is postulated that a bidirectional inhibitory system subserves the regulation of behavioral sleep and convulsions. However, one-way inhibitory system underlies the ethanol-induced hypothermia. PMID:9085718

  2. A randomized placebo-controlled trial of an NMDA receptor antagonist in sleep-disordered breathing.

    PubMed

    Torvaldsson, Stefan; Grote, Ludger; Peker, Yüksel; Basun, Hans; Hedner, Jan

    2005-06-01

    Hypoxemia is a powerful stimulus of glutamate release in the central nervous system (CNS) and a hallmark phenomenon in sleep disordered breathing (SDB). Glutamate effects that include neuronal damage and apoptosis following hypoxemia and apnea following microinjections in animal models are in part mediated via postjunctional N-methyl-D-aspartate (NMDA) receptors. This was a double blind, randomized, placebo-controlled single dose cross-over study of the NMDA receptor antagonist AR-R15896AR in 15 male patients with moderate to severe SDB. Seven patients received 120 mg and eight patients received 350 mg AR-R15896AR or corresponding placebo (given by 2 h infusion) starting half an hour before estimated sleep onset. AR-R15896AR concentrations were in line with the predicting kinetic model. A standard polysomnographic montage was applied. Repeated plasma samples were obtained in nine patients for analysis of plasma glutamate. Glutamate concentration in plasma did not change overnight and was unrelated to severity of SDB. Overall AHI (apnea-hypopnea index; primary efficacy variable) or investigated oxygen saturation variables were not significantly changed after AR-R15896AR at either dosage level. Side effects were mostly confined to the higher dose level and included vivid dreams, nightmares as well as in two cases mild hallucinations. The previously postulated role of glutamate in SDB could not be confirmed after AR-R15896AR induced NMDA-receptor blockade. PMID:15910512

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

    PubMed

    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. PMID:26072736

  4. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines.

    PubMed

    Tolias, Kimberley F; Bikoff, Jay B; Burette, Alain; Paradis, Suzanne; Harrar, Dana; Tavazoie, Sohail; Weinberg, Richard J; Greenberg, Michael E

    2005-02-17

    NMDA-type glutamate receptors play a critical role in the activity-dependent development and structural remodeling of dendritic arbors and spines. However, the molecular mechanisms that link NMDA receptor activation to changes in dendritic morphology remain unclear. We report that the Rac1-GEF Tiam1 is present in dendrites and spines and is required for their development. Tiam1 interacts with the NMDA receptor and is phosphorylated in a calcium-dependent manner in response to NMDA receptor stimulation. Blockade of Tiam1 function with RNAi and dominant interfering mutants of Tiam1 suggests that Tiam1 mediates effects of the NMDA receptor on dendritic development by inducing Rac1-dependent actin remodeling and protein synthesis. Taken together, these findings define a molecular mechanism by which NMDA receptor signaling controls the growth and morphology of dendritic arbors and spines. PMID:15721239

  5. NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice.

    PubMed

    Amiri, Shayan; Alijanpour, Sakineh; Tirgar, Fatemeh; Haj-Mirzaian, Arya; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Rastegar, Mojgan; Ghaderi, Marzieh; Ghazi-Khansari, Mahmoud; Zarrindast, Mohammad-Reza

    2016-08-01

    Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors. PMID:27167081

  6. PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating

    PubMed Central

    Lin, Ying; Jover-Mengual, Teresa; Wong, Judy; Bennett, Michael V. L.; Zukin, R. Suzanne

    2006-01-01

    Neuronal NMDA receptors (NMDARs) colocalize with postsynaptic density protein-95 (PSD-95), a putative NMDAR anchoring protein and core component of the PSD, at excitatory synapses. PKC activation and PSD-95 expression each enhance NMDAR channel opening rate and number of functional channels at the cell surface. Here we show in Xenopus oocytes that PSD-95 and PKC potentiate NMDA gating and trafficking in a nonadditive manner. PSD-95 and PKC each enhance NMDA channel activity, with no change in single-channel conductance, reversal potential or mean open time. PSD-95 and PKC each potentiate NMDA channel opening rate (kβ) and number of functional channels at the cell surface (N), as indicated by more rapid current decay and enhanced charge transfer in the presence of the open channel blocker MK-801. PSD-95 and PKC each increase NMDAR surface expression, as indicated by immunofluorescence. PKC potentiates NMDA channel function and NMDAR surface expression to the same final absolute values in the absence or presence of PSD-95. Thus, PSD-95 partially occludes PKC potentiation. We further show that Ser-1462, a putative phosphorylation target within the PDZ-binding motif of the NR2A subunit, is required for PSD-95-induced potentiation and partial occlusion of PKC potentiation. Coimmunoprecipitation experiments with cortical neurons in culture indicate that PKC activation promotes assembly of NR2 with NR1, and that the newly assembled NMDARs are not associated with PSD-95. These findings predict that synaptic scaffolding proteins and protein kinases convergently modulate NMDAR gating and trafficking at synaptic sites. PMID:17179037

  7. NMDA Receptor Agonism and Antagonism within the Amygdaloid Central Nucleus Suppresses Pain Affect: Differential Contribution of the Ventrolateral Periaqueductal Gray

    PubMed Central

    Spuz, Catherine A.; Tomaszycki, Michelle L.; Borszcz, George S.

    2015-01-01

    The amygdala contributes to the generation of pain affect and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study compared the contribution of N-methyl-D-aspartate (NMDA) receptor agonism and antagonism in CeA to generation of the affective response of rats to an acute noxious stimulus. Vocalizations that occur following a brief tail shock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed, in a dose dependent manner, by bilateral injection into CeA of NMDA (.1 µg, .25 µg, .5 µg, or 1 µg/side), or the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5, 1 µg, 2 µg, or 4 µg/side). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas, spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of NMDA or AP5 into CeA. Injection of NMDA, but not AP5, into CeA increased c-Fos immunoreactivity in the ventrolateral periaqueductal gray (vlPAG), and unilateral injection of the µ-opiate receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP, 0.25 µg) into vlPAG prevented the antinociception generated by injection of NMDA into CeA. These findings demonstrate that although NMDA receptor agonism and antagonism in CeA produce similar suppression of pain behaviors they do so via different neurobiological mechanisms. Perspective The amygdala contributes to production of the emotional dimension of pain. NMDA receptor agonism and antagonism within the central nucleus of the amygdala suppressed rats’ emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders. PMID:25261341

  8. Cholinergic, but not NMDA, receptors in the lateral entorhinal cortex mediate acquisition in trace eyeblink conditioning.

    PubMed

    Tanninen, Stephanie E; Yu, XiaoTian; Giritharan, Thamy; Tran, Lina; Bakir, Rami; Volle, Julien; Morrissey, Mark D; Takehara-Nishiuchi, Kaori

    2015-11-01

    Anatomical and electrophysiological studies collectively suggest that the entorhinal cortex consists of several subregions, each of which is involved in the processing of different types of information. Consistent with this idea, we previously reported that the dorsolateral portion of the entorhinal cortex (DLE), but not the caudomedial portion, is necessary for the expression of a memory association between temporally discontiguous stimuli in trace eyeblink conditioning (Morrissey et al. (2012) J Neurosci 32:5356-5361). The present study examined whether memory acquisition depends on the DLE and what types of local neurotransmitter mechanisms are involved in memory acquisition and expression. Male Long-Evans rats experienced trace eyeblink conditioning, in which an auditory conditioned stimulus (CS) was paired with a mildly aversive electric shock to the eyelid (US) with a stimulus-free interval of 500 ms. Immediately before the conditioning, the rats received a microinfusion of neuroreactive substances into the DLE. We found that reversible inactivation of the DLE with GABAA receptor agonist, muscimol impaired memory acquisition. Furthermore, blockade of local muscarinic acetylcholine receptors (mACh) with scopolamine retarded memory acquisition while blockade of local NMDA receptors with APV had no effect. Memory expression was not impaired by either type of receptor blocker. These results suggest that the DLE is necessary for memory acquisition, and that acquisition depends on the integrity of local mACh receptor-dependent firing modulation, but not NMDA receptor-dependent synaptic plasticity. PMID:25865030

  9. A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling

    PubMed Central

    Vullhorst, Detlef; Mitchell, Robert M.; Keating, Carolyn; Roychowdhury, Swagata; Karavanova, Irina; Tao-Cheng, Jung-Hwa; Buonanno, Andres

    2015-01-01

    The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders. PMID:26027736

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

    PubMed

    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. Presynaptic NMDA receptors – dynamics and distribution in developing axons in vitro and in vivo

    PubMed Central

    Gill, Ishwar; Droubi, Sammy; Giovedi, Silvia; Fedder, Karlie N.; Bury, Luke A. D.; Bosco, Federica; Sceniak, Michael P.; Benfenati, Fabio; Sabo, Shasta L.

    2015-01-01

    ABSTRACT During cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the sub-synaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons – including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development. PMID:25526735

  12. Glossopharyngeal long-term facilitation requires serotonin 5-HT2 and NMDA receptors in rats

    PubMed Central

    Cao, Ying; Liu, Chun; Ling, Liming

    2009-01-01

    Although the glossopharyngeal nerve (IX) is mainly a sensory nerve, it innervates stylopharyngeus and some other pharyngeal muscles, whose excitations would likely improve upper airway patency since electrical IX stimulation increases pharyngeal airway size. As acute intermittent hypoxia (AIH) induces hypoglossal and genioglossal long-term facilitation (LTF), we hypothesized that AIH induces glossopharyngeal LTF, which requires serotonin 5-HT2 and NMDA receptors. Integrated IX activity was recorded in anesthetized, vagotomized, paralyzed and ventilated rats before, during and after 5 episodes of 3-min isocapnic 12% O2 with 3-min intervals of 50% O2. Either saline, ketanserin (5-HT2 antagonist, 2 mg/kg) or MK-801 (NMDA antagonist, 0.2 mg/kg) was (i.v.) injected 30–60 min before AIH. Both phasic and tonic IX activities were persistently increased (both P<0.05) after AIH in vehicle, but not ketanserin or MK-801, rats. Hypoxic glossopharyngeal responses were minimally changed after either drug. These data suggest that AIH induces both phasic and tonic glossopharyngeal LTF, which requires activation of 5-HT2 and NMDA receptors. PMID:20026287

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

    PubMed

    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. PMID:25662715

  14. Effects of blockade of NMDA receptors on cerebral oxygen consumption during hyperosmolar BBB disruption in rats.

    PubMed

    Chi, Oak Z; Barsoum, Sylviana; Grayson, Jeremy; Hunter, Christine; Liu, Xia; Weiss, Harvey R

    2013-03-15

    Hyperosmolar blood-brain barrier (BBB) disruption has been reported to increase cerebral O2 consumption. This study was performed to test whether blockade of N-methyl-d-aspartate (NMDA) receptor would affect cerebral O2 consumption during hyperosmolar BBB disruption. A competitive NMDA receptor antagonist CGS-19755 10mg/kg was injected iv 15min before intracarotid infusion of 25% mannitol. Twelve min after BBB disruption, the BBB transfer coefficient (Ki) of (14)C-α-aminoisobutyric acid ((14)C-AIB) was measured. Regional cerebral blood flow (rCBF), regional arteriolar and venular O2 saturation (SaO2 and SvO2 respectively), and O2 consumption were determined using (14)C-iodoantipyrine autoradiography and cryomicrospectrophotometry in alternate slices of the brain tissue. The Ki of (14)C-AIB was markedly increased with hyperosmolar mannitol in both the control (5.8×) and the CGS treated rats (5.2×). With BBB disruption, the O2 consumption was significantly increased (+39%) only in the control but not in the CGS treated rats and was significantly lower (-29%) in the CGS treated than the control rats. The distribution of SvO2 was significantly shifted to the higher concentrations with CGS treatment. Our data demonstrated an increase of O2 consumption by hyperosmolar BBB disruption and attenuation of the increase with NMDA blockade without affecting the degree of BBB disruption. PMID:23357315

  15. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis.

    PubMed

    Macrez, Richard; Ortega, Maria C; Bardou, Isabelle; Mehra, Anupriya; Fournier, Antoine; Van der Pol, Susanne M A; Haelewyn, Benoit; Maubert, Eric; Lesept, Flavie; Chevilley, Arnaud; de Castro, Fernando; De Vries, Helga E; Vivien, Denis; Clemente, Diego; Docagne, Fabian

    2016-09-01

    Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor. PMID:27435092

  16. Cisplatin induces neuronal activation and increases central AMPA and NMDA receptor subunit gene expression in mice.

    PubMed

    Holland, Ruby A; Leonard, John J; Kensey, Nicholas A; Hannikainen, Paavali A; De Jonghe, Bart C

    2014-09-01

    Although rats and mice do not vomit, these species are widely studied as models of energy balance and sickness behavior. Previous work has shown that rats exhibit similar neuroanatomical activation of brain and visceral afferent pathways following cisplatin chemotherapy compared to vomiting species. However, the neural response to cisplatin in mice is understudied. Here, food intake, body weight, and central c-Fos immunofluorescence were analyzed in the hindbrains of male C57BL/6 mice following IP saline or cisplatin (5mg/kg, and 20mg/kg doses). As glutamate receptor signaling is classically linked to inhibitory feeding pathways in the rodent, gene expression of selected α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor subunits were assessed in the dorsal vagal complex (DVC), parabrachial nucleus (PBN), amygdala, and bed nucleus of the stria terminalis (BNST). Our results show dose-dependent reductions in food intake and body weight following cisplatin treatment, as well as increases in cisplatin-induced c-Fos in the PBN and throughout the DVC. Quantitative PCR analysis shows cisplatin-induced increases in NMDA receptor subunit expression, particularly NR2B, in the DVC, PBN, BNST, and amygdala. In addition, upregulation of AMPA receptor subunits (GluA1 and/or GluA2) were observed in all regions examined except the amygdala. Taken together, these results suggest similar neural pathways mediating cisplatin effects in mice compared to other well-studied species, which are likely mediated by central upregulation of AMPA and NMDA receptors. PMID:24582677

  17. Silent NMDA receptor-mediated synapses are developmentally regulated in the dorsal horn of the rat spinal cord.

    PubMed

    Baba, H; Doubell, T P; Moore, K A; Woolf, C J

    2000-02-01

    In vitro whole cell patch-clamp recording techniques were utilized to study silent pure-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic responses in lamina II (substantia gelatinosa, SG) and lamina III of the spinal dorsal horn. To clarify whether these synapses are present in the adult and contribute to neuropathic pain, transverse lumbar spinal cord slices were prepared from neonatal, naive adult and adult sciatic nerve transected rats. In neonatal rats, pure-NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) were elicited in SG neurons either by focal intraspinal stimulation (n = 15 of 20 neurons) or focal stimulation of the dorsal root (n = 2 of 7 neurons). In contrast, in slices from naive adult rats, no silent pure-NMDA EPSCs were recorded in SG neurons following focal intraspinal stimulation (n = 27), and only one pure-NMDA EPSC was observed in lamina III (n = 23). Furthermore, in rats with chronic sciatic nerve transection, pure-NMDA EPSCs were elicited by focal intraspinal stimulation in only 2 of 45 SG neurons. Although a large increase in Abeta fiber evoked mixed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptor-mediated synapses was detected after sciatic nerve injury, Abeta fiber-mediated pure-NMDA EPSCs were not evoked in SG neurons by dorsal root stimulation. Pure-NMDA receptor-mediated EPSCs are therefore a transient, developmentally regulated phenomenon, and, although they may have a role in synaptic refinement in the immature dorsal horn, they are unlikely to be involved in receptive field plasticity in the adult. PMID:10669507

  18. Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

    PubMed Central

    Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

    2012-01-01

    N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896

  19. Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

    SciTech Connect

    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.

  20. Physiological Roles of Non-Neuronal NMDA Receptors.

    PubMed

    Hogan-Cann, Adam D; Anderson, Christopher M

    2016-09-01

    Glutamate serves as the dominant central nervous system (CNS) excitatory neurotransmitter, in part by activating N-methyl-D-aspartate receptors (NMDARs). While the structure, function, and distribution of neuronal NMDARs have been extensively elucidated, NMDARs are also expressed across a wide spectrum of non-neuronal cells, including central and peripheral glial cells, endothelium, kidney, bone, pancreas, and others. These receptors are poorly understood compared to neuronal receptors, but there is a developing consensus that they have distinct structural and functional properties when activated by glutamate, NMDAR co-agonists, and in some cases by metabolites of tryptophan and methionine. It is also clear that non-neuronal NMDARs may participate in an array of physiological and pathophysiological processes, including but not limited to bone deposition, wound healing, insulin secretion, blood-brain barrier integrity, and myelination. These developing lines of evidence are stimulating exploration of non-neuronal NMDARs as a therapeutic target in several disorders. PMID:27338838

  1. Functional NMDA receptors are expressed by both AII and A17 amacrine cells in the rod pathway of the mammalian retina.

    PubMed

    Zhou, Yifan; Tencerová, Barbora; Hartveit, Espen; Veruki, Margaret L

    2016-01-01

    At many glutamatergic synapses, non-N-methyl-d-aspartate (NMDA) and NMDA receptors are coexpressed postsynaptically. In the mammalian retina, glutamatergic rod bipolar cells are presynaptic to two rod amacrine cells (AII and A17) that constitute dyad postsynaptic partners opposite each presynaptic active zone. Whereas there is strong evidence for expression of non-NMDA receptors by both AII and A17 amacrines, the expression of NMDA receptors by the pre- and postsynaptic neurons in this microcircuit has not been resolved. In this study, using patch-clamp recording from visually identified cells in rat retinal slices, we investigated the expression and functional properties of NMDA receptors in these cells with a combination of pharmacological and biophysical methods. Pressure application of NMDA did not evoke a response in rod bipolar cells, but for both AII and A17 amacrines, NMDA evoked responses that were blocked by a competitive antagonist (CPP) applied extracellularly and an open channel blocker (MK-801) applied intracellularly. NMDA-evoked responses also displayed strong Mg(2+)-dependent voltage block and were independent of gap junction coupling. With low-frequency application (60-s intervals), NMDA-evoked responses remained stable for up to 50 min, but with higher-frequency stimulation (10- to 20-s intervals), NMDA responses were strongly and reversibly suppressed. We observed strong potentiation when NMDA was applied in nominally Ca(2+)-free extracellular solution, potentially reflecting Ca(2+)-dependent NMDA receptor inactivation. These results indicate that expression of functional (i.e., conductance-increasing) NMDA receptors is common to both AII and A17 amacrine cells and suggest that these receptors could play an important role for synaptic signaling, integration, or plasticity in the rod pathway. PMID:26561610

  2. The Role of Hippocampal NMDA Receptors in Long-Term Emotional Responses following Muscarinic Receptor Activation

    PubMed Central

    Hoeller, Alexandre A.; Costa, Ana Paula R.; Bicca, Maíra A.; Matheus, Filipe C.; Lach, Gilliard; Spiga, Francesca; Lightman, Stafford L.; Walz, Roger; Collingridge, Graham L.; Bortolotto, Zuner A.; de Lima, Thereza C. M.

    2016-01-01

    Extensive evidence indicates the influence of the cholinergic system on emotional processing. Previous findings provided new insights into the underlying mechanisms of long-term anxiety, showing that rats injected with a single systemic dose of pilocarpine—a muscarinic receptor (mAChR) agonist—displayed persistent anxiogenic-like responses when evaluated in different behavioral tests and time-points (24 h up to 3 months later). Herein, we investigated whether the pilocarpine-induced long-term anxiogenesis modulates the HPA axis function and the putative involvement of NMDA receptors (NMDARs) following mAChRs activation. Accordingly, adult male Wistar rats presented anxiogenic-like behavior in the elevated plus-maze (EPM) after 24 h or 1 month of pilocarpine injection (150 mg/kg, i.p.). In these animals, mAChR activation disrupted HPA axis function inducing a long-term increase of corticosterone release associated with a reduced expression of hippocampal GRs, as well as consistently decreased NMDAR subunits expression. Furthermore, in another group of rats injected with memantine–an NMDARs antagonist (4 mg/kg, i.p.)–prior to pilocarpine, we found inhibition of anxiogenic-like behaviors in the EPM but no further alterations in the pilocarpine-induced NMDARs downregulation. Our data provide evidence that behavioral anxiogenesis induced by mAChR activation effectively yields short- and long-term alterations in hippocampal NMDARs expression associated with impairment of hippocampal inhibitory regulation of HPA axis activity. This is a novel mechanism associated with anxiety-like responses in rats, which comprise a putative target to future translational studies. PMID:26795565

  3. Time and space profiling of NMDA receptor co-agonist functions.

    PubMed

    Mothet, Jean-Pierre; Le Bail, Matildé; Billard, Jean-Marie

    2015-10-01

    The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization, and biophysical and pharmacological properties, their activation always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last decade has challenged this classical model by showing that another amino acid, d-serine, is the preferential co-agonist for a subset of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and d-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. The purpose of this review was to highlight the particular role of each co-agonist in modulating NMDAR-dependent activities in healthy and diseased brains. We have herein integrated our most advanced knowledge of how glycine and d-serine may orchestrate synapse dynamics and drive neuronal network activity in a time- and synapse-specific manner and how changes in synaptic availability of these amino acids may contribute to cognitive impairments such as those associated with healthy aging, epilepsy, and schizophrenia. The N-Methyl D-Aspartic acid (NMDA) subtype of glutamate receptors are central to many physiological functions and are linked to brain disorders. Their functions require glutamate and a co-agonist d-serine or glycine. After years of intense research and controversy on the identity of the amino acid that serves as the right co-agonist, we are just entering a new era of consensus where glycine and d-serine are teaming up to regulate the function of different subsets of NMDA receptors and at different synapses during different time windows of brain development. PMID:26088787

  4. Involvement of hippocampal NMDA receptors in retrieval of spontaneous object recognition memory in rats.

    PubMed

    Iwamura, Etsushi; Yamada, Kazuo; Ichitani, Yukio

    2016-07-01

    The involvement of hippocampal N-methyl-d-aspartate (NMDA) receptors in the retrieval process of spontaneous object recognition memory was investigated. The spontaneous object recognition test consisted of three phases. In the sample phase, rats were exposed to two identical objects several (2-5) times in the arena. After the sample phase, various lengths of delay intervals (24h-6 weeks) were inserted (delay phase). In the test phase in which both the familiar and the novel objects were placed in the arena, rats' novel object exploration behavior under the hippocampal treatment of NMDA receptor antagonist, AP5, or vehicle was observed. With 5 exposure sessions in the sample phase (experiment 1), AP5 treatment in the test phase significantly decreased discrimination ratio when the delay was 3 weeks but not when it was one week. On the other hand, with 2 exposure sessions in the sample phase (experiment 2) in which even vehicle-injected control animals could not discriminate the novel object from the familiar one with a 3 week delay, AP5 treatment significantly decreased discrimination ratio when the delay was one week, but not when it was 24h. Additional experiment (experiment 3) showed that the hippocampal treatment of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, NBQX, decreased discrimination ratio with all delay intervals tested (24h-3 weeks). Results suggest that hippocampal NMDA receptors play an important role in the retrieval of spontaneous object recognition memory especially when the memory trace weakens. PMID:27036649

  5. GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo.

    PubMed

    Hu, Neng-Wei; Klyubin, Igor; Anwyl, Roger; Anwy, Roger; Rowan, Michael J

    2009-12-01

    Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease. PMID:19918059

  6. Metabotropic glutamate receptor 5, but not 1, modulates NMDA receptor-mediated activation of neuronal nitric oxide synthase.

    PubMed

    Llansola, Marta; Felipo, Vicente

    2010-03-01

    In cerebellar neurons in culture, activation of group I metabotropic glutamate receptors (mGluRs) prevents glutamate and NMDA-induced neuronal death, indicating that it interferes with the excitotoxic mechanisms leading to death. However, it is not known which step of these mechanisms is affected by mGluRs. The aims of this work were to assess: (a) whether activation of group I mGluRs (mGluR1 or mGluR5) impairs NMDA-induced activation of the glutamate-nitric oxide-cGMP pathway; (b) which mGluR (1 or 5) is responsible for this impairment and (c) whether impairment of the pathway occurs at the level of activation of soluble guanylate cyclase by nitric oxide or of activation of neuronal nitric oxide synthase (nNOS) by NMDA. It is shown that activation of mGluR1 enhances the function of the glutamate-nitric oxide-cGMP pathway by increasing activation of soluble guanylate cyclase by nitric oxide. In contrast, mGluR5 activation inhibits the glutamate-nitric oxide-cGMP pathway by reducing NMDA-induced activation of nNOS. This is due to reduced NMDA-induced increase in cAMP, reduced activation of Akt by cAMP and of nNOS by Akt. The impairment of activation of the glutamate-NO-cGMP pathway by activation of mGluR5 would contribute to its neuroprotective effect against excitotoxicity in cerebellar neurons in culture. PMID:20043967

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

    PubMed Central

    Robinson, Samuel D.; Lee, Tet Woo; Christie, David L.; Birch, Nigel P.

    2015-01-01

    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-aminopyridine (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 receptor-associated protein (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. PMID:26500501

  8. Sexually dimorphic development and binding characteristics of NMDA receptors in the brain of the platyfish

    NASA Technical Reports Server (NTRS)

    Flynn, K. M.; Schreibman, M. P.; Yablonsky-Alter, E.; Banerjee, S. P.

    1999-01-01

    This study investigated age- and gender-specific variations in properties of the glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)-R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that the number of cells in the NOR displaying ir-R1 is significantly increased in pubescent and mature female platyfish when compared to immature and senescent animals. In males, there is no significant change in ir-R1 expression in the NOR at any time in their lifespan. The affinity of the noncompetitive antagonist ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in mature females. In males, both MK-801 affinity and maximum binding remain unchanged throughout development. This is the first report of gender differences in the association of NMDA receptors with neuroendocrine brain areas during development. It is also the first report to suggest NMDA receptor involvement in the development of the BPG axis in a nonmammalian vertebrate. Copyright 1999 Academic Press.

  9. Modulation of the NMDA Receptor Through Secreted Soluble Factors.

    PubMed

    Cerpa, Waldo; Ramos-Fernández, Eva; Inestrosa, Nibaldo C

    2016-01-01

    Synaptic activity is a critical determinant in the formation and development of excitatory synapses in the central nervous system (CNS). The excitatory current is produced and regulated by several ionotropic receptors, including those that respond to glutamate. These channels are in turn regulated through several secreted factors that function as synaptic organizers. Specifically, Wnt, brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), and transforming growth factor (TGF) particularly regulate the N-methyl-D-aspartate receptor (NMDAR) glutamatergic channel. These factors likely regulate early embryonic development and directly control key proteins in the function of important glutamatergic channels. Here, we review the secreted molecules that participate in synaptic organization and discuss the cell signaling behind of this fine regulation. Additionally, we discuss how these factors are dysregulated in some neuropathologies associated with glutamatergic synaptic transmission in the CNS. PMID:25429903

  10. Antipsychotic treatment modulates glutamate transport and NMDA receptor expression.

    PubMed

    Zink, Mathias; Englisch, Susanne; Schmitt, Andrea

    2014-11-01

    Schizophrenia patients often suffer from treatment-resistant cognitive and negative symptoms, both of which are influenced by glutamate neurotransmission. Innovative therapeutic strategies such as agonists at metabotropic glutamate receptors or glycin reuptake inhibitors try to modulate the brain's glutamate network. Interactions of amino acids with monoamines have been described on several levels, and first- and second-generation antipsychotic agents (FGAs, SGAs) are known to exert modulatory effects on the glutamatergic system. This review summarizes the current knowledge on effects of FGAs and SGAs on glutamate transport and receptor expression derived from pharmacological studies. Such studies serve as a control for molecular findings in schizophrenia brain tissue and are clinically relevant. Moreover, they may validate animal models for psychosis, foster basic research on antipsychotic substances and finally lead to a better understanding of how monoaminergic and amino acid neurotransmissions are intertwined. In the light of these results, important differences dependent on antipsychotic substances, dosage and duration of treatment became obvious. While some post-mortem findings might be confounded with multifold drug effects, others are unlikely to be influenced by antipsychotic treatment and could represent important markers of schizophrenia pathophysiology. In similarity to the convergence of toxic and psychotomimetic effects of dopaminergic, serotonergic and anti-glutamatergic substances, the therapeutic mechanisms of SGAs might merge on a yet to be defined molecular level. In particular, serotonergic effects of SGAs, such as an agonism at 5HT1A receptors, represent important targets for further clinical research. PMID:25214389

  11. SNAP-25 Is a Target of Protein Kinase C Phosphorylation Critical to NMDA Receptor Trafficking

    PubMed Central

    Lau, C. Geoffrey; Takayasu, Yukihiro; Rodenas-Ruano, Alma; Paternain, Ana V.; Lerma, Juan; Bennett, Michael V. L.

    2010-01-01

    Protein kinase C (PKC) enhances NMDA receptor (NMDAR)-mediated currents and promotes NMDAR delivery to the cell surface via SNARE-dependent exocytosis. Although the mechanisms of PKC potentiation are established, the molecular target of PKC is unclear. Here we show that synaptosomal-associated protein of 25 kDa (SNAP-25), a SNARE protein, is functionally relevant to PKC-dependent NMDAR insertion, and identify serine residue-187 as the molecular target of PKC phosphorylation. Constitutively active PKC delivered via the patch pipette potentiated NMDA (but not AMPA) whole-cell currents in hippocampal neurons. Expression of RNAi targeting SNAP-25 or mutant SNAP-25(S187A) and/or acute disruption of the SNARE complex by treatment with BoNT A, BoNT B or SNAP-25 C-terminal blocking peptide abolished NMDAR potentiation. A SNAP-25 peptide and function-blocking antibody suppressed PKC potentiation of NMDA EPSCs at mossy fiber-CA3 synapses. These findings identify SNAP-25 as the target of PKC phosphorylation critical to PKC-dependent incorporation of synaptic NMDARs and document a postsynaptic action of this major SNARE protein relevant to synaptic plasticity. PMID:20053906

  12. Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation.

    PubMed

    Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F

    2011-07-01

    Using an antibody against 5α-reduced neurosteroids, predominantly allopregnanolone, we found that immunostaining in the CA1 region of rat hippocampal slices was confined to pyramidal neurons. This neurosteroid staining was increased following 15 min administration of 60 mm but not 20 mm ethanol, and the enhancement was blocked by finasteride and dutasteride, selective inhibitors of 5α-reductase, a key enzyme required for allopregnanolone synthesis. Consistent with a prior report indicating that N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation can promote steroid production, we observed that D-2-amino-5-phosphonovalerate (APV), a competitive NMDAR antagonist, blocked the effects of 60 mm ethanol on staining. We previously reported that 60 mm ethanol inhibits the induction of long-term potentiation (LTP), a cellular model for memory formation, in the CA1 region. In the present study, LTP inhibition by 60 mm ethanol was also overcome by both the 5α-reductase inhibitors and by APV. Furthermore, the effects of ethanol on neurosteroid production and LTP were mimicked by a low concentration of NMDA (1 μm), and the ability of NMDA to inhibit LTP and to enhance neurosteroid staining was reversed by finasteride and dutasteride, as well as by APV. These results indicate that ethanol paradoxically enhances GABAergic neurosteroid production by activation of unblocked NMDARs and that acute LTP inhibition by ethanol represents a form of NMDAR-mediated metaplasticity. PMID:21734282

  13. Frequent rhabdomyolysis in anti-NMDA receptor encephalitis.

    PubMed

    Lim, Jung-Ah; Lee, Soon-Tae; Kim, Tae-Joon; Moon, Jangsup; Sunwoo, Jun-Sang; Byun, Jung-Ick; Jung, Keun-Hwa; Jung, Ki-Young; Chu, Kon; Lee, Sang Kun

    2016-09-15

    The aim of this study was to analyze the clinical presentation and provocation factors of rhabdomyolysis in anti-NMDAR encephalitis. Among the 16 patients with anti-NMDAR encephalitis in our institutional cohort, nine patients had elevated CK enzyme levels and clinical evidence of rhabdomyolysis. Rhabdomyolysis was more frequent after immunotherapy. The use of dopamine receptor blocker (DRB) increased the risk of rhabdomyolysis. None of the patients without rhabdomyolysis received DRBs. Rhabdomyolysis is a frequent complication in anti-NMDAR encephalitis and more common after immunotherapy and the use of DRBs increases the risk. Therefore, DRBs should be administered carefully in patients with anti-NMDAR encephalitis. PMID:27609293

  14. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis.

    PubMed

    Kayser, Matthew S; Dalmau, Josep

    2016-09-01

    Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms - and in particular psychosis - early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in anti-NMDAR encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia. PMID:25458857

  15. Enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses in the barrel cortex of Mecp2-null mice.

    PubMed

    Lo, Fu-Sun; Blue, Mary E; Erzurumlu, Reha S

    2016-03-01

    Rett syndrome (RTT) is a neurodevelopmental disorder that results from mutations in the X-linked gene for methyl-CpG-binding protein 2 (MECP2). The underlying cellular mechanism for the sensory deficits in patients with RTT is largely unknown. This study used the Bird mouse model of RTT to investigate sensory thalamocortical synaptic transmission in the barrel cortex of Mecp2-null mice. Electrophysiological results showed an excitation/inhibition imbalance, biased toward inhibition, due to an increase in efficacy of postsynaptic GABAA receptors rather than alterations in inhibitory network and presynaptic release properties. Enhanced inhibition impaired the transmission of tonic sensory signals from the thalamus to the somatosensory cortex. Previous morphological studies showed an upregulation of NMDA receptors in the neocortex of both RTT patients and Mecp2-null mice at early ages [Blue ME, Naidu S, Johnston MV. Ann Neurol 45: 541-545, 1999; Blue ME, Kaufmann WE, Bressler J, Eyring C, O'Driscoll C, Naidu S, Johnston MV. Anat Rec (Hoboken) 294: 1624-1634, 2011]. Although AMPA and NMDA receptor-mediated excitatory synaptic transmission was not altered in the barrel cortex of Mecp2-null mice, extrasynaptic NMDA receptor-mediated responses increased markedly. These responses were blocked by memantine, suggesting that extrasynaptic NMDA receptors play an important role in the pathogenesis of RTT. The results suggest that enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses may underlie impaired somatosensation and that pharmacological blockade of extrasynaptic NMDA receptors may have therapeutic value for RTT. PMID:26683074

  16. Pregnenolone sulfate and its enantiomer: differential modulation of memory in a spatial discrimination task using forebrain NMDA receptor deficient mice

    PubMed Central

    Petit, Géraldine H.; Tobin, Christine; Krishnan, Kathiresan; Moricard, Yves; Covey, Douglas F.; Rondi-Reig, Laure; Akwa, Yvette

    2010-01-01

    This study examined the role of forebrain N-methyl-D-aspartate receptors (NMDA-Rs) in the promnesiant effects of natural (+) pregnenolone sulfate (PREGS) and its synthetic (−) enantiomer ent-PREGS in young adult mice. Using the two-trial arm discrimination task in a Y-maze, PREGS and ent-PREGS administration to control mice increased memory performances. In mice with a knock-out of the NR1 subunit of NMDA-Rs in the forebrain, the promnesiant effect of ent-PREGS was maintained whereas the activity of PREGS was lost. Memory enhancement by PREGS involves the NMDA-R activity in the hippocampal CA1 area and possibly in some locations of the cortical layers, whereas ent-PREGS acts independently of NMDA-R function. PMID:21036556

  17. A patient with encephalitis associated with NMDA receptor antibodies

    PubMed Central

    Sansing, Lauren H; Tüzün, Erdem; Ko, Melissa W; Baccon, Jennifer; Lynch, David R; Dalmau, Josep

    2007-01-01

    SUMMARY Background A 34-year-old woman presented with headache, feverish sensation and anxiety, rapidly followed by homicidal ideation, aggressive agitation, seizures, hypoventilation, hyperthermia and prominent autonomic instability requiring intubation and sedation. She developed episodes of hypotension and bradycardia with periods of asystole lasting up to 15 seconds. Upon weaning off sedation, her eyes opened but she was unresponsive to stimuli. There was muscle rigidity, frequent facial grimacing, rhythmic abdominal contractions, kicking motions of the legs, and intermittent dystonic postures of the right arm. Investigations Routine laboratory testing, toxicology screening, studies for autoimmune and infectious etiologies, brain MRI scan, lumbar puncture, electroencephalogram, whole-body CT scan, abdominal ultrasound, paraneoplastic and voltage-gated potassium channel antibody serologies, analysis of N-methyl-D-aspartate receptor antibodies. Diagnosis Paraneoplastic encephalitis associated with immature teratoma of the ovary and N-methyl-D-aspartate receptor antibodies. Management Intensive care, mechanical ventilation, antiepileptics, laparotomy and left salpingo-oophorectomy, corticosteroids, plasma exchange, intravenous immunoglobulin, cyclophosphamide, physical therapy, and chemotherapy. PMID:17479076

  18. Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

    PubMed Central

    Yang, Yang; Paspalas, Constantinos D.; Jin, Lu E.; Picciotto, Marina R.; Arnsten, Amy F. T.; Wang, Min

    2013-01-01

    The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510–1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477–485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade of α7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110–1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia. PMID:23818597

  19. Opposite function of dopamine D1 and NMDA receptors in striatal cannabinoid-mediated signaling

    PubMed Central

    Daigle, Tanya L.; Wetsel, William C.; Caron, Marc G.

    2011-01-01

    It is well established that the cannabinoid and dopamine systems interact at various levels to regulate basal ganglia function. While it is well known that acute administration of cannabinoids to mice can modify dopamine-dependent behaviors, an understanding of the intraneuronal signaling pathways employed by these agents in the striatum is not well understood. Here we use knockout (KO) mouse models to examine the regulation of striatal ERK1/2 signaling by behaviorally relevant doses of cannabinoids. This cellular pathway has been implicated as a central mediator of drug reward and synaptic plasticity. In C57BL/6J mice, acute administration of cannabinoid agonists, HU-210 and Δ9-THC, promotes a dose- and time-dependent decrease in the phosphorylation of ERK1/2 in dorsal striatum. Co-administration of the CB1 cannabinoid receptor (CB1R) antagonist AM251 with HU-210 prevents ERK1/2 inactivation, indicating a requirement for activation of this receptor. In dopamine D1 receptor (D1R) KO animals treated with HU-210, the magnitude of the HU-210-dependent decrease in striatal ERK1/2 signaling is greater than in wild-type controls. In contrast, the HU-210 administration to NMDA receptor knockdown mice (NR1-Kd) was ineffective at promoting striatal ERK1/2 inactivation. Genetic deletion of other potential ERK1/2 mediators, the dopamine D2 receptors (D2R)s or βarrestin-1 or -2, did not affect HU-210-induced modulation of ERK1/2 signaling in the striatum. These results support the hypothesis that dopamine D1 receptors and NMDA receptors act in an opposite manner to regulate striatal CB1R signal transduction. PMID:22034973

  20. Chronic alcohol remodels prefrontal neurons and disrupts NMDA receptor-mediated fear extinction encoding

    PubMed Central

    Holmes, Andrew; Fitzgerald, Paul J.; MacPherson, Kathryn P.; DeBrouse, Lauren; Colacicco, Giovanni; Flynn, Shaun M.; Masneuf, Sophie; Pleil, Kristen E.; Li, Chia; Marcinkiewcz, Catherine A.; Kash, Thomas L.; Gunduz-Cinar, Ozge; Camp, Marguerite

    2012-01-01

    Alcoholism is frequently co-morbid with posttraumatic stress disorder (PTSD) but it is unclear how alcohol impacts neural circuits mediating recovery from trauma. We found that chronic intermittent ethanol (CIE) impaired fear extinction and remodeled the dendritic arbor of medial prefrontal cortical (mPFC) neurons in mice. CIE impaired extinction encoding by infralimbic (IL) mPFC neurons in vivo, and functionally downregulated burst-mediating NMDA GluN1 receptors. These findings suggest alcohol may increase risk for trauma-related anxiety disorders by disrupting mPFC-mediated extinction of fear. PMID:22941108

  1. Optical control of NMDA receptors with a diffusible photoswitch.

    PubMed

    Laprell, Laura; Repak, Emilienne; Franckevicius, Vilius; Hartrampf, Felix; Terhag, Jan; Hollmann, Michael; Sumser, Martin; Rebola, Nelson; DiGregorio, David A; Trauner, Dirk

    2015-01-01

    N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory, and are implicated in various neuronal disorders. We synthesized a diffusible photochromic glutamate analogue, azobenzene-triazole-glutamate (ATG), which is specific for NMDARs and functions as a photoswitchable agonist. ATG is inactive in its dark-adapted trans-isoform, but can be converted into its active cis-isoform using one-photon (near UV) or two-photon (740 nm) excitation. Irradiation with violet light photo-inactivates ATG within milliseconds, allowing agonist removal on the timescale of NMDAR deactivation. ATG is compatible with Ca(2+) imaging and can be used to optically mimic synaptic coincidence detection protocols. Thus, ATG can be used like traditional caged glutamate compounds, but with the added advantages of NMDAR specificity, low antagonism of GABAR-mediated currents, and precise temporal control of agonist delivery. PMID:26311290

  2. Optical control of NMDA receptors with a diffusible photoswitch

    PubMed Central

    Laprell, Laura; Repak, Emilienne; Franckevicius, Vilius; Hartrampf, Felix; Terhag, Jan; Hollmann, Michael; Sumser, Martin; Rebola, Nelson; DiGregorio, David A.; Trauner, Dirk

    2015-01-01

    N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory, and are implicated in various neuronal disorders. We synthesized a diffusible photochromic glutamate analogue, azobenzene-triazole-glutamate (ATG), which is specific for NMDARs and functions as a photoswitchable agonist. ATG is inactive in its dark-adapted trans-isoform, but can be converted into its active cis-isoform using one-photon (near UV) or two-photon (740 nm) excitation. Irradiation with violet light photo-inactivates ATG within milliseconds, allowing agonist removal on the timescale of NMDAR deactivation. ATG is compatible with Ca2+ imaging and can be used to optically mimic synaptic coincidence detection protocols. Thus, ATG can be used like traditional caged glutamate compounds, but with the added advantages of NMDAR specificity, low antagonism of GABAR-mediated currents, and precise temporal control of agonist delivery. PMID:26311290

  3. Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism

    PubMed Central

    Sullivan, Elyse M; Timi, Patricia; Hong, L Elliot; O'Donnell, Patricio

    2015-01-01

    Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. In this study we developed a tool to record skull EEG in awake-behaving rats in a similar manner to how human EEG are obtained and then used this technique to test whether acute NMDA receptor antagonism alters rodent EEG signals in a similar manner as in humans. Acute MK-801 treatment elevated gamma power and reduced beta band power, which closely mirrored EEG data from healthy volunteers receiving acute ketamine. To explore the mechanisms behind these oscillatory changes, we examined the effects of GABA-A receptor blockade, finding that picrotoxin (PTX) recapitulated the decrease in sound-evoked beta oscillations observed with acute MK-801, but did not produce changes in gamma band power. Chronic treatment with either PTX or MK-801 did not affect frequency-specific oscillatory activity when tested 24 h after the last drug injection, but decreased total broadband oscillatory power. Overall, this study validated a novel platform for recording rodent EEG and demonstrated similar oscillatory changes after acute NMDA receptor antagonism in both humans and rodents, suggesting that skull EEG may be a powerful tool for further translational studies. PMID:25176166

  4. Benzimidazolone bioisosteres of potent GluN2B selective NMDA receptor antagonists.

    PubMed

    Lütnant, Ines; Schepmann, Dirk; Wünsch, Bernhard

    2016-06-30

    Overactivation of the NMDA receptor is associated with excitotoxic events leading to neurodegenerative processes as observed during the development of Alzheimer's disease, ParFnson's disease, Chorea Huntington and epilepsy. Negative allosteric modulators addressing selectively the ifenprodil binding site of GluN2B subunit containing NMDA receptors are of major interest due to their neuroprotective potential accompanied by few side effects. Herein benzimidazolone bioisosteres of potent GluN2B antagonists 1-5 were designed and synthesized. A seven step sequence provided the central intermediate 19 in 28% yield. Elimination of water, methylation, epoxidation, epoxide rearrangement and finally reductive amination afforded the [7]annulenobenzimidazolone 30 with a 3-phenylpropylamino substituent in 6-position. Although 30 fits nicely into the pharmacophore of potent GluN2B antagonists, the gluN2B binding affinity of 30 was only moderate (Ki = 697 nM). Additionally, 30 shows low selectivity over the σ2 receptor (Ki = 549 nM). The moderate GluN2B affinity was explained by the rigid tricyclic structure of the [7]annulenobenzimidazolone 30. PMID:27061977

  5. Pharmacological Intervention of Hippocampal CA3 NMDA Receptors Impairs Acquisition and Long-Term Memory Retrieval of Spatial Pattern Completion Task

    ERIC Educational Resources Information Center

    Fellini, Laetitia; Florian, Cedrick; Courtey, Julie; Roullet, Pascal

    2009-01-01

    Pattern completion is the ability to retrieve complete information on the basis of incomplete retrieval cues. Although it has been demonstrated that this cognitive capacity depends on the NMDA receptors (NMDA-Rs) of the hippocampal CA3 region, the role played by these glutamatergic receptors in the pattern completion process has not yet been…

  6. N-Methyl-d-aspartate (NMDA) Receptor NR2 Subunit Selectivity of a Series of Novel Piperazine-2,3-dicarboxylate Derivatives: Preferential Blockade of Extrasynaptic NMDA Receptors in the Rat Hippocampal CA3-CA1 Synapse

    PubMed Central

    Feng, Bihua; Tsintsadze, Timur S.; Morley, Richard M.; Irvine, Mark W.; Tsintsadze, Vera; Lozovaya, Natasha A.; Jane, David E.; Monaghan, Daniel T.

    2009-01-01

    N-Methyl-d-aspartate (NMDA) receptor antagonists that are highly selective for specific NMDA receptor 2 (NR2) subunits have several potential therapeutic applications; however, to date, only NR2B-selective antagonists have been described. Whereas most glutamate binding site antagonists display a common pattern of NR2 selectivity, NR2A > NR2B > NR2C > NR2D (high to low affinity), (2S*,3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) has a low selectivity for NR2C- and NR2D-containing NMDA receptors. A series of PPDA derivatives were synthesized and then tested at recombinant NMDA receptors expressed in Xenopus laevis oocytes. In addition, the optical isomers of PPDA were resolved; the (−) isomer displayed a 50- to 80-fold greater potency than the (+) isomer. Replacement of the phenanthrene moiety of PPDA with naphthalene or anthracene did not improve selectivity. However, phenylazobenzoyl (UBP125) or phenylethynylbenzoyl (UBP128) substitution significantly improved selectivity for NR2B-, NR2C-, and NR2D-containing receptors over NR2A-containing NMDA receptors. Phenanthrene attachment at the 3 position [(2R*,3S*)-1-(phenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP141); (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP145); (2R*,3S*)-1-(9-chlorophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP160); and (2R*,3S*)-1-(9-iodophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP161)] displayed improved NR2D selectivity. UBP141 and its 9-brominated homolog (UBP145) both display a 7- to 10- fold selectivity for NR2D-containing receptors over NR2B- or NR2A-containing receptors. Schild analysis indicates that these two compounds are competitive glutamate binding site antagonists. Consistent with a physiological role for NR2D-containing receptors in the hippocampus, UBP141 (5 μM) displayed greater selectivity than PPDA for inhibiting the slow-decaying component of the NMDA receptor

  7. Blockade of NMDA receptors reverses the depressant, but not anxiogenic effect of adolescence social isolation in mice.

    PubMed

    Haj-Mirzaian, Arya; Amiri, Shayan; Kordjazy, Nastaran; Rahimi-Balaei, Maryam; Haj-Mirzaian, Arvin; Marzban, Hassan; Aminzadeh, Azadeh; Dehpour, Ahmad Reza; Mehr, Shahram Ejtemaei

    2015-03-01

    Early life social isolation stress (SIS), a well-known chronic stress paradigm, is contributed to a number of pathophysiological and neurochemical changes including depression and anxiety. The underlying mechanisms for these disorders in socially isolated animals have not been fully cleared. Previous studies have shown that N-Methyl-d-aspartate (NMDA) receptor function is changed by social isolation condition. It is now well recognized that NMDA receptor blockade can exhibit antidepressant and anxiolytic actions. In our study, postnatal day 21-25 mice were randomly housed for 4 weeks under either social condition (SC) or isolated condition (IC). Then, animals were subjected to different behavioral experiments to investigate whether blockade of NMDA receptor resulted in behavioral alterations in animals. Social isolation stress induced depressive and anxiety-like behaviors in IC animals in comparison with SC mice. Also, we applied subeffective doses of antagonists including ketamine (1mg/kg), MK-801 (0.05mg/kg), and magnesium sulfate (10mg/kg) to both SC and IC mice prior to behavioral experiments. Administration of a single dose of all mentioned drugs did not affect the SC mice but modulated the depressant effects of SIS on IC mice. Administration of NMDA receptor antagonists decreased the immobility time in the forced swimming test as well as an increase in grooming behavior in splash test. However, anxiety-like behaviors in IC animals remained unchanged in hole-board test and open field test after blockade of NMDA receptors. Taken together, our results showed the possible involvement of the NMDA receptors in the depressive, but not anxiety-like behaviors induced by SIS. PMID:25592321

  8. Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

    PubMed

    Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

    2014-06-01

    Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration. PMID:24338618

  9. Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia.

    PubMed

    Väisänen, Jussi; Ihalainen, Jouni; Tanila, Heikki; Castrén, Eero

    2004-12-01

    1. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists produce behavioral responses that closely resemble both positive and negative symptoms of schizophrenia. These drugs also induce excitatory and neurotoxic effects in limbic cortical areas. 2. We have here mapped the brain areas which show increased activity in response to noncompetitive NMDA-receptor antagonist administration concentrating especially to those brain areas that have been suggested to be relevant in the pathophysiology of schizophrenia. 3. Rats were treated intraperitoneally with a NMDA-receptor antagonist MK801 and activation of brain areas was detected by monitoring the expression of c-fos mRNA by using in situ hybridization. 4. MK801 induced c-fos mRNA expression of in the retrosplenial, entorhinal, and prefrontal cortices. Lower c-fos expression was observed in the layer IV of the parietal and frontal cortex. In the thalamus, c-fos mRNA expression was detected in the midline nuclei and in the reticular nucleus but not in the dorsomedial nucleus. In addition, c-fos mRNA was expressed in the anterior olfactory nucleus, the ventral tegmental area, and in cerebellar granule neurons. 5. NMDA-receptor antagonist ketamine increased dopamine release in the parietal cortex, in the region where NMDA-receptor antagonist increased c-fos mRNA expression. 6. Thus, the psychotropic NMDA-receptor antagonist induced c-fos mRNA expression in most, but not all, brain areas implicated in the pathophysiology of schizophrenia. The high spatial resolution of in situ hybridization may help to define regions of interest for human imaging studies. PMID:15672679

  10. NMDA Receptors in Clinical Neurology: Excitatory Times Ahead

    PubMed Central

    Kalia, Lorraine V.; Kalia, Suneil K.; Salter, Michael W.

    2013-01-01

    Since the N-methyl-D-aspartate receptor (NMDAR) subunits were first cloned less than two decades ago, a substantial amount of research has been invested into understanding the physiological function of NMDARs in the healthy CNS and their pathological roles in a variety of neurological diseases. These include conditions resulting from acute excitotoxic insults (e.g. ischemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (e.g. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis), disorders arising from sensitization of neurons (e.g. epilepsy, neuropathic pain), as well as neurodevelopmental disorders associated with NMDAR hypofunction (e.g. schizophrenia). There has been much focus on selective NMDAR antagonists which have not produced positive results in clinical trials. However, there are other NMDAR-targeted therapies used in current practice which are effective for treating certain neurological disorders. In this review, we describe the evidence for the use of these therapies and provide an overview of drugs being investigated in clinical trials. We also discuss novel NMDAR-based strategies which are emerging in clinical neurology. PMID:18635022

  11. NMDA ANTAGONIST MK-801 SUPPRESSES BEHAVIORAL SEIZURES, AUGMENTS AFTERDISCHARGES, BUT DOES NOT BLOCK DEVELOPMENT OF PERFORANT PATH KINDLING

    EPA Science Inventory

    The role of the N-methyl-d-aspartate (NMDA) in the development and expression of kindled seizures was assessed using a crossover design. ats were stimulated once daily in the perforant path for 10 consecutive days following administration of saline or the NMDA antagonist MK-801 (...

  12. Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice.

    PubMed

    Vignisse, Julie; Steinbusch, Harry W M; Grigoriev, Vladimir; Bolkunov, Alexei; Proshin, Alexey; Bettendorff, Lucien; Bachurin, Sergey; Strekalova, Tatyana

    2014-02-01

    Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6J at 1 or 5mg/kg, ip) with new derivatives of isothiourea (0.5-1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC₅₀ values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance. PMID:23993168

  13. Psychotic symptoms in anti-N-methyl-d-aspartate (NMDA) receptor encephalitis: A case report and challenges.

    PubMed

    Sharma, Pawan; Sagar, Rajesh; Patra, Bichitrananda; Saini, Lokesh; Gulati, Sheffali; Chakrabarty, Biswaroop

    2016-08-01

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, only recently first described, is an increasingly well-recognized inflammatory encephalitis that is seen in children and adults. An 11-year old girl admitted to the psychiatry ward with a presentation of acute psychosis was diagnosed with NMDA receptor encephalitis following neurology referral and was treated accordingly. This case highlights psychiatric manifestations in encephalitis and the need for the psychiatrist to have high index of suspicion when atypical symptoms (e.g., dyskinesia, seizure, fever etc.) present in acutely psychotic patients. PMID:27520914

  14. Overlapping demyelinating syndromes and anti-NMDA receptor encephalitis

    PubMed Central

    Titulaer, Maarten J.; Höftberger, Romana; Iizuka, Takahiro; Leypoldt, Frank; McCracken, Lindsey; Cellucci, Tania; Benson, Leslie A.; Shu, Huidy; Irioka, Takashi; Hirano, Makito; Singh, Gagandeep; Calvo, Alvaro Cobo; Kaida, Kenichi; Morales, Pamela S.; Wirtz, Paul W.; Yamamoto, Tomotaka; Reindl, Markus; Rosenfeld, Myrna R.; Graus, Francesc; Saiz, Albert; Dalmau, Josep

    2014-01-01

    Objective To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods Clinical and radiological analysis of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent MRI and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of NMO-spectrum disorder (5 cases, 4 anti-AQP4-positive), or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG-positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4-positive, 2 MOG-positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis: NMDAR-antibodies were detected only in the 50 anti-NMDAR patients, MOG-antibodies in 3/50 anti-NMDAR and 1/56 NMO patients, and AQP4-antibodies in 48/56 NMO and 1/50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1/23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18/50 anti-NMDAR controls (p=0.011) Interpretation Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (e.g., dyskinesias, psychosis) may have anti-NMDAR encephalitis. PMID:24700511

  15. Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

    PubMed Central

    Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

    2012-01-01

    Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABAA receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists are more likely to be effective in treating TMDT poisoning. PMID:23022509

  16. Ethanol preconditioning of rat cerebellar cultures targets NMDA receptors to the synapse and enhances peroxiredoxin 2 expression.

    PubMed

    Mitchell, Robert M; Tajuddin, Nuzhath; Campbell, Edward M; Neafsey, Edward J; Collins, Michael A

    2016-07-01

    Epidemiological studies indicate that light-moderate alcohol (ethanol) consumers tend to have reduced risks of cognitive impairment and progression to dementia during aging. Exploring possible mechanisms, we previously found that moderate ethanol preconditioning (MEP, 20-30mM) of rat brain cultures for several days instigated neuroprotection against β-amyloid peptides. Our biochemical evidence implicated the NMDA receptor (NMDAR) as a potential neuroprotective "sensor", specifically via synaptic NMDAR signaling. It remains unclear how ethanol modulates the receptor and its downstream targets to engender neuroprotection. Here we confirm with deconvolution microscopy that MEP of rat mixed cerebellar cultures robustly increases synaptic NMDAR localization. Phospho-activation of the non-receptor tyrosine kinases Src and Pyk2, known to be linked to synaptic NMDAR, is also demonstrated. Additionally, the preconditioning enhances levels of an antioxidant protein, peroxiredoxin 2 (Prx2), reported to be downstream of synaptic NMDAR signaling, and NMDAR antagonism with memantine (earlier found to abrogate MEP neuroprotection) blocks the Prx2 elevations. To further link Prx2 with antioxidant-based neuroprotection, we circumvented the ethanol preconditioning-NMDAR pathway by pharmacologically increasing Prx2 with the naturally-occurring cruciferous compound, 3H-1,2-dithiole-3-thione (D3T). Thus, D3T pretreatment elevated Prx2 expression to a similar extent as MEP, while concomitantly preventing β-amyloid neurotoxicity; D3T also protected the cultures from hydrogen peroxide toxicity. The findings support a mechanism that couples synaptic NMDAR signaling, Prx2 expression and augmented antioxidant defenses in ethanol preconditioning-induced neuroprotection. That this mechanism can be emulated by a cruciferous vegetable constituent suggests that such naturally-occurring "neutraceuticals" may be useful in therapy for oxidative stress-related dementias. PMID:27021955

  17. CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy

    PubMed Central

    Wang, Guangfu; Bochorishvili, Genrieta; Chen, Yucai; Salvati, Kathryn A.; Zhang, Peng; Dubel, Steve J.; Perez-Reyes, Edward; Snutch, Terrance P.; Stornetta, Ruth L.; Deisseroth, Karl; Erisir, Alev; Todorovic, Slobodan M.; Luo, Jian-Hong; Kapur, Jaideep; Beenhakker, Mark P.; Zhu, J. Julius

    2015-01-01

    CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE. PMID:26220996

  18. CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy.

    PubMed

    Wang, Guangfu; Bochorishvili, Genrieta; Chen, Yucai; Salvati, Kathryn A; Zhang, Peng; Dubel, Steve J; Perez-Reyes, Edward; Snutch, Terrance P; Stornetta, Ruth L; Deisseroth, Karl; Erisir, Alev; Todorovic, Slobodan M; Luo, Jian-Hong; Kapur, Jaideep; Beenhakker, Mark P; Zhu, J Julius

    2015-07-15

    CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE. PMID:26220996

  19. Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5

    PubMed Central

    Hou, Hailong; Sun, Lu; Siddoway, Benjamin A.; Petralia, Ronald S.; Yang, Hongtian; Gu, Hua; Nairn, Angus C.

    2013-01-01

    The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown. We find that synaptic N-methyl-d-aspartate (NMDA) receptor stimulation in neurons leads to activation of PP1 through a mechanism involving inhibitory phosphorylation at Thr320 by Cdk5. Synaptic stimulation led to proteasome-dependent degradation of the Cdk5 regulator p35, inactivation of Cdk5, and increased auto-dephosphorylation of Thr320 of PP1. We also found that neither inhibitor-1 nor calcineurin were involved in the control of PP1 activity in response to synaptic NMDA receptor stimulation. Rather, the PP1 regulatory protein, inhibitor-2, formed a complex with PP1 that was controlled by synaptic stimulation. Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons. Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity. PMID:24189275

  20. The NMDA Receptor Promotes Sleep in the Fruit Fly, Drosophila melanogaster.

    PubMed

    Tomita, Jun; Ueno, Taro; Mitsuyoshi, Madoka; Kume, Shoen; Kume, Kazuhiko

    2015-01-01

    Considerable evidence indicates that sleep is essential for learning and memory. Drosophila melanogaster has emerged as a novel model for studying sleep. We previously found a short sleeper mutant, fumin (fmn), and identified its mutation in the dopamine transporter gene. We reported similarities in the molecular basis of sleep and arousal regulation between mammals and Drosophila. In aversive olfactory learning tasks, fmn mutants demonstrate defective memory retention, which suggests an association between sleep and memory. In an attempt to discover additional sleep related genes in Drosophila, we carried out a microarray analysis comparing mRNA expression in heads of fmn and control flies and found that 563 genes are differentially expressed. Next, using the pan-neuronal Gal4 driver elav-Gal4 and UAS-RNA interference (RNAi) to knockdown individual genes, we performed a functional screen. We found that knockdown of the NMDA type glutamate receptor channel gene (Nmdar1) (also known as dNR1) reduced sleep. The NMDA receptor (NMDAR) plays an important role in learning and memory both in Drosophila and mammals. The application of the NMDAR antagonist, MK-801, reduced sleep in control flies, but not in fmn. These results suggest that NMDAR promotes sleep regulation in Drosophila. PMID:26023770

  1. Target-Specific Expression of Presynaptic NMDA Receptors in Neocortical Microcircuits

    PubMed Central

    Buchanan, Katherine A.; Blackman, Arne V.; Moreau, Alexandre W.; Elgar, Dale; Costa, Rui P.; Lalanne, Txomin; Tudor Jones, Adam A.; Oyrer, Julia; Sjöström, P. Jesper

    2012-01-01

    Summary Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns. PMID:22884329

  2. Enhanced Polyubiquitination of Shank3 and NMDA receptor in a mouse model of Autism

    PubMed Central

    Bangash, M Ali; Park, Joo Min; Melnikova, Tatiana; Wang, Dehua; Jeon, Soo Kyeong; Lee, Deidre; Syeda, Sbaa; Kim, Juno; Kouser, Mehreen; Schwartz, Joshua; Cui, Yiyuan; Zhao, Xia; Speed, Haley E.; Kee, Sara E.; Tu, Jian Cheng; Hu, Jia-Hua; Petralia, Ronald S.; Linden, David J.; Powell, Craig M.; Savonenko, Alena; Xiao, Bo; Worley, Paul F.

    2011-01-01

    Summary We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C-terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the WT gene product and results in >90 % reduction of Shank3 at synapses. This “gain of function” phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of post-synaptic density proteins, spine morphology and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder. PMID:21565394

  3. Memantine, an NMDA receptor antagonist, improves working memory deficits in DGKβ knockout mice.

    PubMed

    Kakefuda, Kenichi; Ishisaka, Mitsue; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

    2016-09-01

    Diacylglycerol kinase (DGK) β is a type 1 isozyme of the DGK family. We previously reported that DGKβ was deeply involved in neurite spine formation, and DGKβ knockout (KO) mice exhibited behavioral abnormalities concerning spine formation, such as cognitive, emotional, and attentional impairment. Moreover, some of these abnormalities were ameliorated by the administration of a mood stabilizer. However, there is no data about how memory-improving drugs used in the treatment of Alzheimer's disease affect DGKβ KO mice. In the present study, we evaluated the effect of an anti-Alzheimer's drug, memantine on the working memory deficit observed in DGKβ KO mice. In the Y-maze test, the administration of memantine significantly improved working memory of DGKβ KO mice. We also found that the expression levels of the NR2A and NR2B N-methyl-d-aspartate (NMDA) receptor subunits were increased in the prefrontal cortex, but decreased in the hippocampus of DGKβ KO mice. These altered expression levels of NR2 subunits might be related to the effect of an NMDA receptor antagonist, memantine. Taken together, these findings may support the hypothesis that DGKβ has a pivotal role in cognitive function. PMID:27495014

  4. SP-8203 shows neuroprotective effects and improves cognitive impairment in ischemic brain injury through NMDA receptor.

    PubMed

    Noh, Su-Jin; Lee, Jong Min; Lee, Ki Sung; Hong, Hyun Su; Lee, Chul Kyu; Cho, Il Hwan; Kim, Hye-Sun; Suh, Yoo-Hun

    2011-11-01

    The extracts of earth worms, Eisenia andrei, have been used as a therapeutic agent for stroke in the traditional medicine. It is also reported that the protease fraction separated from the extracts has strong anti-thrombotic activity. Besides anti-thrombotic actions, we found that SP-8203, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide, derived from the extracts of earth worms blocked N-methyl-(D)-aspartate (NMDA) receptor-mediated excitotoxicity in a competitive manner. The neuroprotective effects of SP-8203 were attributable to prevention of Ca(2+) influx through NMDA receptors. The systemic administration of SP-8203 markedly reduced neuronal death following middle cerebral artery occlusion in rats. SP-8203 significantly improved spatial learning and memory in the water maze test. These results provided strong pharmacological basis for its potential therapeutic roles in cerebral ischemia. PMID:21835192

  5. The NMDA Receptor Promotes Sleep in the Fruit Fly, Drosophila melanogaster

    PubMed Central

    Tomita, Jun; Ueno, Taro; Mitsuyoshi, Madoka; Kume, Shoen; Kume, Kazuhiko

    2015-01-01

    Considerable evidence indicates that sleep is essential for learning and memory. Drosophila melanogaster has emerged as a novel model for studying sleep. We previously found a short sleeper mutant, fumin (fmn), and identified its mutation in the dopamine transporter gene. We reported similarities in the molecular basis of sleep and arousal regulation between mammals and Drosophila. In aversive olfactory learning tasks, fmn mutants demonstrate defective memory retention, which suggests an association between sleep and memory. In an attempt to discover additional sleep related genes in Drosophila, we carried out a microarray analysis comparing mRNA expression in heads of fmn and control flies and found that 563 genes are differentially expressed. Next, using the pan-neuronal Gal4 driver elav-Gal4 and UAS-RNA interference (RNAi) to knockdown individual genes, we performed a functional screen. We found that knockdown of the NMDA type glutamate receptor channel gene (Nmdar1) (also known as dNR1) reduced sleep. The NMDA receptor (NMDAR) plays an important role in learning and memory both in Drosophila and mammals. The application of the NMDAR antagonist, MK-801, reduced sleep in control flies, but not in fmn. These results suggest that NMDAR promotes sleep regulation in Drosophila. PMID:26023770

  6. Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals.

    PubMed

    Scott, Derek B; Michailidis, Ioannis; Mu, Yuanyue; Logothetis, Diomedes; Ehlers, Michael D

    2004-08-11

    Regulation of the abundance of NMDA receptors (NMDARs) at excitatory synapses is critical during changes in synaptic efficacy underlying learning and memory as well as during synapse formation throughout neural development. However, the molecular signals that govern NMDAR delivery, maintenance, and internalization remain unclear. In this study, we identify a conserved family of membrane-proximal endocytic signals, two within the NMDAR type 1 (NR1) subunit and one within the NR2A and NR2B subunits, necessary and sufficient to drive the internalization of NMDARs. These endocytic motifs reside in the region of NMDAR subunits immediately after the fourth membrane segment, a region implicated in use-dependent rundown and NMDA channel inactivation. Although endocytosis driven by the distal C-terminal domain of NR2B is followed by rapid recycling, internalization mediated by membrane-proximal motifs selectively targets receptors to late endosomes and accelerates degradation. These results define a novel conserved signature of NMDARs regulating internalization and postendocytic trafficking. PMID:15306643

  7. Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Modulates N-Methyl-d-aspartate (NMDA) Receptor-dependent Intracellular Signaling and NMDA-induced Regulation of Postsynaptic Protein Complexes*

    PubMed Central

    Nakajima, Chikako; Kulik, Akos; Frotscher, Michael; Herz, Joachim; Schäfer, Michael; Bock, Hans H.; May, Petra

    2013-01-01

    The lipoprotein receptor LRP1 is essential in neurons of the central nervous system, as was revealed by the analysis of conditional Lrp1-deficient mouse models. The molecular basis of its neuronal functions, however, is still incompletely understood. Here we show by immunocytochemistry, electron microscopy, and postsynaptic density preparation that LRP1 is located postsynaptically. Basal and NMDA-induced phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) as well as NMDA target gene transcription are reduced in LRP1-deficient neurons. In control neurons, NMDA promotes γ-secretase-dependent release of the LRP1 intracellular domain (LRP1-ICD). However, pull-down and chromatin immunoprecipitation (ChIP) assays showed no direct interaction between the LRP1-ICD and either CREB or target gene promoters. On the other hand, NMDA-induced degradation of the postsynaptic scaffold protein PSD-95 was impaired in the absence of LRP1, whereas its ubiquitination was increased, indicating that LRP1 influences the composition of postsynaptic protein complexes. Accordingly, NMDA-induced internalization of the AMPA receptor subunit GluA1 was impaired in LRP1-deficient neurons. These results show a role of LRP1 in the regulation and turnover of synaptic proteins, which may contribute to the reduced dendritic branching and to the neurological phenotype observed in the absence of LRP1. PMID:23760271

  8. The relationship between NMDA receptor function and the high ammonia tolerance of anoxia-tolerant goldfish.

    PubMed

    Wilkie, Michael P; Pamenter, Matthew E; Duquette, Stephanie; Dhiyebi, Hadi; Sangha, Navjeet; Skelton, Geoffrey; Smith, Matthew D; Buck, Leslie T

    2011-12-15

    Acute ammonia toxicity in vertebrates is thought to be characterized by a cascade of deleterious events resembling those associated with anoxic/ischemic injury in the central nervous system. A key event is the over-stimulation of neuronal N-methyl-D-aspartate (NMDA) receptors, which leads to excitotoxic cell death. The similarity between the responses to acute ammonia toxicity and anoxia suggests that anoxia-tolerant animals such as the goldfish (Carassius auratus Linnaeus) may also be ammonia tolerant. To test this hypothesis, the responses of goldfish were compared with those of the anoxia-sensitive rainbow trout (Oncorhynchus mykiss Walbaum) during exposure to high external ammonia (HEA). Acute toxicity tests revealed that goldfish are ammonia tolerant, with 96 h median lethal concentration (LC(50)) values of 199 μmol l(-1) and 4132 μmol l(-1) for NH(3) and total ammonia ([T(Amm)]=[NH(3)]+[NH(4)(+)]), respectively. These values were ~5-6 times greater than corresponding NH(3) and T(Amm) LC(50) values measured in rainbow trout. Further, the goldfish readily coped with chronic exposure to NH(4)Cl (3-5 mmol l(-1)) for 5 days, despite 6-fold increases in plasma [T] to ~1300 μmol l(-1) and 3-fold increases in brain [T(Amm)] to 6700 μmol l(-1). Muscle [T(Amm)] increased by almost 8-fold from ~900 μmol kg(-1) wet mass (WM) to greater than 7000 μmol kg(-1) WM by 48 h, and stabilized. Although urea excretion rates (J(Urea)) increased by 2-3-fold during HEA, the increases were insufficient to offset the inhibition of ammonia excretion that occurred, and increases in urea were not observed in the brain or muscle. There was a marked increase in brain glutamine concentration at HEA, from ~3000 μmol kg(-1) WM to 15,000 μmol kg(-1) WM after 48 h, which is consistent with the hypothesis that glutamine production is associated with ammonia detoxification. Injection of the NMDA receptor antagonists MK801 (0.5-8 mg kg(-1)) or ethanol (1-8 mg kg(-1)) increased trout

  9. Stereotactic injection of cerebrospinal fluid from anti-NMDA receptor encephalitis into rat dentate gyrus impairs NMDA receptor function.

    PubMed

    Würdemann, Till; Kersten, Maxi; Tokay, Tursonjan; Guli, Xiati; Kober, Maria; Rohde, Marco; Porath, Katrin; Sellmann, Tina; Bien, Christian G; Köhling, Rüdiger; Kirschstein, Timo

    2016-02-15

    Autoimmune encephalitis is increasingly recognized in patients with otherwise unexplained encephalopathy with epilepsy. Among these, patients with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis present epileptic seizures, memory deficits, and psychiatric symptoms. However, the functional consequences of such autoantibodies are poorly understood. In order to investigate the pathophysiology of this disease, we stereotactically injected either cerebrospinal fluid (CSF) from three anti-NMDAR encephalitis patients or commercially available anti-NMDAR1 into the dentate gyrus of adult female rats. Control animals were injected with either CSF obtained from three epilepsy patients (ganglioglioma, posttraumatic epilepsy, focal cortical dysplasia) lacking anti-NMDAR or saline. Intracellular recordings from dentate gyrus granule cells showed a significant reduction of the NMDAR-evoked excitatory postsynaptic potentials (NMDAR-EPSPs) in animals treated with anti-NMDAR. As a consequence of this, action potential firing in these cells by NMDAR-EPSPs was significantly impaired. Long-term potentiation in the dentate gyrus was also significantly reduced in rats injected with anti-NMDAR as compared to control animals. This was accompanied by a significantly impaired learning performance in the Morris water maze hidden platform task when the animals had been injected with anti-NMDAR antibody-containing CSF. Our findings suggest that anti-NMDAR lead to reduced NMDAR function in vivo which could contribute to the memory impairment found in patients with anti-NMDAR encephalitis. PMID:26721688

  10. Diurnal inhibition of NMDA-EPSCs at rat hippocampal mossy fibre synapses through orexin-2 receptors

    PubMed Central

    Perin, Martina; Longordo, Fabio; Massonnet, Christine; Welker, Egbert; Lüthi, Anita

    2014-01-01

    Diurnal release of the orexin neuropeptides orexin-A (Ox-A, hypocretin-1) and orexin-B (Ox-B, hypocretin-2) stabilises arousal, regulates energy homeostasis and contributes to cognition and learning. However, whether cellular correlates of brain plasticity are regulated through orexins, and whether they do so in a time-of-day-dependent manner, has never been assessed. Immunohistochemically we found sparse but widespread innervation of hippocampal subfields through Ox-A- and Ox-B-containing fibres in young adult rats. The actions of Ox-A were studied on NMDA receptor (NMDAR)-mediated excitatory synaptic transmission in acute hippocampal slices prepared around the trough (Zeitgeber time (ZT) 4–8, corresponding to 4–8 h into the resting phase) and peak (ZT 23) of intracerebroventricular orexin levels. At ZT 4–8, exogenous Ox-A (100 nm in bath) inhibited NMDA receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) at mossy fibre (MF)–CA3 (to 55.6 ± 6.8% of control, P = 0.0003) and at Schaffer collateral–CA1 synapses (70.8 ± 6.3%, P = 0.013), whereas it remained ineffective at non-MF excitatory synapses in CA3. Ox-A actions were mediated postsynaptically and blocked by the orexin-2 receptor (OX2R) antagonist JNJ10397049 (1 μm), but not by orexin-1 receptor inhibition (SB334867, 1 μm) or by adrenergic and cholinergic antagonists. At ZT 23, inhibitory effects of exogenous Ox-A were absent (97.6 ± 2.9%, P = 0.42), but reinstated (87.2 ± 3.3%, P = 0.002) when endogenous orexin signalling was attenuated for 5 h through i.p. injections of almorexant (100 mg kg−1), a dual orexin receptor antagonist. In conclusion, endogenous orexins modulate hippocampal NMDAR function in a time-of-day-dependent manner, suggesting that they may influence cellular plasticity and consequent variations in memory performance across the sleep–wake cycle. PMID:25085886