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Sample records for assess extrasynaptic nmda

  1. Thinking outside the synapse: glycine at extrasynaptic NMDA receptors.

    PubMed

    Gray, John A; Nicoll, Roger A

    2012-08-03

    In this issue, Papouin et al. show that glycine is the endogenous coagonist for extrasynaptic NMDA receptors (NMDARs), unlike at synapses where the coagonist is d-serine. By enzymatically degrading endogenous glycine, they begin to address the enigmatic physiological and pathological roles for extrasynaptic NMDARs.

  2. Extrasynaptic glutamate NMDA receptors: key players in striatal function.

    PubMed

    Garcia-Munoz, Marianela; Lopez-Huerta, Violeta G; Carrillo-Reid, Luis; Arbuthnott, Gordon W

    2015-02-01

    N-methyl-D-aspartate receptors (NMDAR) are crucial for the function of excitatory neurotransmission and are present at the synapse and on the extrasynaptic membrane. The major nucleus of the basal ganglia, striatum, receives a large glutamatergic excitatory input carrying information about movements and associated sensory stimulation for its proper function. Such bombardment of glutamate synaptic release results in a large extracellular concentration of glutamate that can overcome the neuronal and glial uptake homeostatic systems therefore allowing the stimulation of extrasynaptic glutamate receptors. Here we have studied the participation of their extrasynaptic type in cortically evoked responses or in the presence of NMDARs stimulation. We report that extrasynaptic NMDAR blocker memantine, reduced in a dose-dependent manner cortically induced NMDA excitatory currents in striatal neurons (recorded in zero-Mg(++) plus DNQX 10 μM). Moreover, memantine (2-4 μM) significantly reduced the NMDAR-dependent membrane potential oscillations called up and down states. Recordings of neuronal striatal networks with a fluorescent calcium indicator or with multielectrode arrays (MEA) also showed that memantine reduced in a dose-dependent manner, NMDA-induced excitatory currents and network behavior. We used multielectrode arrays (MEA) to grow segregated cortical and striatal neurons. Once synaptic contacts were developed (>21DIV) recordings of extracellular activity confirmed the cortical drive of spontaneous synchronous discharges in both compartments. After severing connections between compartments, active striatal neurons in the presence of memantine (1 μM) and CNQX (10 μM) were predominantly fast spiking interneurons (FSI). The significance of extrasynaptic receptors in the regulation of striatal function and neuronal network activity is evident.

  3. Organization, control and function of extrasynaptic NMDA receptors

    PubMed Central

    Papouin, Thomas; Oliet, Stéphane H. R.

    2014-01-01

    N-methyl d-aspartate receptors (NMDARs) exist in different forms owing to multiple combinations of subunits that can assemble into a functional receptor. In addition, they are located not only at synapses but also at extrasynaptic sites. There has been intense speculation over the past decade about whether specific NMDAR subtypes and/or locations are responsible for inducing synaptic plasticity and excitotoxicity. Here, we review the latest findings on the organization, subunit composition and endogenous control of NMDARs at extrasynaptic sites and consider their putative functions. Because astrocytes are capable of controlling NMDARs through the release of gliotransmitters, we also discuss the role of the glial environment in regulating the activity of these receptors. PMID:25225095

  4. Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation

    PubMed Central

    Sun, Xu-Ying; Tuo, Qing-Zhang; Liuyang, Zhen-Yu; Xie, Ao-Ji; Feng, Xiao-Long; Yan, Xiong; Qiu, Mei; Li, Shen; Wang, Xiu-Lian; Cao, Fu-Yuan; Wang, Xiao-Chuan; Wang, Jian-Zhi; Liu, Rong

    2016-01-01

    Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation. PMID:27809304

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

    PubMed Central

    Lo, Fu-Sun; Blue, Mary E.

    2015-01-01

    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

  6. 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.

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

    PubMed

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

    2010-11-24

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

  8. NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors.

    PubMed

    Zhou, X; Hollern, D; Liao, J; Andrechek, E; Wang, H

    2013-03-28

    N-methyl-D-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration. The current prevailing theory suggests that synaptic and extrasynaptic NMDAR (syn- and ex-NMDAR) impose counteracting effects on cell fate, and neuronal cell death is mainly mediated by the activation of ex-NMDAR. However, several lines of evidence implicate the limitation of this theory. Here, we demonstrate that activation of NMDAR bi-directionally regulated cell fate through stimulating pro-survival or pro-death signaling. While low-dose NMDA preferentially activated syn-NMDAR and stimulated the extracellular signal-regulated kinase ½-cAMP responsive element-binding protein-brain-derived neurotrophic factor pro-survival signaling, higher doses progressively activated increasing amount of ex-NMDAR along with syn-NMDAR and triggered cell death program. Interestingly, the activation of syn- or ex-NMDAR alone did not cause measurable cell death. Consistently, activation of syn- or ex-NMDAR alone stimulated pro-survival but not pro-death signaling. Next, we found that memantine, which was previously identified as an ex-NMDAR blocker, inhibited intracellular signaling mediated by syn- or ex-NMDAR. Simultaneous blockade of syn- and ex-NMDAR by memantine dose-dependently attenuated NMDAR-mediated death. Moreover, long- but not short-term treatment with high-dose NMDA or oxygen-glucose deprivation triggered cell death and suppressed pro-survival signaling. These data implicate that activation of syn- or ex-NMDAR alone is not neurotoxic. The degree of excitotoxicity depends on the magnitude and duration of syn- and ex-NMDAR coactivation. Finally, genome-wide examination demonstrated that the activation of syn- and ex-NMDAR lead to significant overlapping rather than counteracting transcriptional responses.

  9. Glial regulation of extrasynaptic NMDA receptor-mediated excitation of supraoptic nucleus neurones during dehydration.

    PubMed

    Joe, N; Scott, V; Brown, C H

    2014-01-01

    Magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) project to the posterior pituitary gland where they release the hormones, vasopressin and oxytocin into the circulation to maintain plasma osmolality. Hormone release is proportionate to SON MNC action potential (spike) firing rate. When activated by ambient extracellular glutamate, extrasynaptic NMDA receptors (eNMDARs) mediate a tonic (persistent) depolarisation to increase the probability of action potential firing. In the present study, in vivo single-unit electrophysiological recordings were made from urethane-anaesthetised female Sprague-Dawley rats to investigate the impact of tonic eNMDAR activation on MNC activity. Water deprivation (for up to 48 h) caused an increase in the firing rate of SON MNCs that was associated with a general increase in post-spike excitability. To determine whether eNMDAR activation contributes to the increased MNC excitability during water deprivation, memantine, which preferentially blocks eNMDARs, was administered locally into the SON by microdialysis. Memantine significantly decreased the firing rate of MNCs recorded from 48-h water-deprived rats but had no effect on MNCs recorded from euhydrated rats. In the presence of the glial glutamate transporter-1 (GLT-1) blocker, dihydrokainate, memantine also reduced the MNC firing rate in euhydrated rats. Taken together, these observations suggest that GLT-1 clears extracellular glutamate to prevent the activation of eNDMARs under basal conditions and that, during dehydration, eNMDAR activation contributes to the increased firing rate of MNCs.

  10. Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice.

    PubMed

    Dau, Alejandro; Gladding, Clare M; Sepers, Marja D; Raymond, Lynn A

    2014-02-01

    In the YAC128 mouse model of Huntington disease (HD), elevated extrasynaptic NMDA receptor (Ex-NMDAR) expression contributes to the onset of striatal dysfunction and atrophy. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by early stage dysregulation of intracellular calcium signaling pathways, including calpain and p38 MAPK activation, that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we aimed to identify calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/day), which at a low dose selectively blocks Ex-NMDARs, reduced striatal Ex-NMDAR expression and current in 4-month old YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5months but not 4months of age. In YAC128 mice, memantine at 1mg/kg/day rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. Taken together, our results indicate that Ex-NMDAR activity perpetuates increased extrasynaptic NMDAR expression and drives dysregulated p38 MAPK and CREB signaling in YAC128 mice. Elucidation of the pathways downstream of Ex-NMDARs in HD could help provide novel therapeutic targets for this disease.

  11. Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

    PubMed Central

    Lesept, Flavie; Chevilley, Arnaud; Jezequel, Julie; Ladépêche, Laurent; Macrez, Richard; Aimable, Margaux; Lenoir, Sophie; Bertrand, Thomas; Rubrecht, Laëtitia; Galea, Pascale; Lebouvier, Laurent; Petersen, Karl-Uwe; Hommet, Yannick; Maubert, Eric; Ali, Carine; Groc, Laurent; Vivien, Denis

    2016-01-01

    N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling. PMID:27831563

  12. Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons

    PubMed Central

    Joshi, Pooja; Gabrielli, Martina; Ponzoni, Luisa; Pelucchi, Silvia; Stravalaci, Matteo; Beeg, Marten; Mazzitelli, Sonia; Braida, Daniela; Sala, Mariaelvina; Boda, Enrica; Buffo, Annalisa; Gobbi, Marco; Gardoni, Fabrizio; Matteoli, Michela; Marcello, Elena; Verderio, Claudia

    2017-01-01

    Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer’s disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons. In addition, the drug mobilizes extrasynaptic GLUN2B-containing NMDARs, which are coupled to cell death, to the synapses. Altered ratio of synaptic/extrasynaptic NMDARs decreases calcium responsiveness of neurons to neurotoxic soluble Aβ 1–42 and renders neurons resistant to early alteration of calcium homeostasis. The fast defensive response of FTY720 occurs through a Sphingosine-1-phosphate receptor (S1P-R) -dependent mechanism, as it is lost in the presence of S1P-R1 and S1P-R3 antagonists. We propose that rapid synaptic relocation of NMDARs might have direct impact on amelioration of cognitive performance in transgenic APPswe/PS1dE9 AD mice upon sub-chronic treatment with FTY720. PMID:28134307

  13. Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-mediated Cleavage of STEP

    PubMed Central

    Xu, Jian; Kurup, Pradeep; Zhang, Yongfang; Goebel-Goody, Susan M.; Wu, Peter H.; Hawasli, Ammar H.; Baum, Matthew L.; Bibb, James A.; Lombroso, Paul J.

    2009-01-01

    NMDAR-mediated excitotoxicity plays an important role in several CNS disorders including epilepsy, stroke, and ischemia. Here we demonstrate the involvement of STriatal Enriched protein tyrosine Phosphatase (STEP) in this critical process. STEP61 is an alternatively spliced member of the family that is present in postsynaptic terminals. In an apparent paradox, STEP61 regulates ERK1/2 and p38, two proteins with opposing functions; activated p38 promotes cell death, whereas activated ERK1/2 promotes cell survival. We found that synaptic stimulation of NMDARs promoted STEP61 ubiquitination and degradation, concomitant with ERK1/2 activation. In contrast, extrasynaptic stimulation of NMDARs invoked calpain-mediated proteolysis of STEP61, producing the truncated cleavage product STEP33 and activation of p38. The calpain cleavage site on STEP was mapped to the kinase interacting motif, a domain required for substrate binding. As a result, STEP33 neither interacts with nor dephosphorylates STEP substrates. A synthetic peptide spanning the calpain cleavage site efficiently reduced STEP61 degradation and attenuated p38 activation and cell death in slice models. Furthermore, this peptide was neuroprotective when neurons were subjected to excitotoxicity or cortical slices were exposed to ischemic conditions. These findings suggest a novel mechanism by which differential NMDAR stimulation regulates STEP61 to promote either ERK1/2 or p38 activation and identifies calpain cleavage of STEP61 as a valid target for the development of neuroprotective therapy. PMID:19625523

  14. A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity

    PubMed Central

    Naskar, Krishna; Stern, Javier E

    2014-01-01

    Neuronal activity is controlled by a fine-tuned balance between intrinsic properties and extrinsic synaptic inputs. Moreover, neighbouring astrocytes are now recognized to influence a wide spectrum of neuronal functions. Yet, how these three key factors act in concert to modulate and fine-tune neuronal output is not well understood. Here, we show that in rat hypothalamic magnocellular neurosecretory cells (MNCs), glutamate NMDA receptors (NMDARs) are negatively coupled to the transient, voltage-gated A-type K+ current (IA). We found that activation of NMDARs by extracellular glutamate levels influenced by astrocyte glutamate transporters resulted in a significant inhibition of IA. The NMDAR–IA functional coupling resulted from activation of extrasynaptic NMDARs, was calcium- and protein kinase C-dependent, and involved enhanced steady-state, voltage-dependent inactivation of IA. The NMDAR–IA coupling diminished the latency to the first evoked spike in response to membrane depolarization and increased the total number of evoked action potentials, thus strengthening the neuronal input/output function. Finally, we found a blunted NMDA-mediated inhibition of IA in dehydrated rats. Together, our findings support a novel signalling mechanism that involves a functional coupling between extrasynaptic NMDARs and A-type K+ channels, which is influenced by local astrocytes. We show this signalling complex to play an important role in modulating hypothalamic neuronal excitability, which may contribute to adaptive responses during a sustained osmotic challenge such as dehydration. PMID:24835172

  15. The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors.

    PubMed

    Trabelsi, Yosra; Amri, Mohamed; Becq, Hélène; Molinari, Florence; Aniksztejn, Laurent

    2017-02-01

    Glutamate transporters (EAATs) are important to maintain spatial and temporal specificity of synaptic transmission. Their efficiency to uptake and transport glutamate into the intracellular space depends on several parameters including the intracellular concentrations of Na(+) and glutamate, the elevations of which may slow down the cycling rate of EAATs. In astrocytes, glutamate is maintained at low concentration due to the presence of specific enzymes such as glutamine synthase (GS). GS inhibition results in cytosolic accumulation of glutamate suggesting that the conversion of glutamate by GS is important for EAATs operation. Here we recorded astrocytes from juvenile rat neocortical slices and analyzed the consequences of elevated intracellular glutamate concentrations and of GS inhibition on the time course of synaptically evoked transporter current (STC). In slices from rats treated with methionine sulfoximine (MSO), a GS inhibitor, STC evoked by short burst of high frequency stimulation (HFS; 100 Hz for 100 ms) but not by low frequency stimulation (LFS; 0.1 Hz) was twice slower than STC evoked from saline injected rats. Same results were obtained for astrocytes recorded with pipette containing 3-10 mM glutamate and compared with cells recorded with 0 or1 mM glutamate in the patch pipette. We also showed that HFS elicited significantly larger NMDAR-excitatory postsynaptic currents (EPSCs) with a stronger peri/extrasynaptic component in pyramidal cells from MSO-treated compared with saline treated rats. Taken together our data demonstrate that the conversion of glutamate by GS is fundamental to ensure an efficient clearance of glutamate by EAATs and to prevent glutamate spillover. GLIA 2017;65:401-415.

  16. Synaptic NMDA Receptors Mediate Hypoxic Excitotoxic Death

    PubMed Central

    Wroge, Christine M.; Hogins, Joshua; Eisenman, Larry; Mennerick, Steven

    2012-01-01

    Excessive NMDA receptor activation and excitotoxicity underlies pathology in many neuropsychiatric and neurological disorders, including hypoxia/ischemia. Thus, the development of effective therapeutics for these disorders demands a complete understanding of NMDA receptor (NMDAR) activation during excitotoxic insults. The extrasynaptic NMDAR hypothesis posits that synaptic NMDARs are neurotrophic/neuroprotective and extrasynaptic NMDARs are neurotoxic. In part, the extrasynaptic hypothesis is built on observed selectivity for extrasynaptic receptors of a neuroprotective use-dependent NMDAR channel blocker, memantine. In rat hippocampal neurons we found that a neuroprotective concentration of memantine shows little selectivity for extrasynaptic NMDARs when all receptors are tonically activated by exogenous glutamate. This led us to test the extrasynaptic NMDAR hypothesis using metabolic challenge, where the source of excitotoxic glutamate buildup may be largely synaptic. Three independent approaches suggest strongly that synaptic receptors participate prominently in hypoxic excitotoxicity. First, block of glutamate transporters with a non-substrate antagonist exacerbated rather than prevented damage, consistent with a primarily synaptic source of glutamate. Second, selective, preblock of synaptic NMDARs with a slowly reversible, use-dependent antagonist protected nearly fully against prolonged hypoxic insult. Third, glutamate pyruvate transaminase (GPT), which degrades ambient but not synaptic glutamate, did not protect against hypoxia but protected against exogenous glutamate damage. Together, these results suggest that synaptic NMDARs can mediate excitotoxicity, particularly when the glutamate source is synaptic and when synaptic receptor contributions are rigorously defined. Moreover, the results suggest that in some situations therapeutically targeting extrasynaptic receptors may be inappropriate. PMID:22573696

  17. Differential effects of N-acetyl-aspartyl-glutamate on synaptic and extrasynaptic NMDA receptors are subunit- and pH-dependent in the CA1 region of the mouse hippocampus.

    PubMed

    Khacho, Pamela; Wang, Boyang; Ahlskog, Nina; Hristova, Elitza; Bergeron, Richard

    2015-10-01

    Ischemic strokes cause excessive release of glutamate, leading to overactivation of N-methyl-d-aspartate receptors (NMDARs) and excitotoxicity-induced neuronal death. For this reason, inhibition of NMDARs has been a central focus in identifying mechanisms to avert this extensive neuronal damage. N-acetyl-aspartyl-glutamate (NAAG), the most abundant neuropeptide in the brain, is neuroprotective in ischemic conditions in vivo. Despite this evidence, the exact mechanism underlying its neuroprotection, and more specifically its effect on NMDARs, is currently unknown due to conflicting results in the literature. Here, we uncover a pH-dependent subunit-specific action of NAAG on NMDARs. Using whole-cell electrophysiological recordings on acute hippocampal slices from adult mice and on HEK293 cells, we found that NAAG increases synaptic GluN2A-containing NMDAR EPSCs, while effectively decreasing extrasynaptic GluN2B-containing NMDAR EPSCs in physiological pH. Intriguingly, the results of our study further show that in low pH, which is a physiological occurrence during ischemia, NAAG depresses GluN2A-containing NMDAR EPSCs and amplifies its inhibitory effect on GluN2B-containing NMDAR EPSCs, as well as upregulates the surface expression of the GluN2A subunit. Altogether, our data demonstrate that NAAG has differential effects on NMDAR function based on subunit composition and pH. These findings suggest that the role of NAAG as a neuroprotective agent during an ischemic stroke is likely mediated by its ability to reduce NMDAR excitation. The inhibitory effect of NAAG on NMDARs and its enhanced function in acidic conditions make NAAG a prime therapeutic agent for the treatment of ischemic events.

  18. Anesthetic action on extra-synaptic receptors: effects in neural population models of EEG activity

    PubMed Central

    Hashemi, Meysam; Hutt, Axel; Sleigh, Jamie

    2014-01-01

    The role of extra-synaptic receptors in the regulation of excitation and inhibition in the brain has attracted increasing attention. Because activity in the extra-synaptic receptors plays a role in regulating the level of excitation and inhibition in the brain, they may be important in determining the level of consciousness. This paper reviews briefly the literature on extra-synaptic GABA and NMDA receptors and their affinity to anesthetic drugs. We propose a neural population model that illustrates how the effect of the anesthetic drug propofol on GABAergic extra-synaptic receptors results in changes in neural population activity and the electroencephalogram (EEG). Our results show that increased tonic inhibition in inhibitory cortical neurons cause a dramatic increase in the power of both δ− and α− bands. Conversely, the effects of increased tonic inhibition in cortical excitatory neurons and thalamic relay neurons have the opposite effect and decrease the power in these bands. The increased δ-activity is in accord with observed data for deepening propofol anesthesia; but is absolutely dependent on the inclusion of extrasynaptic (tonic) GABA action in the model. PMID:25540612

  19. Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling.

    PubMed

    Wang, Wen-Yuan; Jia, Li-Jie; Luo, Yan; Zhang, Hong-Hai; Cai, Fang; Mao, Hui; Xu, Wei-Cai; Fang, Jun-Biao; Peng, Zhi-You; Ma, Zheng-Wen; Chen, Yan-Hong; Zhang, Juan; Wei, Zhen; Yu, Bu-Wei; Hu, Shuang-Fei

    2016-01-01

    It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors

  20. Regulating anxiety with extrasynaptic inhibition

    PubMed Central

    Botta, Paolo; Demmou, Lynda; Kasugai, Yu; Markovic, Milica; Xu, Chun; Fadok, Jonathan P.; Lu, Tingjia; Poe, Michael M.; Xu, Li; Cook, James M.; Rudolph, Uwe; Sah, Pankaj; Ferraguti, Francesco; Lüthi, Andreas

    2015-01-01

    Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ+ neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes. PMID:26322928

  1. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage

    PubMed Central

    Soria, Federico N.; Pérez-Samartín, Alberto; Martin, Abraham; Gona, Kiran Babu; Llop, Jordi; Szczupak, Boguslaw; Chara, Juan Carlos; Matute, Carlos; Domercq, María

    2014-01-01

    During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death. PMID:25036707

  2. Extrasynaptic vesicle recycling in mature hippocampal neurons.

    PubMed

    Ratnayaka, Arjuna; Marra, Vincenzo; Branco, Tiago; Staras, Kevin

    2011-11-08

    Fast neuronal signalling relies on highly regulated vesicle fusion and recycling at specialized presynaptic terminals. Recently, examples of non-classical neurotransmission have also been reported, where fusion of vesicles can occur at sites remote from conventional synapses. This has potentially broad biological implications, but the underlying mechanisms are not well established. Here we show that a complete vesicle recycling pathway can occur at discrete axonal sites in mature hippocampal neurons and that extrasynaptic fusion is a robust feature of native tissue. We demonstrate that laterally mobile vesicle clusters trafficking between synaptic terminals become transiently stabilized by evoked action potentials and undergo complete but delayed Ca(2+)-dependent fusion along axons. This fusion is associated with dynamic actin accumulation and, subsequently, vesicles can be locally recycled, re-acidified and re-used. Immunofluorescence and ultrastructural work demonstrates that extrasynaptic fusion sites can have apposed postsynaptic specializations, suggesting that mobile vesicle recycling may underlie highly dynamic neuron-neuron communication.

  3. Astrocytic Actions on Extrasynaptic Neuronal Currents

    PubMed Central

    Pál, Balázs

    2015-01-01

    In the last few decades, knowledge about astrocytic functions has significantly increased. It was demonstrated that astrocytes are not passive elements of the central nervous system (CNS), but active partners of neurons. There is a growing body of knowledge about the calcium excitability of astrocytes, the actions of different gliotransmitters and their release mechanisms, as well as the participation of astrocytes in the regulation of synaptic functions and their contribution to synaptic plasticity. However, astrocytic functions are even more complex than being a partner of the “tripartite synapse,” as they can influence extrasynaptic neuronal currents either by releasing substances or regulating ambient neurotransmitter levels. Several types of currents or changes of membrane potential with different kinetics and via different mechanisms can be elicited by astrocytic activity. Astrocyte-dependent phasic or tonic, inward or outward currents were described in several brain areas. Such currents, together with the synaptic actions of astrocytes, can contribute to neuromodulatory mechanisms, neurosensory and -secretory processes, cortical oscillatory activity, memory, and learning or overall neuronal excitability. This mini-review is an attempt to give a brief summary of astrocyte-dependent extrasynaptic neuronal currents and their possible functional significance. PMID:26696832

  4. Synthesis of C5-tetrazole derivatives of 2-amino-adipic acid displaying NMDA glutamate receptor antagonism.

    PubMed

    Lenda, Fatimazohra; Crouzin, Nadine; Cavalier, Mélanie; Guiramand, Janique; Lanté, Fabien; Barbanel, Gérard; Cohen-Solal, Catherine; Martinez, Jean; Guenoun, Farhate; Lamaty, Frédéric; Vignes, Michel

    2011-03-01

    Five derivatives of 2-amino-adipic acid bearing a tetrazole-substituted in C5 position were synthesized. These compounds displayed selective antagonism towards N-methyl-D: -aspartate (NMDA) receptors compared with AMPA receptors, and they were devoid of any neurotoxicity. Among these five analogues, one exhibited a higher affinity for synaptic NMDA responses than the other four. Therefore, C5 tetrazole-substituted of 2-amino-adipic acid represent an interesting series of new NMDA receptor antagonists. This approach may be considered as a new strategy to develop ligands specifically targeted to synaptic or extra-synaptic NMDA receptors.

  5. Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity.

    PubMed

    Zhou, Xianju; Ding, Qi; Chen, Zhuoyou; Yun, Huifang; Wang, Hongbing

    2013-08-16

    GluN2A and GluN2B are the major subunits of functional NMDA receptors (NMDAR). Previous studies have suggested that GluN2A and GluN2B may differentially mediate NMDAR function at synaptic and extrasynaptic locations and play opposing roles in excitotoxicity, such as neurodegeneration triggered by ischemic stroke and brain injury. By using pharmacological and molecular approaches to suppress or enhance the function of GluN2A and GluN2B in cultured cortical neurons, we examined NMDAR-mediated, bidirectional regulation of prosurvival signaling (i.e. the cAMP response element-binding protein (CREB)-Bdnf cascade) and cell death. Inhibition of GluN2A or GluN2B attenuated the up-regulation of prosurvival signaling triggered by the activation of either synaptic or extrasynaptic NMDAR. Inhibition of GluN2A or GluN2B also attenuated the down-regulation of prosurvival signaling triggered by the coactivation of synaptic and extrasynaptic receptors. The effects of GluN2B on CREB-Bdnf signaling were larger than those of GluN2A. Consistently, compared with suppression of GluN2A, suppression of GluN2B resulted in more reduction of NMDA- and oxygen glucose deprivation-induced excitotoxicity as well as NMDAR-mediated elevation of intracellular calcium. Moreover, excitotoxicity and down-regulation of CREB were exaggerated in neurons overexpressing GluN2A or GluN2B. Together, we found that GluN2A and GluN2B are involved in the function of both synaptic and extrasynaptic NMDAR, demonstrating that they play similar rather than opposing roles in NMDAR-mediated bidirectional regulation of prosurvival signaling and neuronal death.

  6. A NMDA receptor glycine site partial agonist, GLYX-13, that simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus

    PubMed Central

    Zhang, Xiao-lei; Sullivan, John A.; Moskal, Joseph R.; Stanton, Patric K.

    2008-01-01

    N-methyl-D-aspartate glutamate receptors (NMDAR) are a key route for Ca2+ influx into neurons important to both activity-dependent synaptic plasticity and, when uncontrolled, triggering events that cause neuronal degeneration and death. Among regulatory binding sites on the NMDAR complex is a glycine binding site, distinct from the glutamate binding site, which must be co-activated for NMDAR channel opening. We developed a novel glycine site partial agonist, GLYX-13, which is both nootropic and neuroprotective in vivo. Here, we assessed the effects of GLYX-13 on long-term synaptic plasticity and NMDAR transmission at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. GLYX-13 simultaneously enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission, while reducing long-term depression (LTD). GLYX-13 reduced NMDA receptor-mediated synaptic currents in CA1 pyramidal neurons evoked by low-frequency Schaffer collateral stimulation, but enhanced NMDAR currents during high-frequency bursts of activity, and these actions were occluded by a saturating concentration of the glycine site agonist D-serine. Direct two-photon imaging of Schaffer collateral burst-evoked increases in [Ca2+] in individual dendritic spines revealed that GLYX-13 selectively enhanced burst-induced NMDAR-dependent spine Ca2+ influx. Examining the rate of MK-801 block of synaptic versus extrasynaptic NMDAR-gated channels revealed that GLYX-13 selectively enhanced activation of burst-driven extrasynaptic NMDARs, with an action that was blocked by the NR2B-selective NMDAR antagonist ifenprodil. Our data suggest that GLYX-13 may have unique therapeutic potential as a learning and memory enhancer because of its ability to simultaneously enhance LTP and suppress LTD. PMID:18796308

  7. A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus.

    PubMed

    Zhang, Xiao-lei; Sullivan, John A; Moskal, Joseph R; Stanton, Patric K

    2008-12-01

    N-methyl-D-aspartate glutamate receptors (NMDARs) are a key route for Ca2+ influx into neurons important to both activity-dependent synaptic plasticity and, when uncontrolled, triggering events that cause neuronal degeneration and death. Among regulatory binding sites on the NMDAR complex is a glycine binding site, distinct from the glutamate binding site, which must be co-activated for NMDAR channel opening. We developed a novel glycine site partial agonist, GLYX-13, which is both nootropic and neuroprotective in vivo. Here, we assessed the effects of GLYX-13 on long-term synaptic plasticity and NMDAR transmission at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. GLYX-13 simultaneously enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission, while reducing long-term depression (LTD). GLYX-13 reduced NMDA receptor-mediated synaptic currents in CA1 pyramidal neurons evoked by low frequency Schaffer collateral stimulation, but enhanced NMDAR currents during high frequency bursts of activity, and these actions were occluded by a saturating concentration of the glycine site agonist d-serine. Direct two-photon imaging of Schaffer collateral burst-evoked increases in [Ca2+] in individual dendritic spines revealed that GLYX-13 selectively enhanced burst-induced NMDAR-dependent spine Ca2+ influx. Examining the rate of MK-801 block of synaptic versus extrasynaptic NMDAR-gated channels revealed that GLYX-13 selectively enhanced activation of burst-driven extrasynaptic NMDARs, with an action that was blocked by the NR2B-selective NMDAR antagonist ifenprodil. Our data suggest that GLYX-13 may have unique therapeutic potential as a learning and memory enhancer because of its ability to simultaneously enhance LTP and suppress LTD.

  8. An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development.

    PubMed

    Gu, Xinglong; Zhou, Liang; Lu, Wei

    2016-01-26

    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, whereas 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.

  9. [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.

  10. Presynaptic and extrasynaptic regulation of posterior nucleus of thalamus.

    PubMed

    Park, Anthony; Li, Ying; Masri, Radi; Keller, Asaf

    2017-03-22

    The posterior nucleus of thalamus (PO) is a higher-order nucleus involved in sensorimotor processing, including nociception. An important characteristic of PO is its wide range of activity profiles that vary across states of arousal, thought to underlie differences in somatosensory perception subject to attention and degree of consciousness. Further, PO loses the ability to down-regulate its activity level in some forms of chronic pain, suggesting that regulatory mechanisms underlying the normal modulation of PO activity may be pathologically altered. Yet, the mechanisms responsible for regulating such a wide dynamic range of activity are unknown. Here, we test a series of hypotheses regarding the function of several presynaptic receptors on both GABAergic and glutamatergic afferents targeting PO in mouse, using acute slice electrophysiology. We found that presynaptic GABAB receptors are present on both GABAergic and glutamatergic terminals in PO, but only those on GABAergic terminals are tonically active. We also found that release from GABAergic terminals, but not glutamatergic terminals, is suppressed by cholinergic activation, and that a subpopulation of GABAergic terminals is regulated by cannabinoids. Finally, we discovered the presence of tonic currents mediated by extrasynaptic GABAA receptors in PO that are heterogeneously distributed across the nucleus. Thus, we demonstrate that multiple regulatory mechanisms concurrently exist in PO, and we propose that regulation of inhibition, rather than excitation, is the more consequential mechanism by which PO activity can be regulated.

  11. Extrasynaptic exocytosis and its mechanisms: a source of molecules mediating volume transmission in the nervous system

    PubMed Central

    Trueta, Citlali; De-Miguel, Francisco F.

    2012-01-01

    We review the evidence of exocytosis from extrasynaptic sites in the soma, dendrites, and axonal varicosities of central and peripheral neurons of vertebrates and invertebrates, with emphasis on somatic exocytosis, and how it contributes to signaling in the nervous system. The finding of secretory vesicles in extrasynaptic sites of neurons, the presence of signaling molecules (namely transmitters or peptides) in the extracellular space outside synaptic clefts, and the mismatch between exocytosis sites and the location of receptors for these molecules in neurons and glial cells, have long suggested that in addition to synaptic communication, transmitters are released, and act extrasynaptically. The catalog of these molecules includes low molecular weight transmitters such as monoamines, acetylcholine, glutamate, gama-aminobutiric acid (GABA), adenosine-5-triphosphate (ATP), and a list of peptides including substance P, brain-derived neurotrophic factor (BDNF), and oxytocin. By comparing the mechanisms of extrasynaptic exocytosis of different signaling molecules by various neuron types we show that it is a widespread mechanism for communication in the nervous system that uses certain common mechanisms, which are different from those of synaptic exocytosis but similar to those of exocytosis from excitable endocrine cells. Somatic exocytosis has been measured directly in different neuron types. It starts after high-frequency electrical activity or long experimental depolarizations and may continue for several minutes after the end of stimulation. Activation of L-type calcium channels, calcium release from intracellular stores and vesicle transport towards the plasma membrane couple excitation and exocytosis from small clear or large dense core vesicles in release sites lacking postsynaptic counterparts. The presence of synaptic and extrasynaptic exocytosis endows individual neurons with a wide variety of time- and space-dependent communication possibilities

  12. Extrasynaptic Neurotransmission in the Modulation of Brain Function. Focus on the Striatal Neuronal–Glial Networks

    PubMed Central

    Fuxe, Kjell; Borroto-Escuela, Dasiel O.; Romero-Fernandez, Wilber; Diaz-Cabiale, Zaida; Rivera, Alicia; Ferraro, Luca; Tanganelli, Sergio; Tarakanov, Alexander O.; Garriga, Pere; Narváez, José Angel; Ciruela, Francisco; Guescini, Michele; Agnati, Luigi F.

    2012-01-01

    Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular networks

  13. Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic δGABAA Receptors in the Hippocampus

    PubMed Central

    Carver, Chase Matthew; Chuang, Shu-Hui

    2016-01-01

    Zinc (Zn2+) is an essential cofactor in mammalian cells and neurons. Zn2+ is released from synaptic vesicles of certain nerve terminals in the hippocampus during neuronal activity. Zn2+ has been shown to inhibit synaptic GABAA receptors and alter the hippocampal network excitability. However, the ability of Zn2+ to block extrasynaptic receptors remains unclear. Endogenous neurosteroids, such as allopregnanolone (AP), regulate neuronal excitability by allosteric activation of synaptic and extrasynaptic GABAA receptors. Neurosteroids activate extrasynaptic δGABAA receptor-mediated tonic inhibition in dentate gyrus granule cells (DGGCs), thereby contributing to the regulation of downstream circuit excitability. Here we report a novel inhibitory role of Zn2+ at neurosteroid-sensitive, extrasynaptic δGABAA receptors by electrophysiological recordings in DGGCs from adult mice. Zn2+ displayed a concentration-dependent, reversible noncompetitive blockade of AP-sensitive tonic current in DGGCs (IC50, 16 μm). Tonic current was fully blocked by Zn2+, akin to the GABAA receptor antagonist gabazine. Zn2+ inhibition of tonic current was lacking in DGGCs from δ-subunit knock-out mice. Moreover, AP-activated synaptic receptor-mediated phasic currents were not affected by Zn2+. Finally, intrahippocampal infusion of Zn2+ elicited rapid epileptiform activity and significantly blocked the antiseizure activity of AP in the kindling model of epilepsy. Thus, Zn2+ inhibition of neurosteroid-sensitive, extrasynaptic GABAA receptors in the hippocampus has direct implications in many brain hyperexcitability conditions, such as seizures, epileptogenesis, and epilepsy. Zn2+ interactions may aid to further understand the physiology of extrasynaptic GABAA receptors. SIGNIFICANCE STATEMENT Zn2+ is most abundant in the synaptic vesicles of hippocampal mossy fibers. Zn2+ release occurs with neuronal excitation, including seizure events, and exerts powerful excitability effects in the

  14. Triheteromeric NMDA Receptors at Hippocampal Synapses

    PubMed Central

    Tovar, Kenneth R.; McGinley, Matthew J.; Westbrook, Gary L.

    2013-01-01

    NMDA receptors are composed of two GluN1 (N1) and two GluN2 (N2) subunits. Constituent N2 subunits control the pharmacological and kinetic characteristics of the receptor. NMDA receptors in hippocampal or cortical neurons are often thought of as diheteromeric, i.e., containing only one type of N2 subunit. However, triheteromeric receptors with more than one type of N2 subunit also have been reported and the relative contribution of di- and triheteromeric NMDA receptors at synapses has been difficult to assess. Because wild-type hippocampal principal neurons express N1, N2A and N2B, we used cultured hippocampal principal neurons from N2A and N2B-knockout mice as templates for diheteromeric synaptic receptors. Summation of N1/N2B and N1/N2A excitatory postsynaptic currents could not account for the deactivation kinetics of wild-type excitatory postsynaptic currents (EPSCs) however. To make a quantitative estimate of NMDA receptor subtypes at wild-type synapses, we used the deactivation kinetics, as well as the effects of the competitive antagonist NVP-AAM077. Our results indicate that three types of NMDA receptors contribute to the wild-type EPSC, with at least two-thirds being triheteromeric receptors. Functional isolation of synaptic triheteromeric receptors revealed deactivation kinetics and pharmacology distinct from either diheteromeric receptor subtype. Because of differences in open probability, synaptic triheteromeric receptors outnumbered N1/N2A receptors by 5.8 to 1 and N1/N2B receptors by 3.2 to 1. Our results suggest that triheteromeric NMDA receptors must be either preferentially assembled or preferentially localized at synapses. PMID:23699525

  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. Contribution of NMDA and non-NMDA receptors to in vivo glutamate-induced calpain activation in the rat striatum. Relation to neuronal damage.

    PubMed

    Del Río, Perla; Montiel, Teresa; Massieu, Lourdes

    2008-08-01

    Glutamate, the major excitatory neurotransmitter, can cause the death of neurons by a mechanism known as excitotoxicity. This is a calcium-dependent process and activation of the NMDA receptor subtype contributes mainly to neuronal damage, due to its high permeability to calcium. Activation of calpain, a calcium-dependent cysteine protease, has been implicated in necrotic excitotoxic neuronal death. We have investigated the contribution of NMDA and non-NMDA ionotropic receptors to calpain activation and neuronal death induced by the acute administration of glutamate into the rat striatum. Calpain activity was assessed by the cleavage of the cytoskeletal protein, alpha-spectrin. Caspase-3 activity was also studied because glutamate can also lead to apoptosis. Results show no caspase-3 activity, but a strong calpain activation involving both NMDA and non-NMDA receptors. Although neuronal damage is mediated mainly by the NMDA receptor subtype, it can not be attributed solely to calpain activity.

  17. 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.

  18. An extrasynaptic GABAergic signal modulates a pattern of forward movement in Caenorhabditis elegans

    PubMed Central

    Shen, Yu; Wen, Quan; Liu, He; Zhong, Connie; Qin, Yuqi; Harris, Gareth; Kawano, Taizo; Wu, Min; Xu, Tianqi; Samuel, Aravinthan DT; Zhang, Yun

    2016-01-01

    As a common neurotransmitter in the nervous system, γ-aminobutyric acid (GABA) modulates locomotory patterns in both vertebrates and invertebrates. However, the signaling mechanisms underlying the behavioral effects of GABAergic modulation are not completely understood. Here, we demonstrate that a GABAergic signal in C. elegans modulates the amplitude of undulatory head bending through extrasynaptic neurotransmission and conserved metabotropic receptors. We show that the GABAergic RME head motor neurons generate undulatory activity patterns that correlate with head bending and the activity of RME causally links with head bending amplitude. The undulatory activity of RME is regulated by a pair of cholinergic head motor neurons SMD, which facilitate head bending, and inhibits SMD to limit head bending. The extrasynaptic neurotransmission between SMD and RME provides a gain control system to set head bending amplitude to a value correlated with optimal efficiency of forward movement. DOI: http://dx.doi.org/10.7554/eLife.14197.001 PMID:27138642

  19. Neuronal activity in the hub of extrasynaptic Schwann cell-axon interactions

    PubMed Central

    Samara, Chrysanthi; Poirot, Olivier; Domènech-Estévez, Enric; Chrast, Roman

    2013-01-01

    The integrity and function of neurons depend on their continuous interactions with glial cells. In the peripheral nervous system glial functions are exerted by Schwann cells (SCs). SCs sense synaptic and extrasynaptic manifestations of action potential propagation and adapt their physiology to support neuronal activity. We review here existing literature data on extrasynaptic bidirectional axon-SC communication, focusing particularly on neuronal activity implications. To shed light on underlying mechanisms, we conduct a thorough analysis of microarray data from SC-rich mouse sciatic nerve at different developmental stages and in neuropathic models. We identify molecules that are potentially involved in SC detection of neuronal activity signals inducing subsequent glial responses. We further suggest that alterations in the activity-dependent axon-SC crosstalk impact on peripheral neuropathies. Together with previously reported data, these observations open new perspectives for deciphering glial mechanisms of neuronal function support. PMID:24324401

  20. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors

    PubMed Central

    Mortensen, Martin; Ebert, Bjarke; Wafford, Keith; Smart, Trevor G

    2010-01-01

    The activation characteristics of synaptic and extrasynaptic GABAA receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of α1β3γ2, α4β3γ2 and α4β3δ receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At δ subunit-containing extrasynaptic-type GABAA receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on α4β3δ receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. PMID:20176630

  1. γ-Hydroxybutyric acid (GHB) is not an agonist of extrasynaptic GABAA receptors.

    PubMed

    Connelly, William M; Errington, Adam C; Crunelli, Vincenzo

    2013-01-01

    γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4β1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents.

  2. Extrasynaptic α6 Subunit-Containing GABAA Receptors Modulate Excitability in Turtle Spinal Motoneurons

    PubMed Central

    Andres, Carmen; Aguilar, Justo; González-Ramírez, Ricardo; Elias-Viñas, David; Felix, Ricardo; Delgado-Lezama, Rodolfo

    2014-01-01

    Motoneurons are furnished with a vast repertoire of ionotropic and metabotropic receptors as well as ion channels responsible for maintaining the resting membrane potential and involved in the regulation of the mechanisms underlying its membrane excitability and firing properties. Among them, the GABAA receptors, which respond to GABA binding by allowing the flow of Cl− ions across the membrane, mediate two distinct forms of inhibition in the mature nervous system, phasic and tonic, upon activation of synaptic or extrasynaptic receptors, respectively. In a previous work we showed that furosemide facilitates the monosynaptic reflex without affecting the dorsal root potential. Our data also revealed a tonic inhibition mediated by GABAA receptors activated in motoneurons by ambient GABA. These data suggested that the high affinity GABAA extrasynaptic receptors may have an important role in motor control, though the molecular nature of these receptors was not determined. By combining electrophysiological, immunofluorescence and molecular biology techniques with pharmacological tools here we show that GABAA receptors containing the α6 subunit are expressed in adult turtle spinal motoneurons and can function as extrasynaptic receptors responsible for tonic inhibition. These results expand our understanding of the role of GABAA receptors in motoneuron tonic inhibition. PMID:25531288

  3. 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.

  4. Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs.

    PubMed

    Sanderson, Thomas M; Collingridge, Graham L; Fitzjohn, Stephen M

    2011-07-27

    The removal of AMPA receptors from synapses is a major component of long-term depression (LTD). How this occurs, however, is still only partially understood. To investigate the trafficking of AMPA receptors in real-time we previously tagged the GluA2 subunit of AMPA receptors with ecliptic pHluorin and studied the effects of NMDA receptor activation. In the present study we have compared the effect of NMDA receptor and group I mGluR activation, using GluA2 tagged with super ecliptic pHluorin (SEP-GluA2) expressed in cultured hippocampal neurons. Surprisingly, agonists of the two receptors, which are both able to induce chemical forms of LTD, had clearly distinct effects on AMPA receptor trafficking. In agreement with our previous work we found that transient NMDA receptor activation results in an initial decrease in surface GluA2 from extrasynaptic sites followed by a delayed reduction in GluA2 from puncta (putative synapses). In contrast, transient activation of group I mGluRs, using DHPG, led to a pronounced but more delayed decrease in GluA2 from the dendritic shafts. Surprisingly, there was no average change in the fluorescence of the puncta. Examination of fluorescence at individual puncta, however, indicated that alterations did take place, with some puncta showing an increase and others a decrease in fluorescence. The effects of DHPG were, like DHPG-induced LTD, prevented by treatment with a protein tyrosine phosphatase (PTP) inhibitor. The electrophysiological correlate of the effects of DHPG in the SEP-GluA2 infected cultures was a reduction in mEPSC frequency with no change in amplitude. The implications of these findings for the initial mechanisms of expression of both NMDA receptor- and mGluR-induced LTD are discussed.

  5. Taurine is a potent activator of extrasynaptic GABA(A) receptors in the thalamus.

    PubMed

    Jia, Fan; Yue, Minerva; Chandra, Dev; Keramidas, Angelo; Goldstein, Peter A; Homanics, Gregg E; Harrison, Neil L

    2008-01-02

    Taurine is one of the most abundant free amino acids in the brain. In a number of studies, taurine has been reported to activate glycine receptors (Gly-Rs) at moderate concentrations (> or = 100 microM), and to be a weak agonist at GABA(A) receptors (GABA(A)-Rs), which are usually activated at high concentrations (> or = 1 mM). In this study, we show that taurine reduced the excitability of thalamocortical relay neurons and activated both extrasynaptic GABA(A)-Rs and Gly-Rs in neurons in the mouse ventrobasal (VB) thalamus. Low concentrations of taurine (10-100 microM) decreased neuronal input resistance and firing frequency, and elicited a steady outward current under voltage clamp, but had no effects on fast inhibitory synaptic currents. Currents elicited by 50 microM taurine were abolished by gabazine, insensitive to midazolam, and partially blocked by 20 microM Zn2+, consistent with the pharmacological properties of extrasynaptic GABA(A)-Rs (alpha4beta2delta subtype) involved in tonic inhibition in the thalamus. Tonic inhibition was enhanced by an inhibitor of taurine transport, suggesting that taurine can act as an endogenous activator of these receptors. Taurine-evoked currents were absent in relay neurons from GABA(A)-R alpha4 subunit knock-out mice. The amplitude of the taurine current was larger in neurons from adult mice than juvenile mice. Taurine was a more potent agonist at recombinant alpha4beta2delta GABA(A)-Rs than at alpha1beta2gamma2 GABA(A)-Rs. We conclude that physiological concentrations of taurine can inhibit VB neurons via activation of extrasynaptic GABA(A)-Rs and that taurine may function as an endogenous regulator of excitability and network activity in the thalamus.

  6. Increased extrasynaptic GluN2B expression is involved in cognitive impairment after isoflurane anesthesia.

    PubMed

    Li, Lunxu; Li, Zhengqian; Cao, Yiyun; Fan, Dongsheng; Chui, Dehua; Guo, Xiangyang

    2016-07-01

    There is increasing concern regarding the postoperative cognitive dysfunction (POCD) in the aging population, and general anesthetics are believed to be involved. Isoflurane exposure induced increased N-methyl-D-aspartic acid receptor (NMDAR) GluN2B subunit expression following anesthesia, which was accompanied by alteration of the cognitive function. However, whether isoflurane affects this expression in different subcellular compartments, and is involved in the development of POCD remains to be elucidated. The aims of the study were to investigate the effects of isoflurane on the expression of the synaptic and extrasynaptic NMDAR subunits, GluN2A and GluN2B, as well as the associated alteration of cognitive function in aged rats. The GluN2B antagonist, Ro25-6981, was given to rats exposed to isoflurane to determine the role of GluN2B in the isoflurane-induced alteration of cognitive function. The results showed that spatial learning and memory tested in the Morris water maze (MWM) was impaired at least 7 days after isoflurane exposure, and was returned to control levels 30 days thereafter. Ro25-6981 treatment can alleviate this impairment. Extrasynaptic GluN2B protein expression, but not synaptic GluN2B or GluN2A, increased significantly after isoflurane exposure compared to non-isoflurane exposure, and returned to control levels approximately 30 days thereafter. The results of the present study indicated that isoflurane induced the prolonged upregulation of extrasynaptic GluN2B expression after anesthesia and is involved in reversible cognitive impairment.

  7. CXCR4 and NMDA Receptors Are Functionally Coupled in Rat Hippocampal Noradrenergic and Glutamatergic Nerve Endings.

    PubMed

    Di Prisco, Silvia; Olivero, Guendalina; Merega, Elisa; Bonfiglio, Tommaso; Marchi, Mario; Pittaluga, Anna

    2016-12-01

    Previous studies had shown that the HIV-1 capsidic glycoprotein gp120 (strain IIIB) modulates presynaptic release-regulating NMDA receptors on noradrenergic and glutamatergic terminals. This study aims to assess whether the chemokine CXC4 receptors (CXCR4s) has a role in the gp120-mediated effects. The effect of CXCL12, the endogenous ligand at CXCR4, on the NMDA-mediated releasing activity was therefore investigated. Rat hippocampal synaptosomes were preloaded with [(3)H]noradrenaline ([(3)H]NA) or [(3)H]D-aspartate ([(3)H]D-Asp) and acutely exposed to CXCL12, to NMDA or to both agonists. CXCL12, inactive on its own, facilitated the NMDA-evoked tritium release. The NMDA antagonist MK-801 abolished the NMDA/CXCL12-evoked tritium release of both radiolabelled tracers, while the CXCR4 antagonist AMD 3100 halved it, suggesting that rat hippocampal nerve endings possess presynaptic release-regulating CXCR4 receptors colocalized with NMDA receptors. Accordingly, Western blot analysis confirmed the presence of CXCR4 proteins in synaptosomal plasmamembranes. In both synaptosomal preparations, CXCL12-induced facilitation of NMDA-mediated release was dependent upon PLC-mediated src-induced events leading to mobilization of Ca(2+) from intraterminal IP3-sensitive stores Finally, the gp120-induced facilitation of NMDA-mediated release of [(3)H]NA and [(3)H]D-Asp was prevented by AMD 3100. We propose that CXCR4s are functionally coupled to NMDA receptors in rat hippocampal noradrenergic and glutamatergic terminals and account for the gp120-induced modulation of the NMDA-mediated central effects. The NMDA/CXCR4 cross-talk could have a role in the neuropsychiatric symptoms often observed in HIV-1 positive patients.

  8. 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

  9. PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61

    PubMed Central

    Won, Sehoon; Incontro, Salvatore; Nicoll, Roger A.; Roche, Katherine W.

    2016-01-01

    Phosphorylation regulates surface and synaptic expression of NMDA receptors (NMDARs). Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal-enriched protein tyrosine phosphatase (STEP) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472, which is a critical residue that mediates NMDAR endocytosis. STEP reduces the surface expression of NMDARs by promoting dephosphorylation of GluN2B Y1472, whereas the synaptic scaffolding protein postsynaptic density protein 95 (PSD-95) stabilizes the surface expression of NMDARs. However, nothing is known about a potential functional interaction between STEP and PSD-95. We now report that STEP61 binds to PSD-95 but not to other PSD-95 family members. We find that PSD-95 expression destabilizes STEP61 via ubiquitination and degradation by the proteasome. Using subcellular fractionation, we detect low amounts of STEP61 in the PSD fraction. However, STEP61 expression in the PSD is increased upon knockdown of PSD-95 or in vivo as detected in PSD-95–KO mice, demonstrating that PSD-95 excludes STEP61 from the PSD. Importantly, only extrasynaptic NMDAR expression and currents were increased upon STEP knockdown, as is consistent with low STEP61 localization in the PSD. Our findings support a dual role for PSD-95 in stabilizing synaptic NMDARs by binding directly to GluN2B but also by promoting synaptic exclusion and degradation of the negative regulator STEP61. PMID:27457929

  10. Memory retrieval requires ongoing protein synthesis and NMDA receptor activity-mediated AMPA receptor trafficking.

    PubMed

    Lopez, Joëlle; Gamache, Karine; Schneider, Rilla; Nader, Karim

    2015-02-11

    Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synthesis, memory retrieval has long been considered a passive readout of previously established plasticity. However, previous findings suggest that memory retrieval may be more dynamic than previously thought. This study therefore aimed at investigating the molecular mechanisms underlying memory retrieval in the rat. Infusion of protein synthesis inhibitors (rapamycin or anisomycin) in the amygdala 10 min before memory retrieval transiently impaired auditory fear memory expression, suggesting ongoing protein synthesis is required to enable memory retrieval. We then investigated the role of protein synthesis in NMDA receptor activity-mediated AMPA receptor trafficking. Coinfusion of an NMDA receptor antagonist (ifenprodil) or infusion of an AMPA receptor endocytosis inhibitor (GluA23Y) before rapamycin prevented this memory impairment. Furthermore, rapamycin transiently decreased GluA1 levels at the postsynaptic density (PSD), but did not affect extrasynaptic sites. This effect at the PSD was prevented by an infusion of GluA23Y before rapamycin. Together, these data show that ongoing protein synthesis is required before memory retrieval is engaged, and suggest that this protein synthesis may be involved in the NMDAR activity-mediated trafficking of AMPA receptors that takes place during memory retrieval.

  11. Extrasynaptic δ-containing GABAA receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

    PubMed Central

    Nie, Hong; Rewal, Mridula; Gill, T. Michael; Ron, Dorit; Janak, Patricia H.

    2011-01-01

    Recent findings suggest that extrasynaptic δ-subunit–containing GABAA receptors are sensitive to low-to-moderate concentrations of alcohol, raising the possibility that these receptors mediate the reinforcing effects of alcohol after consumption of one or a few drinks. We used the technique of viral-mediated RNAi to reduce expression of the GABAA receptor δ-subunit in adult rats in localized regions of the nucleus accumbens (NAc) to test the hypothesis that δ-subunit–containing GABAA receptors in the NAc are necessary for oral alcohol consumption. We found that knockdown of the δ-subunit in the medial shell region of the NAc, but not in the ventral or lateral shell or in the core, reduced alcohol intake. In contrast, δ-subunit knockdown in the medial shell did not affect intake of a 2% sucrose solution, suggesting that the effects of GABAA receptor δ-subunit reduction are specific to alcohol. These results provide strong evidence that extrasynaptic δ-subunit–containing GABAA receptors in the medial shell of the NAc are critical for the reinforcing effects of oral ethanol. PMID:21368141

  12. Inverse relationship between seizure expression and extrasynaptic NMDAR function following chronic NMDAR inhibition.

    PubMed

    Bausch, Suzanne B; He, Shuijin; Dong, Yu

    2010-07-01

    We showed previously that electrographic seizures involving dentate granule cells in organotypic hippocampal slice cultures were dramatically reduced following chronic treatment with the NR2B-selective antagonist, Ro25,6981, but were increased following chronic treatment with the high-affinity competitive antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D-APV). To begin to investigate the potential mechanisms underlying the differential effects of N-methyl-D-aspartate receptor (NMDAR) antagonists on seizures, electrophysiologic experiments were conducted in dentate granule cells in hippocampal slice cultures treated for the entire 17-21 day culture period with vehicle, Ro25,6981 or D-APV. Initial experiments revealed a lack of an association between miniature excitatory postsynaptic current (mEPSC) measures and seizures suggesting that shifts in mEPSC were unlikely to account for the differential effects of D-APV and Ro25,6981 on seizures. However, the amplitude of tonic NMDAR-mediated currents was reduced in cultures treated chronically with D-APV and dramatically enhanced in cultures treated chronically with Ro25,6981. Because tonic NMDAR currents are mediated primarily by extrasynaptic NMDAR, these data show an inverse relationship between changes in extrasynaptic NMDAR function and alterations in seizure expression.

  13. GluN2A Subunit-Containing NMDA Receptors Are the Preferential Neuronal Targets of Homocysteine

    PubMed Central

    Sibarov, Dmitry A.; Abushik, Polina A.; Giniatullin, Rashid; Antonov, Sergei M.

    2016-01-01

    by GluN2A-containing NMDA receptors. On the other hand, HCY toxicity may be limited by desensitization typical for HCY-induced activation of GluN2B-containing extrasynaptic receptors. Our findings, therefore, provide an evidence for the physiological relevance of endogenous HCY, which may represent an effective endogenous modulator of the central excitatory neurotransmission. PMID:27847466

  14. Age-dependent effects on social interaction of NMDA GluN2A receptor subtype-selective antagonism.

    PubMed

    Green, Torrian L; Burket, Jessica A; Deutsch, Stephen I

    2016-07-01

    NMDA receptor-mediated neurotransmission is implicated in the regulation of normal sociability in mice. The heterotetrameric NMDA receptor is composed of two obligatory GluN1 and either two "modulatory" GluN2A or GluN2B receptor subunits. GluN2A and GluN2B-containing receptors differ in terms of their developmental expression, distribution between synaptic and extrasynaptic locations, and channel kinetic properties, among other differences. Because age-dependent differences in disruptive effects of GluN2A and GluN2B subtype-selective antagonists on sociability and locomotor activity have been reported in rats, the current investigation explored age-dependent effects of PEAQX, a GluN2A subtype-selective antagonist, on sociability, stereotypic behaviors emerging during social interaction, and spatial working memory in 4- and 8-week old male Swiss Webster mice. The data implicate an age-dependent contribution of GluN2A-containing NMDA receptors to the regulation of normal social interaction in mice. Specifically, at a dose of PEAQX devoid of any effect on locomotor activity and mouse rotarod performance, the social interaction of 8-week old mice was disrupted without any effect on the social salience of a stimulus mouse. Moreover, PEAQX attenuated stereotypic behavior emerging during social interaction in 4- and 8-week old mice. However, PEAQX had no effect on spontaneous alternations, a measure of spatial working memory, suggesting that neural circuits mediating sociability and spatial working memory may be discrete and dissociable from each other. Also, the data suggest that the regulation of stereotypic behaviors and sociability may occur independently of each other. Because expression of GluN2A-containing NMDA receptors occurs at a later developmental stage, they may be more involved in mediating the pathogenesis of ASDs in patients with histories of "regression" after a period of normal development than GluN2B receptors.

  15. Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors.

    PubMed

    Liu, Shui-bing; Zhao, Ming-gao

    2013-04-01

    Excessive activation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in the pathophysiology of chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Some studies reported that NR2A and NR2B play different roles in the central nervous system (CNS). The NR2A subunit is primarily found in the synapses and is required for glutamate-mediated neuronal survival. On the other hand, the NR2B subunit is primarily found in the extrasynaptic sites and is required for glutamate-mediated neuronal death in both in vitro and in vivo experiments. Estrogen is a steroid hormone well known for its widespread effects such as neuroprotection in the brain. Classically, estrogen can bind to two kinds of nuclear receptors, namely, estrogen receptor α (ERα) and estrogen receptor β (ERβ), and produce physiological and neuroprotective effects. Aside from nuclear receptors, estrogen has one membrane receptor, which can either be G-protein-coupled receptor 30 (GPR30), Gq-mER, or ER-X. NMDA exposure clearly promotes NR2B subunit phosphorylation at Ser-1303 and causes neuronal cell death. GPR30 mediates rapid non-genomic effects to protect neurons against injury by inhibiting p-DAPK1 dephosphorylation, which inhibits NR2B subunit phosphorylation at Ser-1303. In addition, NMDA exposure and global ischemia activate the autophagy pathway and induce cell death, which are markedly blocked by the NR2B antagonist Ro 25-6981. Thus, NR2B signaling, autophagy induction and cell death may be closely related. Ro 25-6981 inhibits the dissociation of the NR2B-Beclin-1 signaling complex and delays autophagy in vivo, thus confirming the link between NR2B signaling and autophagy. In short, ERα, ERβ, and GPR30 are involved in the neuroprotection of estrogen in the CNS. Additional research must be conducted to reveal the mechanism of estrogen action fully and to identify better targets for the development of more effective drugs. This

  16. Catamenial-like seizure exacerbation in mice with targeted ablation of extrasynaptic δGABA-a receptors in the brain.

    PubMed

    Clossen, Bryan L; Reddy, Doodipala Samba

    2017-02-25

    Neurosteroids play a key role in catamenial epilepsy, a menstrual cycle-related seizure clustering in women with epilepsy. While neurosteroids act on all GABA-A receptor isoforms, they cause greater effects on extrasynaptic δGABA-A receptors that mediate tonic inhibition in the brain. Previously, we identified a potential GABA-A receptor mechanism for catamenial epilepsy. However, the precise functional role of extrasynaptic δGABA-A receptors in the pathophysiology of catamenial epilepsy remains unclear. In this study, we utilized mice lacking extrasynaptic δGABA-A receptors (δKO) to investigate whether reduction of tonic inhibition affects catamenial seizure susceptibility or intensity. Intact female wildtype (WT) and δKO mice were subjected to hippocampus kindling until they exhibited stage 5 seizures. Elevated gonadal hormone-based neurosteroid levels were induced by standard gonadotropin regimen and neurosteroid withdrawal (NSW) was triggered by finasteride. NSW increased susceptibility to, as well the intensity of evoked catamenial-like seizures in WT and δKO mice. However, fully kindled δKO mice exhibited an accelerated and augmented response to NSW, with a more rapid increase in seizure susceptibility and intensity than WT mice undergoing the NSW paradigm. Moreover, δKO mice in NSW showed reduced benzodiazepine sensitivity, but in stark contrast to the increased neurosteroid sensitivity observed in WT animals, δKO mice displayed no change in neurosteroid sensitivity in response to NSW. The increased catamenial seizure exacerbation and alterations in antiseizure drug responses are consistent with NSW-induced changes in the abundance of δGABA-A receptors. Collectively, these findings provide evidence of a potential protective role for extrasynaptic δGABA-A receptors in catamenial-like seizures. © 2017 Wiley Periodicals, Inc.

  17. Differential Regulation of GABAB Receptor Trafficking by Different Modes of N-methyl-d-aspartate (NMDA) Receptor Signaling*

    PubMed Central

    Kantamneni, Sriharsha; Gonzàlez-Gonzàlez, Immaculada M.; Luo, Jia; Cimarosti, Helena; Jacobs, Susan C.; Jaafari, Nadia; Henley, Jeremy M.

    2014-01-01

    Inhibitory GABAB receptors (GABABRs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABABRs are heterodimers of GABAB1 and GABAB2 subunits and here we show that the trafficking and surface expression of GABABRs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABABR recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABABRs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABAB1 but decreases GABAB2 surface expression. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABABR trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival. PMID:24425870

  18. A translational approach for NMDA receptor profiling as a vulnerability biomarker for depression and schizophrenia.

    PubMed

    Gunduz-Bruce, Handan; Kenney, Joshua; Changlani, Suravi; Peixoto, Aldo; Gueorguieva, Ralitza; Leone, Cheryl; Stachenfeld, Nina

    2017-03-13

    Altered N-methyl-D-aspartate (NMDA) receptor activity and glutamate signaling may underlie the pathogenesis of both schizophrenia and depression in subgroups of patients. In schizophrenia, pharmacologic modeling, postmortem and imaging data suggest reduced NMDA signaling. In contrast, recent clinical trials demonstrating the efficacy of the NMDA antagonist ketamine in severely depressed patients suggest increased NMDA receptor signaling. We conducted a proof of concept study to assess whether there is any in vivo evidence for an inverse association in depression and schizophrenia with respect to the NMDA receptor function. For this purpose we used a translational approach, based on findings from animal studies that NMDA receptor is a key mediator of arginine-vasopressin (AVP) release into the bloodstream. Using hypertonic saline to induce AVP release, as done in animal studies, we found that in depressed patients, NMDA receptor mediated AVP release induced by hypertonic saline infusion was significantly increased 0.24 (0.15) pg/ml P[AVP] /mOsmol POsm , P< 0.05 compared to schizophrenia patients 0.07 (0.07) pg/ml P[AVP] /mOsmol POsm , in whom same response was abnormally low. Slopes for healthy control were 0.11 (0.09) pg/ml P[AVP] /mOsmol POsm , and not different than either group. These findings are consistent with implicated NMDA receptor related abnormalities in depression and schizophrenia in subgroups of patients, and provide the first in vivo evidence towards this dichotomy. This article is protected by copyright. All rights reserved.

  19. Exacerbation of NMDA, AMPA, and L-glutamate excitotoxicity by the succinate dehydrogenase inhibitor malonate.

    PubMed

    Greene, J G; Greenamyre, J T

    1995-05-01

    We report that a subtoxic dose of the succinate dehydrogenase (SDH) inhibitor malonate greatly enhances the neurotoxicity of three different excitatory amino acid agonists: N-methyl-D-aspartate (NMDA), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA), and L-glutamate. In male Sprague-Dawley rats, intrastriatal stereotaxic injection of malonate alone (0.6 mumol), NMDA alone (15 nmol), S-AMPA alone (1 nmol), or glutamate alone (0.6 mumol) produced negligible toxicity as assessed by measurement of lesion volume. Coinjection of subtoxic malonate with NMDA produced a large lesion (15.2 +/- 1.4 mm3), as did coinjection of malonate with S-AMPA (11.0 +/- 1.0 mm3) or glutamate (12.8 +/- 0.7 mm3). Administration of the noncompetitive NMDA antagonist MK-801 (5 mg/kg i.p.) completely blocked the toxicity of malonate plus NMDA (0.5 +/- 0.3 mm3). This dose of MK-801 had little effect on the lesion produced by malonate plus S-AMPA (9.0 +/- 0.7 mm3), but it attenuated the toxicity of malonate plus glutamate by approximately 40% (7.5 +/- 0.9 mm3). Coinjection of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX; 2 nmol) had no effect on malonate plus NMDA or malonate plus glutamate toxicity (12.3 +/- 1.8 and 14.0 +/- 0.9 mm3, respectively) but greatly attenuated malonate plus S-AMPA toxicity (1.5 +/- 0.9 mm3). Combination of the two antagonists conferred no additional neuroprotection in any paradigm. These results indicate that metabolic inhibition exacerbates both NMDA receptor- and non-NMDA receptor-mediated excitotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. NMDA receptor and schizophrenia: a brief history.

    PubMed

    Coyle, Joseph T

    2012-09-01

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

  1. Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study.

    PubMed

    Cano-Cebrián, M J; Zornoza-Sabina, T; Guerri, C; Polache, A; Granero, L

    2003-02-01

    The effects of acamprosate on the in vivo dopamine extracellular levels in the nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in these effects were investigated. Microdialysis in freely moving rats was used to assess dopamine levels before and during simultaneous perfusion of acamprosate and/or different agonists or antagonists of NMDA receptors. Perfusion with acamprosate at concentrations of 0.5 and 5 mM provoked a concentration-dependent increase in extracellular dopamine in nucleus accumbens. The lowest concentration of acamprosate assayed (0.05 mM) had no effect on dopamine levels. Infusion of NMDA (25 and 500 microM) and the glutamate uptake blocker, L-trans-pyrrolidine-2,4-dicarboxilic acid (PDC) (0.5 mM) into the NAc caused a significant increase in DA, whereas acamprosate (0.05 mM) co-infusion with these compounds blocked or attenuated the NMDA and PDC-induced increases in DA levels. Co-infusion of the selective antagonist of NMDA receptors, DL-2-amino-5-phosphonopentanoic acid (AP5) (400 microM) with acamprosate (0.5 mM), did not reduce the increase of DA levels induced by acamprosate. These results demonstrate that acamprosate is able to modulate DA extracellular levels in NAc via NMDA receptors and suggest that acamprosate acts as an antagonist of NMDA receptors.

  2. 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

  3. NMDA Receptor Antagonists for Treatment of Depression

    PubMed Central

    Ates-Alagoz, Zeynep; Adejare, Adeboye

    2013-01-01

    Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery. PMID:24276119

  4. Surface expression of NMDA receptor changes during memory consolidation in the crab Neohelice granulata.

    PubMed

    Hepp, Yanil; Salles, Angeles; Carbo-Tano, Martin; Pedreira, Maria Eugenia; Freudenthal, Ramiro

    2016-08-01

    The aim of the present study was to analyze the surface expression of the NMDA-like receptors during the consolidation of contextual learning in the crab Neohelice granulata Memory storage is based on alterations in the strength of synaptic connections between neurons. The glutamatergic synapses undergo various forms of N-methyl-D aspartate receptor (NMDAR)-dependent changes in strength, a process that affects the abundance of other receptors at the synapse and underlies some forms of learning and memory. Here we propose a direct regulation of the NMDAR. Changes in NMDAR's functionality might be induced by the modification of the subunit's expression or cellular trafficking. This trafficking does not only include NMDAR's movement between synaptic and extra-synaptic localizations but also the cycling between intracellular compartments and the plasma membrane, a process called surface expression. Consolidation of contextual learning affects the surface expression of the receptor without affecting its general expression. The surface expression of the GluN1 subunit of the NMDAR is down-regulated immediately after training, up-regulated 3 h after training and returns to naïve and control levels 24 h after training. The changes in NMDAR surface expression observed in the central brain are not seen in the thoracic ganglion. A similar increment in surface expression of GluN1 in the central brain is observed 3 h after administration of the competitive GABAA receptor antagonist, bicuculline. These consolidation changes are part of a plasticity event that first, during the down-regulation, stabilizes the trace and later, at 3-h post-training, changes the threshold for synapse activation.

  5. DOSE RESPONSE DEETERMINATION OF NMDA ANTAGONISTS AND GABA AGONIST ON SUSTAINED ATTENTION.

    EPA Science Inventory

    We have shown that acute inhalation of toluene impairs sustained attention as assessed with a visual signal detection task (SDT). In vitro studies indicate that the NMDA and GABA systems are primary targets of anesthetic agents and organic solvents such as toluene. Pharmacologica...

  6. 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…

  7. Chronic administration of nicotine enhances NMDA-activated currents in the prefrontal cortex and core part of the nucleus accumbens of rats.

    PubMed

    Ávila-Ruiz, Tania; Carranza, Vladimir; Gustavo, López-López; Limón, Daniel I; Martínez, Isabel; Flores, Gonzalo; Flores-Hernández, Jorge

    2014-06-01

    Nicotine is an addictive substance of tobacco. It has been suggested that nicotine acts on glutamatergic (N-methyl-d-aspartate, NMDA) neurotransmission affecting dopamine release in the mesocorticolimbic system. This effect is reflected in neuroadaptative changes that can modulate neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) core (cNAcc) and shell (sNAcc) regions. We evaluated the effect of chronic administration of nicotine (4.23 mg/kg/day for 14 days) on NMDA activated currents in dissociated neurons from the PFC, and NAcc (from core and shell regions). We assessed nicotine blood levels by mass spectrophotometry and we confirmed that nicotine increases locomotor activity. An electrophysiological study showed an increase in NMDA currents in neurons from the PFC and core part of the NAcc in animals treated with nicotine compared to those of control rats. No change was observed in neurons from the shell part of the NAcc. The enhanced glutamatergic activity observed in the neurons of rats with chronic administration of nicotine may explain the increased locomotive activity also observed in such rats. To assess one of the possible causes of increased NMDA currents, we used magnesium, to block NMDA receptor that contains the NR2B subunit. If there is a change in percent block of NMDA currents, it means that there is a possible change in expression of NMDA receptor subunits. Our results showed that there is no difference in the blocking effect of magnesium on the NMDA currents. The magnesium lacks of effect after nicotinic treatment suggests that there is no change in expression of NR2B subunit of NMDA receptors, then, the effect of nicotine treatment on amplitude of NMDA currents may be due to an increase in the quantity of receptors or to a change in the unitary conductance, rather than a change in the expression of the subunits that constitute it.

  8. Anti-NMDA Receptor Encephalitis and Vaccination

    PubMed Central

    Wang, Hsiuying

    2017-01-01

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

  9. Anti-NMDA Receptor Encephalitis and Vaccination.

    PubMed

    Wang, Hsiuying

    2017-01-18

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

  10. 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.

  11. Peripheral NMDA and non-NMDA receptors contribute to nociception: an electrophysiological study.

    PubMed

    Wang, C; Wang, Y; Zhao, Z

    2000-05-01

    The present study investigated the effects of peripheral administration of N-methy-D-aspartate (NMDA) and non-NMDA receptor antagonists on C-fiber evoked responses of the spinal dorsal horn neurons in the spinalized rats. When DL-2-amino-5-phosphonovaleric acid (AP5) (10 mM, 1 mM, 0.1 mM, 20 microl) or 6, 7-dinitroquinoxaline-2, 3-dione (DNQX) (1 mM, 0.1 mM, 0.01 mM, 20 microl) was subcutaneously injected into the receptive field on the hindplantar region, C-fiber evoked responses of the dorsal horn neurons were profoundly inhibited in a dose-dependent manner. Three hours after subcutaneous injection of carrageenan into the ipsilateral hindpaw, NMDA and non-NMDA antagonist-induced inhibition of C-fiber evoked responses was more potent than that in the normal rat (Student's t-test, p < 0.05). In the carragenan-treated rats, DNQX-induced inhibition was stronger than AP-5-induced one (Student's t-test, p < 0.05). The results suggest that peripheral NMDA and non-NMDA receptors are involved in mediating excitation of nociceptors.

  12. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

    PubMed Central

    Dalmau, Josep; Gleichman, Amy J; Hughes, Ethan G; Rossi, Jeffrey E; Peng, Xiaoyu; Lai, Meizan; Dessain, Scott K; Rosenfeld, Myrna R; Balice-Gordon, Rita; Lynch, David R

    2008-01-01

    Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. PMID:18851928

  13. Influence of a threonine residue in the S2 ligand binding domain in determining agonist potency and deactivation rate of recombinant NR1a/NR2D NMDA receptors.

    PubMed

    Chen, Philip E; Johnston, Alexander R; Mok, M H Selina; Schoepfer, Ralf; Wyllie, David J A

    2004-07-01

    NR1/NR2D NMDA receptors display unusually slow deactivation kinetics which may be critical for their role as extrasynaptic receptors. A threonine to alanine point mutation has been inserted at amino acid position 692 of the NR2D subunit (T692A). Recombinant NR1a/NR2D(T692A) NMDA receptors have been expressed in Xenopus laevis oocytes and their pharmacological and single-channel properties examined using two-electrode voltage-clamp and patch-clamp recording techniques. Glutamate dose-response curves from NR1a/NR2D(T692A) receptor channels produced an approximately 1600-fold reduction in glutamate potency compared to wild-type NR1a/NR2D receptors. There was no change in Hill slopes or gross reduction in mean maximal currents recorded in oocytes expressing either wild-type or mutant receptors. The mutation did not affect the potency of the co-agonist glycine. The shifts in potency produced by NR2D(T692A) containing receptors when activated by other glutamate-site agonists such as aspartate or NMDA were 30- to 60-fold compared to wild-type. Single-channel conductance levels of NR1a/NR2D(T692A) mutant receptors were indistinguishable from wild-type NR2D-containing channels. Additionally NR1a/NR2D(T692A) receptors showed the transitional asymmetry that is characteristic of NR2D-containing NMDA receptors. Rapid applications of glutamate on outside-out patches containing NR1a/NR2D(T692A) receptors produced macroscopic current deactivations that were about 60-fold faster than wild-type NR1a/NR2D receptors. Our results suggest that this conserved threonine residue plays a crucial role in ligand binding to NMDA NR2 receptor subunits and supports the idea that the slow decay kinetics associated with NR1a/NR2D NMDA receptors can be explained by the slow dissociation of glutamate from this NMDA receptor subtype.

  14. Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

    PubMed Central

    Afroz, Sonia; Parato, Julie; Shen, Hui; Smith, Sheryl Sue

    2016-01-01

    Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4βδ GABAA receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4βδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4βδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4βδ GABARs. In their absence, pruning is prevented and cognition is not optimal. DOI: http://dx.doi.org/10.7554/eLife.15106.001 PMID:27136678

  15. A family of photoswitchable NMDA receptors

    PubMed Central

    Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, 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

  16. Spatial learning and goldfish telencephalon NMDA receptors.

    PubMed

    Gómez, Yolanda; Vargas, Juan Pedro; Portavella, Manuel; López, Juan Carlos

    2006-05-01

    Recent results have demonstrated that the mammalian hippocampus and the dorso-lateral telencephalon of ray-finned fishes share functional similarities in relation to spatial memory systems. In the present study, we investigated whether the physiological mechanisms of this hippocampus-dependent spatial memory system were also similar in mammals and ray-finned fishes, and therefore possibly conserved through evolution in vertebrates. In Experiment 1, we studied the effects of the intracranial administration of the noncompetitive NMDA receptor antagonist MK-801 during the acquisition of a spatial task. The results indicated dose-dependent drug-induced impairment of spatial memory. Experiment 2 evaluated if the MK-801 produced disruption of retrieval of a learned spatial response. Data showed that the administration of MK-801 did not impair the retrieval of the information previously stored. The last experiment analyzed the involvement of the telencephalic NMDA receptors in a spatial and in a cue task. Results showed a clear impairment in spatial learning but not in cue learning when NMDA receptors were blocked. As a whole, these results indicate that physiological mechanisms of this hippocampus-dependent system could be a general feature in vertebrate, and therefore phylogenetically conserved.

  17. 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.

  18. Beneficial effects of the NMDA antagonist ketamine on decision processes in visual search.

    PubMed

    Shen, Kelly; Kalwarowsky, Sarah; Clarence, Wendy; Brunamonti, Emiliano; Paré, Martin

    2010-07-21

    The ability of sensory-motor circuits to integrate sensory evidence over time is thought to underlie the process of decision-making in perceptual discrimination. Recent work has suggested that the NMDA receptor contributes to mediating neural activity integration. To test this hypothesis, we trained three female rhesus monkeys (Macaca mulatta) to perform a visual search task, in which they had to make a saccadic eye movement to the location of a target stimulus presented among distracter stimuli of lower luminance. We manipulated NMDA-receptor function by administering an intramuscular injection of the noncompetitive NMDA antagonist ketamine and assessed visual search performance before and after manipulation. Ketamine was found to lengthen response latency in a dose-dependent fashion. Surprisingly, it was also observed that response accuracy was significantly improved when lower doses were administered. These findings suggest that NMDA receptors play a crucial role in the process of decision-making in perceptual discrimination. They also further support the idea that multiple neural representations compete with one another through mutual inhibition, which may explain the speed-accuracy trade-off rule that shapes discrimination behavior: lengthening integration time helps resolve small differences between choice alternatives, thereby improving accuracy.

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

    PubMed

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

    2015-06-01

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

  20. NMDA receptor modulators: an updated patent review (2013 – 2014)

    PubMed Central

    Strong, Katie L; Jing, Yao; Prosser, Anthony R; Traynelis, Stephen F; Liotta, Dennis C

    2016-01-01

    Introduction The NMDA receptor mediates a slow component of excitatory synaptic transmission, and NMDA receptor dysfunction has been implicated in numerous neurological disorders. Thus, interest in developing modulators that are able to regulate the channel continues to be strong. Recent research has led to the discovery of a number of compounds that hold therapeutic and clinical value. Deeper insight into the NMDA inter-subunit interactions and structural motifs gleaned from the recently solved crystal structures of the NMDA receptor should facilitate a deeper understanding of how these compounds modulate the receptor. Areas covered This article discusses the known pharmacology of NMDA receptors. A discussion of the patent literature since 2012 is also included, with an emphasis on those that claimed new chemical entities as regulators of the NMDA receptor. Expert Opinion The number of patents involving novel NMDA receptor modulators suggests a renewed interest in the NMDA receptor as a therapeutic target. Subunit-selective modulators continue to show promise, and the development of new subunit-selective NMDA receptor modulators appears poised for continued growth. Although a modest number of channel blocker patents were published, successful clinical outcomes involving ketamine have led to a resurgent interest in low-affinity channel blockers as therapeutics. PMID:25351527

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

    PubMed

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

    2013-10-01

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

  2. NMDA antagonists increase recovery of evoked potentials from slices of rat olfactory cortex after anoxia.

    PubMed Central

    Yassin, M.; Scholfield, C. N.

    1994-01-01

    1. The role of glutamate in producing tissue damage during cerebral anoxia was investigated in brain slices using antagonists to the NMDA and AMPA receptor types. 2. Tissue function was assessed by field recordings of the synaptically evoked potentials elicited by stimulating the main afferent input to the olfactory cortex, the lateral olfactory tract. Anoxia was produced by bathing the slice in glucose-free solution equilibrated with 95% N2/5% CO2. 3. The amount of recovery of the evoked potential was inversely dependent on the period of anoxia and temperature: at 24 degrees C, 15 min of anoxia followed by reoxygenation produced a 14.6 +/- 4.1% recovery whereas there was no recovery at 35 degrees C. 4. Dizocilpine and ketamine had no effect on synaptic transmission in oxygenated media but following anoxia they produced an increased recovery of the responses: from 14.6 +/- 4.1% to 48.3 +/- 7.8% for dizocilpine (10 microM) and 21.6 +/- 7.7% to 87.2 +/- 7.1% for ketamine (200 microM); the tissue endurance to anoxia was increased by around 5 min. 5. Blockade of the AMPA receptors did not influence recovery in spite of the depressed synaptic transmission. A similar synaptic attenuation produced by lignocaine provided some increase in post-anoxic recovery. 6. The NMDA receptor antagonist, AP5, antagonized NMDA at 50 microM by 3.7 fold and at 200 microM by 15 fold but only 200 microM increased post-anoxic recovery. This suggests that a substantial degree of NMDA antagonist is required before anoxic tissue damage due to NMDA receptor activation can be nullified. The antagonist to the glycine binding site, 7-chlorokynurenic acid also increased recovery.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7913373

  3. Tonic Inhibition of Accumbal Spiny Neurons by Extrasynaptic α4βδ GABAA Receptors Modulates the Actions of Psychostimulants

    PubMed Central

    Maguire, Edward P.; Macpherson, Tom; Swinny, Jerome D.; Dixon, Claire I.; Herd, Murray B.; Belelli, Delia; Stephens, David N.

    2014-01-01

    Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/− or α4−/− mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/− mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4D1−/−) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4−/− or α4D1−/− mice, blocked cocaine enhancement of CPP. In comparison, α4D2−/− mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors. PMID:24431441

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

    PubMed

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

    2013-02-06

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

  5. MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function

    PubMed Central

    Szklarczyk, Arek; Ewaleifoh, Osefame; Beique, Jean-Claude; Wang, Yue; Knorr, David; Haughey, Norman; Malpica, Tanya; Mattson, Mark P.; Huganir, Richard; Conant, Katherine

    2008-01-01

    Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that play a role in the inflammatory response. These enzymes have been well studied in the context of cancer biology and inflammation. Recent studies, however, suggest that these enzymes also play roles in brain development and neurodegenerative disease. Select MMPs can target proteins critical to synaptic structure and neuronal survival, including integrins and cadherins. Here, we show that one member of the MMP family, MMP-7, which may be released from cells, including microglia, can target a protein critical to synaptic function. Through analysis of extracts from murine cortical slice preparations, we show that MMP-7 cleaves the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor to generate an N-terminal fragment of ∼65 kDa. Moreover, studies with recombinant protein show that MMP-7-mediated cleavage of NR1 occurs at amino acid 517, which is extracellular and just distal to the first transmembrane domain. Data suggest that NR2A, which shares sequence homology with NR1, is also cleaved following treatment of slices with MMP-7, while select AMPA receptor subunits are not. Consistent with a potential effect of MMP-7 on ligand binding, additional experiments demonstrate that NMDA-mediated calcium flux is significantly diminished by MMP-7 pretreatment of cultures. In addition, the AMPA/NMDA ratio is increased by MMP-7 pretreatment. These data suggest that synaptic function may be altered in neurological conditions associated with increased levels of MMP-7.—Szklarczyk, A., Ewaleifoh, O., Beique, J.-C., Wang, Y., Knorr, D., Haughey, N., Malpica, T., Mattson, M. P., Huganir, R., Conant, K. MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function. PMID:18644839

  6. Regulation of extrasynaptic 5-HT by serotonin reuptake transporter function in 5-HT-absorbing neurons underscores adaptation behavior in Caenorhabditis elegans.

    PubMed

    Jafari, Gholamali; Xie, Yusu; Kullyev, Andrey; Liang, Bin; Sze, Ji Ying

    2011-06-15

    Serotonin [5-hydroxytryptamine (5-HT)]-absorbing neurons use serotonin reuptake transporter (SERT) to uptake 5-HT from extracellular space but do not synthesize it. While 5-HT-absorbing neurons have been identified in diverse organisms from Caenorhabditis elegans to humans, their function has not been elucidated. Here, we show that SERT in 5-HT-absorbing neurons controls behavioral response to food deprivation in C. elegans. The AIM and RIH interneurons uptake 5-HT released from chemosensory neurons and secretory neurons. Genetic analyses suggest that 5-HT secreted by both synaptic vesicles and dense core vesicles diffuse readily to the extrasynaptic space adjacent to the AIM and RIH neurons. Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5-HT. Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of selective serotonin reuptake inhibitors in humans.

  7. Neuroprotection by acetoacetate and β-hydroxybutyrate against NMDA-induced RGC damage in rat—possible involvement of kynurenic acid

    PubMed Central

    Thaler, Sebastian; Choragiewicz, Tomasz J.; Rejdak, Robert; Fiedorowicz, Michal; Turski, Waldemar A.; Tulidowicz-Bielak, Maria; Zrenner, Eberhart; Schuettauf, Frank

    2010-01-01

    Purpose This study investigated the effects of systemically administered lithium acetoacetate (ACA) and sodium β-hydroxybutyrate (BHB) in a rat model of N-methyl-D-aspartate (NMDA)-induced damage of retinal ganglion cells (RGC). Additionally, the influence of ACA and BHB on kynurenic acid (KYNA) production was assessed in vitro in bovine retinal slices. Methods Female adult Brown–Norway rats in groups of 5–8 animals were used. ACA and BHB were administered intraperitoneally once a day for 21 consecutive days, and phosphate buffered saline (PBS) was administered to control animals. After 2 weeks, the animals received intraocular NMDA (2 μl of a 10 mM solution in PBS) or intraocular PBS as a control. On day 19, retinal ganglion cells were labeled retrogradely with hydroxystilbamidine. Two days later, RGC density (cells per mm2) was assessed on retinal flatmounts. Additionaly, bovine retinal slices were incubated with NMDA and ACA or BHB at concentrations of 1.0 mM and 3.0 mM, and de novo KYNA production was measured using HPLC. Results Intraperitoneal ACA (250 mg/kg) or BHB (291.2 mg/kg) significantly protected RGC against NMDA-induced neurodegeneration. De novo KYNA production in bovine retinal slices was lowered by NMDA. Both ACA and BHB at a concentration of 3.0 mM significantly reduced the effects of NMDA. Conclusions ACA and BHB had a significant dose-dependent neuroprotective effect on RGC in a rat model of NMDA-induced RGC damage. Both ketone bodies also significantly attenuated NMDA-induced reduction of retinal KYNA production in vitro, suggesting that this mechanism may be essential for the neuroprotective effects of ACA and BHB in vivo. Our results imply that ketone bodies may represent an additional treatment option in chronic neurodegenerative disorders of the eye. PMID:20532550

  8. 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

  9. Extrasynaptic localization of glycine receptors in the rat supraoptic nucleus: further evidence for their involvement in glia-to-neuron communication.

    PubMed

    Deleuze, C; Alonso, G; Lefevre, I A; Duvoid-Guillou, A; Hussy, N

    2005-01-01

    Neurons of the rat supraoptic nucleus (SON) express glycine receptors (GlyRs), which are implicated in the osmoregulation of neuronal activity. The endogenous agonist of the receptors has been postulated to be taurine, shown to be released from astrocytes. We here provide additional pieces of evidence supporting the absence of functional glycinergic synapses in the SON. First, we show that blockade of GlyRs with strychnine has no effect on either the amplitude or frequency of miniature inhibitory postsynaptic currents recorded in SON neurons, whereas they were all suppressed by the GABA(A) antagonist gabazine. Then, double immunostaining of sections with presynaptic markers and either GlyR or GABA(A) receptor (GABA(A)R) antibodies indicates that, in contrast with GABA(A)Rs, most GlyR membrane clusters are not localized facing presynaptic terminals, indicative of their extrasynaptic localization. Moreover, we found a striking anatomical association between SON GlyR clusters and glial fibrillary acidic protein (GFAP)-positive astroglial processes, which contain high levels of taurine. This type of correlation is specific to GlyRs, since GABA(A)R clusters show no association with GFAP-positive structures. These results substantiate and strengthen the concept of extrasynaptic GlyRs mediating a paracrine communication between astrocytes and neurons in the SON.

  10. Activation of glycine and extrasynaptic GABA(A) receptors by taurine on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis.

    PubMed

    Nguyen, Thi Thanh Hoang; Bhattarai, Janardhan Prasad; Park, Soo Joung; Han, Seong Kyu

    2013-01-01

    The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) has been known for the processing and transmission of orofacial nociceptive information. Taurine, one of the most plentiful free amino-acids in humans, has proved to be involved in pain modulation. In this study, using whole-cell patch clamp technique, we investigated the direct membrane effects of taurine and the action mechanism behind taurine-mediated responses on the SG neurons of the Vc. Taurine showed non-desensitizing and repeatable membrane depolarizations and inward currents which remained in the presence of amino-acid receptors blocking cocktail (AARBC) with tetrodotoxin, indicating that taurine acts directly on the postsynaptic SG neurons. Further, application of taurine at different doses (10  μM to 3 mM) showed a concentration dependent depolarizations and inward currents with the EC50 of 84.3  μM and 723  μM, respectively. Taurine-mediated responses were partially blocked by picrotoxin (50  μM) and almost completely blocked by strychnine (2  μM), suggesting that taurine-mediated responses are via glycine receptor (GlyR) activation. In addition, taurine (1 mM) activated extrasynaptic GABA(A) receptor (GABA(A)R)-mediated currents. Taken together, our results indicate that taurine can be a target molecule for orofacial pain modulation through the activation of GlyRs and/or extrasynaptic GABA(A)Rs on the SG neurons.

  11. Role of NMDA receptors in the syndrome of behavioral changes produced by predator stress.

    PubMed

    Blundell, Jacqueline; Adamec, Robert; Burton, Paul

    2005-09-15

    Effects on behavioral response to predator stress of competitive block of NMDA receptors with doses of .1, 1.0 and 10 mg/kg of CPP (3-(2-carboxypiperazin4-yl)propyl-l-phosphonic acid) were studied. An affect test battery assessed behavioral response to stress and employed hole board, elevated plus maze, light/dark box, social interaction, social avoidance and response to acoustic startle tests. Doses of 1-10 mg/kg of CPP administered ip 30 min prior to predator stress blocked the effects of predator stress on some but not all behaviors measured 8-9 days later. Predator stress normally reduces open arm exploration and risk assessment in the plus maze, decreases entries into the lighted arm of the light dark box and delays habituation of the acoustic startle response. CPP blocked all of these effects of predator stress. A dose of 10 mg/kg of CPP was required for all behaviors except habituation to startle. Block of effects on habituation to startle occurred at 1 and 10 mg/kg. Behaviors in which effects of predator stress were not blocked by CPP included reduction in unprotected head dips in the elevated plus maze and reduced social interaction. In addition, predator stress was without effect on social avoidance measured with the Haller test. These findings extend previous work showing NMDA receptor dependence of effects of predator stress on behavior in the elevated plus maze and on amplitude of acoustic startle response. Novel findings include NMDA receptor dependence of predator stress effects on light dark box behavior and startle habituation. Taken together, the findings add to a body of evidence showing that a syndrome of behavioral changes follows predator stress. Components of this syndrome of behavioral changes likely depend on changes in separable neural substrates initiated in part by NMDA receptors as well as by other neurochemical means.

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

    PubMed Central

    Black, Stefanie A. G.; Stys, Peter K.; Zamponi, Gerald W.; Tsutsui, Shigeki

    2014-01-01

    Although it is well established that misfolding of the cellular prion protein (PrPC) into the β-sheet-rich, aggregated scrapie conformation (PrPSc) causes a variety of transmissible spongiform encephalopathies (TSEs), the physiological roles of PrPC are still incompletely understood. There is accumulating evidence describing the roles of PrPC in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrPC that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrPC play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrPSc-induced neuronal death. Moreover, in mice lacking PrPC, infarct size is increased after focal cerebral ischemia, and absence of PrPC increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrPC was found to be a receptor for oligomeric beta-amyloid (Aβ) peptides, suggesting a role for PrPC in Alzheimer's disease (AD). Our recent findings suggest that Aβ peptides enhance NMDA receptor current by perturbing the normal copper- and PrPC-dependent regulation of these receptors. Here, we review evidence highlighting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrPC-mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrPC-mediated regulation and identifying PrPC binding site(s) on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for AD and other neurodegenerative disorders involving dysfunction of PrPC. PMID:25364752

  13. NMDA neurotransmission as a critical mediator of borderline personality disorder

    PubMed Central

    Grosjean, Bernadette; Tsai, Guochuan E.

    2007-01-01

    Studies of the neurobehavioural components of borderline personality disorder (BPD) have shown that symptoms and behaviours of BPD are partly associated with disruptions in basic neurocognitive processes, in particular, in the executive neurocognition and memory systems. A growing body of data indicates that the glutamatergic system, in particular, the N-methyl-D-aspartate (NMDA) subtype receptor, plays a major role in neuronal plasticity, cognition and memory and may underlie the pathophysiology of multiple psychiatric disorders. In this paper, we review the literature regarding BPD and its cognitive deficits and the current data on glutamatergic and NMDA neurotransmission. We propose that multiple cognitive dysfunctions and symptoms presented by BPD patients, like dissociation, psychosis and impaired nociception, may result from the dysregulation of the NMDA neurotransmission. This impairment may be the result of a combination of biological vulnerability and environmental influences mediated by the NMDA neurotransmission. PMID:17353939

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

    PubMed

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

    2008-02-01

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

  15. Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine

    PubMed Central

    Kargieman, Lucila; Santana, Noemí; Mengod, Guadalupe; Celada, Pau; Artigas, Francesc

    2007-01-01

    NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models because of their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. These deficits are of particular interest because an early improvement in cognitive performance predicts a better long-term clinical outcome. Here, we examined the effect of the noncompetitive NMDA-R antagonist phencyclidine (PCP) on PFC function to understand the cellular and network elements involved in its schizomimetic actions. PCP induces a marked disruption of the activity of the PFC in the rat, increasing and decreasing the activity of 45% and 33% of the pyramidal neurons recorded, respectively (22% of the neurons were unaffected). Concurrently, PCP markedly reduced cortical synchrony in the delta frequency range (0.3–4 Hz) as assessed by recording local field potentials. The subsequent administration of the antipsychotic drugs haloperidol and clozapine reversed PCP effects on pyramidal cell firing and cortical synchronization. PCP increased c-fos expression in PFC pyramidal neurons, an effect prevented by the administration of clozapine. PCP also enhanced c-fos expression in the centromedial and mediodorsal (but not reticular) nuclei of the thalamus, suggesting the participation of enhanced thalamocortical excitatory inputs. These results shed light on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade. PMID:17785415

  16. Spinal NMDA NR1 Subunit Expression Following Transient TNBS Colitis

    PubMed Central

    Zhou, QiQi; Price, Donald D.; Caudle, Robert M.; Verne, G. Nicholas

    2009-01-01

    Background: N-methyl-D-aspartic acid (NMDA) receptors play an important role in the development of hypersensitivity to visceral and somatic stimuli following inflammation or tissue injury. Our objective was to investigate the role of NMDA NR1 receptors in the spinal cord (T10-L1; L4-S1) of a subset of rats that remain hypersensitive following histological resolution of TNBS-induced colitis compared to saline treated rats and rats that had recovered both behaviorally and histologically. We hypothesized that NMDA NR1 subunit expression mediates hypersensitivity following transient TNBS colitis. Methods: Male Sprague-Dawley rats (150g-250g) received 20mg/rat intracolonic trinitrobenzene sulfonic acid (TNBS) in 50% ethanol or saline. Animals underwent nociceptive visceral/somatic pain testing 16 weeks after resolution of TNBS colitis. Animals were sacrificed and their spinal cord (T10-L1; L4-S1) was retrieved and 2-dimensional polyacrylamide gel electrophoresis and immunohistocytochemistry techniques were used to investigate spinal-NMDA receptor expression. Results: NR1001 was the only NMDA NR1 receptor subunit that was expressed in recovered and control rats, whereas hypersensitive animals expressed NR1011 and NR1111 as well as NR1001 subunits. Immunohistochemistry analysis demonstrated increased expression of NMDA NR1-N1, C1, and C2-plus expression in lamina I & II of the spinal cord (T10-L1; L4-S1) in hypersensitive rats but not in recovered/control rats. Conclusions: Selective increases in the expression of the NMDA NR1 splice variants occur in hypersensitive rats following resolution of TNBS colitis. This suggests that the NMDA NR1 receptor play an important role in the development of neuronal plasticity and central sensitization. The recombination of NR1 splice variants may serve as a key functional protein that maintains hypersensitivity following resolution of TNBS colitis. PMID:19406112

  17. 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.

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

    PubMed

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

    2009-01-01

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

  19. Cardiac sympathetic dysfunction in anti-NMDA receptor encephalitis.

    PubMed

    Byun, Jung-Ick; Lee, Soon-Tae; Moon, Jangsup; Jung, Keun-Hwa; Shin, Jung-Won; Sunwoo, Jun-Sang; Lim, Jung-Ah; Shin, Yong-Won; Kim, Tae-Joon; Lee, Keon-Joo; Park, Kyung-Il; Jung, Ki-Young; Lee, Sang Kun; Chu, Kon

    2015-12-01

    Patients with anti-NMDA receptor (anti-NMDAR) encephalitis frequently suffer from autonomic dysfunctions, which can cause substantial morbidity. This study assessed cardiac autonomic functions in patients with anti-NMDAR encephalitis using heart rate variability (HRV) analysis. This was a retrospective single-center case-control study. Eleven patients with anti-NMDAR encephalitis and 15 age- and sex-matched controls were included in this study. To ensure that autonomic dysfunction does not occur in any encephalitis, we additionally analyzed HRV of 9 patients with herpes encephalitis (HSE) and compared with that of NMDAR encephalitis patients and controls. Five minute resting stationary electrocardiogram was collected from each subject, and HRV was analyzed. Total power and low frequency (LF) power were lower in anti-NMDAR encephalitis patients than those in controls (p=0.005, 0.001 respectively), indicating cardiac autonomic dysfunction especially in sympathetic system. Patients with HSE showed no significant difference in HRV parameters compared with that of controls. Cardiac autonomic dysfunction was associated with 3 month functional outcome in anti-NMDAR encephalitis patients.

  20. Low nanomolar GABA effects at extrasynaptic α4β1/β3δ GABA(A) receptor subtypes indicate a different binding mode for GABA at these receptors.

    PubMed

    Karim, Nasiara; Wellendorph, Petrine; Absalom, Nathan; Bang, Line Haunstrup; Jensen, Marianne Lerbech; Hansen, Maja Michelle; Lee, Ho Joon; Johnston, Graham A R; Hanrahan, Jane R; Chebib, Mary

    2012-08-15

    Ionotropic GABA(A) receptors are a highly heterogenous population of receptors assembled from a combination of multiple subunits. The aims of this study were to characterize the potency of GABA at human recombinant δ-containing extrasynaptic GABA(A) receptors expressed in Xenopus oocytes using the two-electrode voltage clamp technique, and to investigate, using site-directed mutagenesis, the molecular determinants for GABA potency at α4β3δ GABA(A) receptors. α4/δ-Containing GABA(A) receptors displayed high sensitivity to GABA, with mid-nanomolar concentrations activating α4β1δ (EC₅₀=24 nM) and α4β3δ (EC₅₀=12 nM) receptors. In the majority of oocytes expressing α4β3δ subtypes, GABA produced a biphasic concentration-response curve, and activated the receptor with low and high concentrations (EC₅₀(1)=16 nM; EC₅₀(2)=1.2 μM). At α4β2δ, GABA had low micromolar activity (EC₅₀=1 μM). An analysis of 10 N-terminal singly mutated α4β3δ receptors shows that GABA interacts with amino acids different to those reported for α1β2γ2 GABA(A) receptors. Residues Y205 and R207 of the β3-subunit significantly affected GABA potency, while the residue F71 of the α4- and the residue Y97 of the β3-subunit did not significantly affect GABA potency. Mutating the residue R218 of the δ-subunit, equivalent to the GABA binding residue R207 of the β2-subunit, reduced the potency of GABA by 670-fold, suggesting a novel GABA binding site at the δ-subunit interface. Taken together, GABA may have different binding modes for extrasynaptic δ-containing GABA(A) receptors compared to their synaptic counterparts.

  1. Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission.

    PubMed

    Hampson, A J; Bornheim, L M; Scanziani, M; Yost, C S; Gray, A T; Hansen, B M; Leonoudakis, D J; Bickler, P E

    1998-02-01

    Anandamide is an endogenous ligand of cannabinoid receptors that induces pharmacological responses in animals similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). Typical pharmacological effects of cannabinoids include disruption of pain, memory formation, and motor coordination, systems that all depend on NMDA receptor mediated neurotransmission. We investigated whether anandamide can influence NMDA receptor activity by examining NMDA-induced calcium flux (deltaCa2+NMDA) in rat brain slices. The presence of anandamide reduced deltaCa2+NMDA and the inhibition was disrupted by cannabinoid receptor antagonist, pertussis toxin treatment, and agatoxin (a calcium channel inhibitor). Whereas these treatments prevented anandamide inhibiting deltaCa2+NMDA, they also revealed another, underlying mechanism by which anandamide influences deltaCa2+NMDA. In the presence of cannabinoid receptor antagonist, anandamide potentiated deltaCa2+NMDA in cortical, cerebellar, and hippocampal slices. Anandamide (but not THC) also augmented NMDA-stimulated currents in Xenopus oocytes expressing cloned NMDA receptors, suggesting a capacity to directly modulate NMDA receptor activity. In a similar manner, anandamide enhanced neurotransmission across NMDA receptor-dependent synapses in hippocampus in a manner that was not mimicked by THC and was unaffected by cannabinoid receptor antagonist. These data demonstrate that anandamide can modulate NMDA receptor activity in addition to its role as a cannabinoid receptor ligand.

  2. Red nucleus glutamate facilitates neuropathic allodynia induced by spared nerve injury through non-NMDA and metabotropic glutamate receptors.

    PubMed

    Yu, Jing; Ding, Cui-Ping; Wang, Jing; Wang, Ting; Zhang, Tao; Zeng, Xiao-Yan; Wang, Jun-Yang

    2015-12-01

    Previous studies have demonstrated that glutamate plays an important role in the development of pathological pain. This study investigates the expression changes of glutamate and the roles of different types of glutamate receptors in the red nucleus (RN) in the development of neuropathic allodynia induced by spared nerve injury (SNI). Immunohistochemistry indicated that glutamate was constitutively expressed in the RN of normal rats. After SNI, the expression levels of glutamate were significantly increased in the RN at 1 week and reached the highest level at 2 weeks postinjury compared with sham-operated and normal rats. The RN glutamate was colocalized with neurons, oligodendrocytes, and astrocytes but not microglia under physiological and neuropathic pain conditions. To elucidate further the roles of the RN glutamate and different types of glutamate receptors in the development of neuropathic allodynia, antagonists to N-methyl-D-aspartate (NMDA), non-NMDA, or metabotropic glutamate receptors (mGluRs) were microinjected into the RN contralateral to the nerve-injury side of rats with SNI, and the paw withdrawal threshold (PWT) was dynamically assessed with von Frey filaments. Microinjection of the NMDA receptor antagonist MK-801 into the RN did not show any effect on SNI-induced mechanical allodynia. However, microinjection of the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione or the mGluR antagonist (±)-α-methyl-(4-carboxyphenyl) glycine into the RN significantly increased the PWT and alleviated SNI-induced mechanical allodynia. These findings suggest that RN glutamate is involved in regulating neuropathic pain and facilitates the development of SNI-induced neuropathic allodynia. The algesic effect of glutamate is transmitted by the non-NMDA glutamate receptor and mGluRs.

  3. Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

    PubMed

    Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam

    2017-04-14

    Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function.

  4. Quinolinic acid induces neuritogenesis in SH-SY5Y neuroblastoma cells independently of NMDA receptor activation.

    PubMed

    Hernandez-Martinez, Juan-Manuel; Forrest, Caroline M; Darlington, L Gail; Smith, Robert A; Stone, Trevor W

    2017-03-01

    Glutamate and nicotinamide adenine dinucleotide (NAD(+) ) have been implicated in neuronal development and several types of cancer. The kynurenine pathway of tryptophan metabolism includes quinolinic acid (QA) which is both a selective agonist at N-methyl-D-aspartate (NMDA) receptors and also a precursor for the formation of NAD(+) . The effect of QA on cell survival and differentiation has therefore been examined on SH-SY5Y human neuroblastoma cells. Retinoic acid (RA, 10 μm) induced differentiation of SH-SY5Y cells into a neuronal phenotype showing neurite growth. QA (50-150 nm) also caused a concentration-dependent increase in the neurite/soma ratio, indicating differentiation. Both RA and QA increased expression of the neuronal marker β3-tubulin in whole-cell homogenates and in the neuritic fraction assessed using a neurite outgrowth assay. Expression of the neuronal proliferation marker doublecortin revealed that, unlike RA, QA did not decrease the number of mitotic cells. QA-induced neuritogenesis coincided with an increase in the generation of reactive oxygen species. Neuritogenesis was prevented by diphenylene-iodonium (an inhibitor of NADPH oxidase) and superoxide dismutase, supporting the involvement of reactive oxygen species. NMDA itself did not promote neuritogenesis and the NMDA antagonist dizocilpine (MK-801) did not prevent quinolinate-induced neuritogenesis, indicating that the effects of QA were independent of NMDA receptors. Nicotinamide caused a significant increase in the neurite/soma ratio and the expression of β3-tubulin in the neuritic fraction. Taken together, these results suggest that QA induces neuritogenesis by promoting oxidizing conditions and affecting the availability of NAD(+) , independently of NMDA receptors.

  5. Structural insights into competitive antagonism in NMDA receptors

    PubMed Central

    Jespersen, Annie; Tajima, Nami; Fernandez-Cuervo, Gabriela; Garnier-Amblard, Ethel C.; Furukawa, Hiro

    2014-01-01

    Summary There has been a great level of enthusiasm to down-regulate overactive N-methyl-d-aspartate (NMDA) receptors to protect neurons from excitotoxicity. NMDA receptors play pivotal roles in basic brain development and functions as well as in neurological disorders and diseases. However, mechanistic understanding of antagonism in NMDA receptors is limited due to complete lack of antagonist-bound structures for the l-glutamate-binding GluN2 subunits. Here we report the crystal structures of GluN1/GluN2A NMDA receptor ligand-binding domain (LBD) heterodimers in complex with GluN1- and GluN2-targeting antagonists. The crystal structures reveal that the antagonists, D-(−)-2-Amino-5-phosphonopentanoic acid (d-AP5) and 1-(Phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), have discrete binding modes and mechanisms for opening of the bilobed architecture of GluN2A LBD compared to the agonist-bound form. The current study shows distinct ways by which the conformations of NMDA receptor LBDs may be controlled and coupled to receptor inhibition and provides possible strategies to develop therapeutic compounds with higher subtype-specificity. PMID:24462099

  6. Cortical hypometabolism demonstrated by PET in relapsing NMDA receptor encephalitis.

    PubMed

    Pillai, Sekhar C; Gill, Deepak; Webster, Richard; Howman-Giles, Robert; Dale, Russell C

    2010-09-01

    N-methyl-d-aspartate (NMDA) receptor encephalitis is a newly defined type of autoimmune encephalitis. Two girls (age 3 years, case 1, and 7 years, case 2) with relapsing NMDA receptor encephalitis each had the classic clinical features of encephalopathy, movement disorders, psychiatric symptoms, seizures, insomnia, and mild autonomic dysfunction. Both patients had persistent neuropsychiatric disability, despite immune therapies. Positron emission tomography (PET) scans were performed during clinical relapse at 6 weeks (case 1) and 5 months (case 2). In both cases, the scans demonstrated reduced fluorodeoxyglucose metabolism in the cerebral cortex, with the temporal regions being most affected. PET imaging was more sensitive than magnetic resonance imaging in these patients. In contrast, the one previous report of acute NMDA receptor encephalitis indicated cortical hypermetabolism. Thus, NMDA receptor encephalitis may be associated with variable PET findings, possibly dependent upon the timing of the study, or other factors. Future studies should investigate whether cortical hypometabolism is associated with a relapsing course, and whether it is predictive of a poorer outcome in NMDA receptor encephalitis.

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

    PubMed

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

    2006-05-01

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

  8. Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals.

    PubMed

    Peterson, Bethany L; Park, Thomas J; Larson, John

    2012-01-11

    Adult naked mole-rats show a number of systemic adaptations to a crowded underground habitat that is low in oxygen and high in carbon dioxide. Remarkably, brain slice tissue from adult naked mole-rats also is extremely tolerant to oxygen deprivation as indicated by maintenance of synaptic transmission under hypoxic conditions as well as by a delayed neuronal depolarization during anoxia. These characteristics resemble hypoxia tolerance in brain slices from neonates in a variety of mammal species. An important component of neonatal tolerance to hypoxia involves the subunit composition of NMDA receptors. Neonates have a high proportion of NMDA receptors with GluN2D subunits which are protective because they retard calcium entry into neurons during hypoxic episodes. Therefore, we hypothesized that adult naked mole-rats retain a protective, neonatal-like, NMDA receptor subunit profile. We used immunoblotting to assess age-related changes in NMDA receptor subunits in naked mole-rats and mice. The results show that adult naked mole-rat brain retains a much greater proportion of the hypoxia-protective GluN2D subunit compared to adult mice. However, age-related changes in other subunits (GluN2A and GluN2B) from the neonatal period to adulthood were comparable in mice and naked mole-rats. Hence, adult naked mole-rat brain only retains the neonatal NMDA receptor subunit that is associated with hypoxia tolerance.

  9. Effects of NMDA and non-NMDA ionotropic glutamate receptors in the medial preoptic area on body temperature in awake rats.

    PubMed

    Sengupta, Trina; Jaryal, Ashok Kumar; Mallick, Hruda Nanda

    2016-10-01

    Glutamate when microinjected at the medial preoptic area (mPOA) influences brain temperature (Tbr) and body temperature (Tb) in rats. Glutamate and its various receptors are present at the mPOA. The aim of this study was to identify the contribution of each of the ionotropic glutamatergic receptors at the mPOA on changes in Tbr and Tb in freely moving rats. Adult male Wistar rats (n=40) were implanted with bilateral guide cannula with indwelling styli above the mPOA. A telemetric transmitter was implanted at the peritoneum to record Tb and locomotor activity (LMA). A precalibrated thermocouple wire implanted near the hypothalamus was used to assess Tbr. Specific agonist for each ionotropic glutamate receptor was microinjected into the mPOA and its effects on temperature and LMA were measured in the rats. The rats were also microinjected with the respective ionotropic receptor antagonists, 15min prior to the microinjection of each agonist. Amongst amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainic acid, AMPA increased Tb and LMA when injected at the mPOA. Specific antagonists for AMPA receptors was able to attenuate this increase (p<0.005). Pharmacological blockade of NMDA was able to lower Tbr only. Microinjection of kainic acid and its antagonist had no effect on the variables. The finding of the study suggests that activation of the AMPA receptors at the mPOA, leads to the rise in body temperature.

  10. Neuroprotective effects of creatine administration against NMDA and malonate toxicity.

    PubMed

    Malcon, C; Kaddurah-Daouk, R; Beal, M F

    2000-03-31

    We examined whether creatine administration could exert neuroprotective effects against excitotoxicity mediated by N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. Oral administration of 1% creatine significantly attenuated striatal excitotoxic lesions produced by NMDA, but had no effect on lesions produced by AMPA or kainic acid. Both creatine and nicotinamide can exert significant protective effects against malonate-induced striatal lesions. We, therefore, examined whether nicotinamide could exert additive neuroprotective effects with creatine against malonate-induced lesions. Nicotinamide with creatine produced significantly better neuroprotection than creatine alone against malonate-induced lesions. Creatine can, therefore, produce significant neuroprotective effects against NMDA mediated excitotoxic lesions in vivo and the combination of nicotinamide with creatine exerts additive neuroprotective effects.

  11. Lead inhibition of NMDA channels in native and recombinant receptors.

    PubMed

    Gavazzo, P; Gazzoli, A; Mazzolini, M; Marchetti, C

    2001-10-08

    NMDA channels are key targets for lead (Pb2+) neurotoxicity and Pb2+-induced inhibition of NMDA current is age- and subunit-dependent. In rat cerebellar granule cells maintained in high KCl, glycine affinity as well as sensitivity to ifenprodil change significantly with the days in vitro, indicating a reduction of NR2B subunit expression. Pb2+ blocked NMDA current with IC50 approximately 4 microM and this effect decreased significantly during the second week in vitro. In Xenopus laevis oocytes expressing recombinant NR1-NR2A, NR1-NR2B or NR1-NR2C receptors, Pb2+ inhibited glutamate-activated currents with IC50 of 3.3, 2.5 and 4.7 microM respectively. These data indicate that Pb2+ action is dependent on subunit composition and suggest that down-regulation of the NR2B subunit is correlated to a diminished sensitivity to Pb2+ inhibition.

  12. 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...

  13. Approach to the Management of Pediatric-Onset Anti-N-Methyl-d-Aspartate (Anti-NMDA) Receptor Encephalitis: A Case Series.

    PubMed

    Brenton, J Nicholas; Kim, Joshua; Schwartz, Richard H

    2016-08-01

    Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a treatable cause of autoimmune encephalitis. It remains unclear if the natural history of this disease is altered by choice of acute therapy or the employment of chronic immunotherapy. Chart review was undertaken for pediatric patients diagnosed with anti-NMDA receptor encephalitis. Data obtained included patient demographics, disease manifestations, treatment course, and clinical outcomes. Ten patients with anti-NMDA receptor encephalitis were identified. All patients were treated with immunotherapy in the acute period, and all patients experienced good recovery. Neurologic relapse did not occur in any patient. All patients received varied forms of chronic immunosuppression to prevent relapses. Complications of chronic immunotherapy occurred in 50% of patients. The benefits of chronic immunotherapy and the duration of use should be carefully weighed against the risks. Complications from immunotherapy are not uncommon and can be serious. Clinical trials assessing the benefit of long-term immunotherapy in this population are needed.

  14. 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.

  15. Influence of Pharmacological Manipulations of NMDA and Cholinergic Receptors on Working versus Reference Memory in a Dual Component Odor Span Task

    ERIC Educational Resources Information Center

    MacQueen, David A.; Dalrymple, Savannah R.; Drobes, David J.; Diamond, David M.

    2016-01-01

    Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-D-aspartate receptor (NMDA-r) antagonists and is sensitive to…

  16. IGF-1-Involved Negative Feedback of NR2B NMDA Subunits Protects Cultured Hippocampal Neurons Against NMDA-Induced Excitotoxicity.

    PubMed

    Li, Yun; Sun, Wei; Han, Song; Li, Jianing; Ding, Shu; Wang, Wei; Yin, Yanling

    2017-01-01

    Insulin-like growth factor 1 (IGF-1) is a multifunctional protein involved in neuronal polarity and axonal guidance. In our previous study, it was discovered that IGF-1 alleviated 50-μM NMDA-induced excitotoxicity against neuronal autophagy via depression of NR2B p-Ser1303 activation. However, it was found that NMDA at a higher dose did not cause neuronal autophagy. And, the performance of IGF-1 under severe excitotoxicity still needs to be clarified. In this study, we observed that IGF-1 can salvage the hippocampal neurons in an autophagy-independent manner after 150-μM NMDA exposure using thiazolyl blue tetrazolium bromide (MTT), lactate dehydrogenase (LDH), Western blot assay, and transmission electron microscopy. In addition, over-activation of post-synaptic NMDARs was found with the whole-cell patch clamp recording method. In order to explore whether there is a positive feedback way for post-synaptic NMDARs and the different pathway caused by 150 μM NMDA, the phosphorylation level of Fyn and the phosphorylation site of NR2B were investigated. It was observed that NR2B p-Tyr1472 was increased by the activation of Fyn after 150-μM NMDA exposure. When the neutralizing antibody against NR2B p-Ser1303 was added into the medium, both the activations of Fyn and NR2B p-Tyr1472 were blocked, suggesting NR2B p-Ser1303 may be the initial step of NMDA-induced excitotoxicity. In addition, since IGF-1 can block the initial step of NR2B activation, its effect is concluded to continue with the development of excitotoxicity. Overall, this study strongly indicates that the relationship between different phosphorylation sites of NR2B should be laid more emphasis on, which may be a vital target for the NR2B-involved excitotoxicity.

  17. Exogenous t-PA Administration Increases Hippocampal Mature BDNF Levels. Plasmin- or NMDA-Dependent Mechanism?

    PubMed Central

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

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA)/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA) receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (r)t-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg) administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v.) while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p.) in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling. PMID:24670989

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

    PubMed

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

    2014-01-01

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

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

    PubMed

    Jacobs, Stephanie; Tsien, Joe Z

    2017-02-01

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

  20. Specific Roles of NMDA Receptor Subunits in Mental Disorders

    PubMed Central

    Yamamoto, H.; Hagino, Y.; Kasai, S.; Ikeda, K.

    2015-01-01

    N-methyl-D-aspartate (NMDA) receptor plays important roles in learning and memory. NMDA receptors are a tetramer that consists of two glycine-binding subunits GluN1, two glutamate-binding subunits (i.e., GluN2A, GluN2B, GluN2C, and GluN2D), a combination of a GluN2 subunit and glycine-binding GluN3 subunit (i.e., GluN3A or GluN3B), or two GluN3 subunits. Recent studies revealed that the specific expression and distribution of each subunit are deeply involved in neural excitability, plasticity, and synaptic deficits. The present article summarizes reports on the dysfunction of NMDA receptors and responsible subunits in various neurological and psychiatric disorders, including schizophrenia, autoimmune-induced glutamatergic receptor dysfunction, mood disorders, and autism. A key role for the GluN2D subunit in NMDA receptor antagonist-induced psychosis has been recently revealed. PMID:25817860

  1. [Anti-NMDA receptor encephalitis: two paediatric cases].

    PubMed

    González-Toro, M Cristina; Jadraque-Rodríguez, Rocío; Sempere-Pérez, Ángela; Martínez-Pastor, Pedro; Jover-Cerdá, Jenaro; Gómez-Gosálvez, Francisco

    2013-12-01

    Introduccion. La encefalitis asociada a anticuerpos antirreceptores de N-metil-D-aspartato (NMDA) es una patologia neurologica autoinmune documentada en la poblacion pediatrica de manera creciente en los ultimos años. Se presentan dos casos de nuestra experiencia con clinica similar. Casos clinicos. Caso 1: niña de 5 años que inicia un cuadro de convulsiones y alteracion de conciencia, asociando trastornos del movimiento y regresion de habilidades previamente adquiridas que evoluciona a autismo. Caso 2: niña de 13 años que presenta hemiparesia izquierda, movimientos anomalos, trastorno de conducta y disautonomia. En ambos casos se obtienen anticuerpos antirreceptores de NMDA positivos en el liquido cefalorraquideo y se diagnostican de encefalitis antirreceptor de NMDA. En el primer caso se inicia el tratamiento con perfusion intravenosa de corticoides e inmunoglobulinas y es necesario asociar rituximab. En el segundo, corticoides e inmunoglobulinas. La evolucion fue favorable en ambas pacientes, con una leve alteracion del lenguaje como secuela en el primer caso y una recaida en el segundo caso, con resolucion completa. Conclusion. La encefalitis antirreceptor de NMDA es un trastorno tratable y es importante el diagnostico y tratamiento precoz, ya que mejora el pronostico y disminuye las recaidas.

  2. Novel benzopolycyclic amines with NMDA receptor antagonist activity.

    PubMed

    Valverde, Elena; Sureda, Francesc X; Vázquez, Santiago

    2014-05-01

    A new series of benzopolycyclic amines active as NMDA receptor antagonists were synthesized. Most of them exhibited increased activity compared with related analogues previously published. All the tested compounds were more potent than clinically approved amantadine and one of them displayed a lower IC50 value than memantine, an anti-Alzheimer's approved drug.

  3. [Two cases of anti-NMDA receptor encephalitis].

    PubMed

    Nakamura, Kazue; Takahashi, Tsutomu; Matsuoka, Tadasu; Kido, Mikio; Uehara, Takashi; Suzuki, Michio

    2011-01-01

    Anti-NMDA receptor encephalitis, reported by Dalmau et al., is a paraneoplastic encephalitis frequently associated with ovarian teratoma. After the manifestation of schizophrenia-like psychotic symptoms in the initial stage, serious neurological symptoms such as convulsions and central hypoventilation develop. We report two cases of 17-year-old girls with anti-NMDA receptor encephalitis who exhibited different clinical courses. Case 1 showed a typical course of anti-NMDA receptor encephalitis associated with sustained consciousness disturbance requiring long-term artificial respiration. Case 2 underwent surgery for an ovarian teratoma in the early stages of the disorder, did not show convulsions or central hypoventilation, and recovered without any sequelae. Early resection of the ovarian teratoma and the immune suppression therapy may have contributed to the rapid recovery and favorable outcome in case 2. Psychiatrists are the first to see a majority of patients with anti-NMDA receptor encephalitis because of psychiatric symptoms and behavioral changes observed in the initial stage. For successful treatment, psychiatrists need to cooperate with neurologists and gynecologists early in the course of this disorder. Psychiatrists' knowledge of the symptoms and clinical course of this form of encephalitis is essential for early detection and adequate treatment, which may be life-saving and contribute to good functional outcomes.

  4. [Anti-NMDA-receptor encephalitis. An interdisciplinary clinical picture].

    PubMed

    Prüss, H; Dalmau, J; Arolt, V; Wandinger, K-P

    2010-04-01

    Anti-NMDA-receptor encephalitis is a severe and considerably underdiagnosed form of encephalitis with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, hypoventilation, epileptic seizures, autonomic dysfunction and dyskinesias. Most patients are primarily seen by psychiatrists, often on the assumption of a drug-induced psychosis. Anti-NMDA-receptor encephalitis had initially been described in young women with ovarian teratoma, but is also common in women without tumour, in men and in children. The diagnosis is based on the characteristic clinical picture, supporting findings of brain MRI, electroencephalogram and cerebrospinal fluid (CSF), and the presence of highly specific autoantibodies directed against the NR1 subunit of NMDA-type glutamate receptors in the serum or CSF. In particular, anti-NMDA-receptor encephalitis must be excluded in patients with 'encephalitis of unknown cause'. In principle, the prognosis is favourable and recovery from symptoms can be expected even after prolonged intensive care treatment and mechanical ventilation. However, improvement correlates with prompt identification of the disorder, early immunotherapy and - in the case of a malignancy - with complete tumour removal. Patient care requires an interdisciplinary approach including neurologists, psychiatrists, paediatricians, oncologists and gynaecologists.

  5. The possible involvement of NMDA glutamate receptor in the etiopathogenesis of bipolar disorder.

    PubMed

    Fountoulakis, Konstantinos N

    2012-01-01

    Glutamate is the most abundant excitatory neurotransmitter in the brain and the ionotropic NMDA receptor is one of the major classes of its receptors, thought to play an important role in schizophrenia and mood disorders. The current systematic review summarized the evidence concerning the involvement of NMDA receptors in the pathophysiology of bipolar disorder. Genetic studies point to the genes encoding the NMDA 1, 2A and 2B subunits while neuropathological studies suggest a possible region specific decrease in the density of NMDA receptor and more consistently a reduced NMDA-mediated glutamatergic activity in patients with bipolar disorder in the frame of slower NMDA kinetics because of lower contribution of NR2A subunits. However the literature is poor and incomplete; future research is necessary to elucidate the mechanisms underlying bipolar disorder and its specific relationship to a possible NMDA malfunction and to explore the possibility of developing novel therapeutic agents.

  6. Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

    PubMed Central

    Zhang, Qi; Guo, Fei; Fu, Zhi-wen; Zhang, Bing; Huang, Cheng-gang; Li, Yang

    2016-01-01

    Aim: N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. Methods: NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg−1·d−1) or a positive-control drug, fluoxetine (10 mg·kg−1·d−1) for 3 weeks. Behavioral assessments were carried out every week. Results: In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. Conclusion: YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression. PMID:26687936

  7. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice.

    PubMed

    Walker, Adam K; Budac, David P; Bisulco, Stephanie; Lee, Anna W; Smith, Robin A; Beenders, Brent; Kelley, Keith W; Dantzer, Robert

    2013-08-01

    We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O'Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokine expression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA

  8. Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice.

    PubMed

    Zhang, Xiaoqin; Xin, Xin; Dong, Yuanlin; Zhang, Yiying; Yu, Buwei; Mao, Jianren; Xie, Zhongcong

    2013-11-06

    Postoperative cognitive dysfunction (POCD) is associated with impairments in daily functioning, and increased morbidity and mortality. However, the causes and neuropathogenesis of POCD remain largely unknown. Uncontrolled pain often occurs postoperatively. We therefore set out to determine the effects of surgical incision-induced nociception on the cognitive function and its underlying mechanisms in 3- and 9-month-old mice. The mice had surgical incision in the hindpaw and then were tested for nociceptive threshold, learning, and memory. Brain levels of NMDA receptor and cyclin-dependent kinase 5 (CDK5) were also assessed. We found that surgical incision-induced nociception in mice led to a decreased freezing time in the tone test (which assesses the hippocampus-independent learning and memory function), but not the context test, of Fear Conditioning System at 3 and 7 d, but not 30 d post incision in 9-month-old, but not 3-month-old mice. Consistently, the surgical incision selectively decreased synaptic NMDA receptor 2B levels in the medial prefrontal cortex, and increased levels of tumor necrosis factor-α and CDK5 in the cortex, but not hippocampus, of the mice. Finally, eutectic mixture of local anesthetics and CDK5 inhibitor, roscovitine, attenuated the surgical incision-induced reduction in the synaptic NMDA receptor 2B levels and learning impairment. These results suggested that surgical incision-induced nociception reduced the synaptic NMDA receptor 2B level in the medial prefrontal cortex of mice, which might lead to hippocampus-independent learning impairment, contributing to POCD. These findings call for further investigation to determine the role of surgical incision-induced nociception in POCD.

  9. The effect of the NMDA channel blocker memantine on salicylate-induced tinnitus in rats.

    PubMed

    Ralli, M; Troiani, D; Podda, M V; Paciello, F; Eramo, S L M; de Corso, E; Salvi, R; Paludetti, G; Fetoni, A R

    2014-06-01

    Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The

  10. Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers.

    PubMed

    Nutt, David; Wilson, Sue; Lingford-Hughes, Anne; Myers, Jim; Papadopoulos, Andreas; Muthukumaraswamy, Suresh

    2015-01-01

    A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA reuptake inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here.

  11. GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization.

    PubMed

    Fritschy, J M; Meskenaite, V; Weinmann, O; Honer, M; Benke, D; Mohler, H

    1999-03-01

    GABAB (gamma-aminobutyric acid)-receptors have been implicated in central nervous system (CNS) functions, e.g. cognition and pain perception, and dysfunctions including spasticity and absence epilepsy. To permit an analysis of the two known GABAB-receptor splice variants GABAB-R1a (GB1a) and GABAB-R1b (GB1b), their distribution pattern has been differentiated in the rat brain, using Western blotting and immunohistochemistry with isoform-specific antisera. During postnatal maturation, the expression of the two splice variants was differentially regulated with GB1a being preponderant at birth. In adult brain, GB1b-immunoreactivity (-IR) was predominant, and the two isoforms largely accounted for the pattern of GABAB-receptor binding sites in the brain. Receptor heterogeneity was pronounced in the hippocampus, where both isoforms occurred in CA1, but only GB1b in CA3. Similarly, in the cerebellum, GB1b was exclusively found in Purkinje cells in a zebrin-like pattern. The staining was most pronounced in Purkinje cell dendrites and spines. Using electron microscopy, over 80% of the spine profiles in which a synaptic contact with a parallel fibre was visible contained GB1b-IR at extrasynaptic sites. This subcellular localization is unrelated to GABAergic inputs, indicating that the role of GABAB-receptors in vivo extends beyond synaptic GABAergic neurotransmission and may, in the cerebellum, involve taurine as a ligand.

  12. Theta/gamma networks with slow NMDA channels learn sequences and encode episodic memory: role of NMDA channels in recall.

    PubMed

    Jensen, O; Lisman, J E

    1996-01-01

    This paper examines the role of slow N-methyl-D-aspartate (NMDA) channels (deactivation approximately 150 msec) in networks that multiplex different memories in different gamma subcycles of a low frequency theta oscillation. The NMDA channels are in the synapses of recurrent collaterals and govern synaptic modification in accord with known physiological properties. Because slow NMDA channels have a time constant that spans several gamma cycles, synaptic connections will form between cells that represent different memories. This enables brain structures that have slow NMDA channels to store heteroassociative sequence information in long-term memory. Recall of this stored sequence information can be initiated by presentation of initial elements of the sequence. The remaining sequence is then recalled at a rate of one memory every gamma cycle. A new role for the NMDA channel suggested by our finding is that recall at gamma frequency works well if slow NMDA channels provide the dominant component of the EPSP at the synapse of recurrent collaterals: The slow onset of these channels and their long duration allows the firing of one memory during one gamma cycle to trigger the next memory during the subsequent gamma cycle. An interesting feature of the readout mechanism is that the activation of a given memory is due to cumulative input from multiple previous memories in the stored sequence, not just the previous one. The network thus stores sequence information in a doubly redundant way: Activation of a memory depends on the strength of synaptic inputs from multiple cells of multiple previous memories. The cumulative property of sequence storage has support from the psychophysical literature. Cumulative learning also provides a solution to the disambiguation problem that occurs when different sequences have a region of overlap. In a final set of simulations, we show how coupling an autoassociative network to a heteroassociative network allows the storage of episodic

  13. Time-limited modulation of appetitive Pavlovian memory by D1 and NMDA receptors in the nucleus accumbens

    PubMed Central

    Dalley, Jeffrey W.; Lääne, Kristjan; Theobald, David E. H.; Armstrong, Hannah C.; Corlett, Philip R.; Chudasama, Yogita; Robbins, Trevor W.

    2005-01-01

    Recent research has implicated the nucleus accumbens (NAc) in consolidating recently acquired goal-directed appetitive memories, including spatial learning and other instrumental processes. However, an important but unresolved issue is whether this forebrain structure also contributes to the consolidation of fundamental forms of appetitive learning acquired by Pavlovian associative processes. In addition, although dopaminergic and glutamatergic influences in the NAc have been implicated in instrumental learning, it is unclear whether similar mechanisms operate during Pavlovian conditioning. To evaluate these issues, the effects of posttraining intra-NAc infusions of D1, D2, and NMDA receptor antagonists, as well as d-amphetamine, were determined on Pavlovian autoshaping in rats, which assesses learning by discriminated approach behavior to a visual conditioned stimulus predictive of food reward. Intracerebral infusions were given either immediately after each conditioning session to disrupt early memory consolidation or after a delay of 24 h. Findings indicate that immediate, but not delayed, infusions of both D1 (SCH 23390) and NMDA (AP-5) receptor antagonists significantly impair learning on this task. By contrast, amphetamine and the D2 receptor antagonist sulpiride were without significant effect. These findings provide the most direct demonstration to date that D1 and NMDA receptors in the NAc contribute to, and are necessary for, the early consolidation of appetitive Pavlovian learning. PMID:15833811

  14. Diminution of the NMDA receptor NR2B subunit in cortical and subcortical areas of WAG/Rij rats.

    PubMed

    Karimzadeh, Fariba; Soleimani, Mansoureh; Mehdizadeh, Mehdi; Jafarian, Maryam; Mohamadpour, Maliheh; Kazemi, Hadi; Joghataei, Mohammad-Taghi; Gorji, Ali

    2013-12-01

    Modulation of glutamatergic NMDA receptors affects the synchronization of spike discharges in in WAG/Rij rats, a valid genetic animal model of absence epilepsy. In this study, we describe the alteration of NR2B subunit of NMDA receptors expression in WAG/Rij rats in different somatosensory cortical layers and in hippocampal CA1 area. Experimental groups were divided into four groups of six rats of both WAG/Rij and Wistar strains with 2 and 6 months of age. The distribution of NR2B receptors was assessed by immunohistochemical staining in WAG/Rij and compared with age-matched Wistar rats. The expression of NR2B subunit was significantly decreased in different somatosensory cortical layers in 2- and 6-month-old WAG/Rij rats. In addition, the distribution of NR2B in hippocampal CA1 area was lower in 6-month-old WAG/Rij compared with age-matched Wistar rats. The reduction of NR2B receptors in different brain areas points to disturbance of glutamate receptors expression in cortical and subcortical areas in WAG/Rij rats. An altered subunit assembly of NMDA receptors may underlie cortical hyperexcitability in absence epilepsy.

  15. Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice.

    PubMed

    Blokhina, Elena A; Kashkin, Vladimir A; Zvartau, Edwin E; Danysz, Wojciech; Bespalov, Anton Y

    2005-03-01

    Previous studies have indicated that blockade of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors prevents acquisition of instrumental behaviors reinforced by food and drugs such as morphine and cocaine. The present study aimed to extend this evidence by testing whether NMDA receptor channel blocker, memantine, would exert similar effects on acquisition of cocaine and nicotine self-administration in mice. Inasmuch as memantine also acts as nicotinic receptor channel blocker, this study assessed the effects of mecamylamine and MRZ 2/621 that are more selective nicotinic blockers. Adult male Swiss mice were allowed to self-administer cocaine (0.8-2.4 microg/infusion) or nicotine (0.08-0.32 microg/infusion) during the 30-min test. Pretreatment with memantine (0.1-10 mg/kg) prevented acquisition of nicotine but not cocaine self-administration. Pretreatment with mecamylamine (0.3-3 mg/kg) and MRZ 2/621 (0.3-10 mg/kg) produced dose-dependent suppression of both cocaine and nicotine self-administration. Taken together with the previous reports, these results indicate that nicotinic receptor blockers antagonize acute reinforcing effects of cocaine while NMDA receptor blockade may have limited effectiveness.

  16. 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.

  17. Parafascicular thalamic nucleus deep brain stimulation decreases NMDA receptor GluN1 subunit gene expression in the prefrontal cortex.

    PubMed

    Fernández-Cabrera, Mónica R; Selvas, Abraham; Miguéns, Miguel; Higuera-Matas, Alejandro; Vale-Martínez, Anna; Ambrosio, Emilio; Martí-Nicolovius, Margarita; Guillazo-Blanch, Gemma

    2017-04-21

    The rodent parafascicular nucleus (PFn) or the centromedian-parafascicular complex of primates is a posterior intralaminar nucleus of the thalamus related to cortical activation and maintenance of states of consciousness underlying attention, learning and memory. Deep brain stimulation (DBS) of the PFn has been proved to restore arousal and consciousness in humans and to enhance performance in learning and memory tasks in rats. The primary expected effect of PFn DBS is to induce plastic changes in target neurons of brain areas associated with cognitive function. In this study, Wistar rats were stimulated for 20mins in the PFn following a DBS protocol that had previously facilitated memory in rats. NMDA and GABAB receptor binding, and gene expression of the GluN1subunit of the NMDA receptor (NMDAR) were assessed in regions related to cognitive functions, such as the prefrontal cortex and hippocampus. The results showed that PFn DBS induced a decrease in NMDAR GluN1 subunit gene expression in the cingulate and prelimbic cortices, but no significant statistical differences were found in the density of NMDA or GABAB receptors in any of the analyzed regions. Taken together, our findings suggest a possible role for the NMDAR GluN1 subunit in the prefrontal cortex in the procognitive actions of the PFn DBS.

  18. Glutamate requires NMDA receptors to modulate alpha2 adrenoceptor in medulla oblongata cultured cells of newborn rats.

    PubMed

    Marinho da Silva, Sergio; Carrettiero, Daniel C; Chadi, Débora R F

    2014-04-03

    α2 Adrenoceptors (α2-ARs) are important in regulating the central control of blood pressure in medulla oblongata. However, it is unclear how this receptor is modulated by different receptors, especially the glutamatergic. In the present study, we studied the influence of ionotropic glutamatergic receptors over the α2-ARs in cultured cells of the medulla oblongata of newborn rats. For this purpose, the protein level of the α2-ARs was assessed after administration to the cultured cells of glutamate (glu), the agonists NMDA and kainate (KA), the NMDA receptor antagonist MK801 and the KA receptor antagonist DNQX. Results indicate that the α2-AR protein levels were increased after the treatments with glu and NMDA, and the addition of MK801 to this treatment thwarted this increase. Notwithstanding the fact that KA did not alter the receptor protein level, the combined treatment of DNQX with glu prevented the α2-AR protein modulation. In conclusion, the present study suggests that ionotropic glutamatergic receptors could be related to the α2-AR protein regulation in the medulla oblongata.

  19. Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells

    PubMed Central

    Brandalise, Federico; Carta, Stefano; Helmchen, Fritjof; Lisman, John; Gerber, Urs

    2016-01-01

    The computational repertoire of neurons is enhanced by regenerative electrical signals initiated in dendrites. These events, referred to as dendritic spikes, can act as cell-intrinsic amplifiers of synaptic input. Among these signals, dendritic NMDA spikes are of interest in light of their correlation with synaptic LTP induction. Because it is not possible to block NMDA spikes pharmacologically while maintaining NMDA receptors available to initiate synaptic plasticity, it remains unclear whether NMDA spikes alone can trigger LTP. Here we use dendritic recordings and calcium imaging to analyse the role of NMDA spikes in associative LTP in CA3 pyramidal cells. We show that NMDA spikes produce regenerative branch-specific calcium transients. Decreasing the probability of NMDA spikes reduces LTP, whereas increasing their probability enhances LTP. NMDA spikes and LTP occur without back-propagating action potentials. However, action potentials can facilitate LTP induction by promoting NMDA spikes. Thus, NMDA spikes are necessary and sufficient to produce the critical postsynaptic depolarization required for associative LTP in CA3 pyramidal cells. PMID:27848967

  20. Impact of calcium-activated potassium channels on NMDA spikes in cortical layer 5 pyramidal neurons

    PubMed Central

    Bock, Tobias

    2016-01-01

    Active electrical events play an important role in shaping signal processing in dendrites. As these events are usually associated with an increase in intracellular calcium, they are likely to be under the control of calcium-activated potassium channels. Here, we investigate the impact of calcium-activated potassium channels on N-methyl-d-aspartate (NMDA) receptor-dependent spikes, or NMDA spikes, evoked by glutamate iontophoresis onto basal dendrites of cortical layer 5 pyramidal neurons. We found that small-conductance calcium-activated potassium channels (SK channels) act to reduce NMDA spike amplitude but at the same time, also decrease the iontophoretic current required for their generation. This SK-mediated decrease in NMDA spike threshold was dependent on R-type voltage-gated calcium channels and indicates a counterintuitive, excitatory effect of SK channels on NMDA spike generation, whereas the capacity of SK channels to suppress NMDA spike amplitude is in line with the expected inhibitory action of potassium channels on dendritic excitability. Large-conductance calcium-activated potassium channels had no significant impact on NMDA spikes, indicating that these channels are either absent from basal dendrites or not activated by NMDA spikes. These experiments reveal complex and opposing interactions among NMDA receptors, SK channels, and voltage-gated calcium channels in basal dendrites of cortical layer 5 pyramidal neurons during NMDA spike generation, which are likely to play an important role in regulating the way these neurons integrate the thousands of synaptic inputs they receive. PMID:26936985

  1. A lasting effect of postnatal sevoflurane anesthesia on the composition of NMDA receptor subunits in rat prefrontal cortex.

    PubMed

    Zhang, Xiaoyu; Shen, Fengyan; Xu, Daojie; Zhao, Xuan

    2016-11-01

    Sevoflurane is widely used in pediatric anesthesia and studies have shown that it is capable of inducing neurodegeneration and subsequent cognitive disorders in the developing brain. However, the evidence that anesthetics are toxic to the human brain is insufficient. N-Methyl-d-aspartate (NMDA) receptors, critical for learning and memory, display expression changes with age and can be modulated by inhalation anesthetics. Generally, NMDA receptor (NR) type 1 is expressed at birth, peaks around the third postnatal week, and then declines slightly to adult levels. NR2Bs slowly decrease and NR2As gradually increase during postnatal development. These developmental switches of NMDA receptor subunits composition mark the transition from immature to adult neural processing and allow for the final maturation of associative learning abilities. In this study, we aimed to evaluate the effect of repeated sevoflurane anesthesia on NMDA receptor subunits composition in the developing rat brain and related behavioral disorders. Six-day-old male Sprague Dawley rats were randomly allocated into either a control group (group con) or a sevoflurane group (group sevo). Group sevo inhaled 2.1% sevoflurane carried by 70% oxygen for 2h each day from postnatal day (PND) 6 to PND 8. The same procedure, without applying the sevoflurane, was executed in group con. The membrane protein expression of NR1, NR2A and NR2B in the prefrontal cortex (PFC) and hippocampus was assessed at the end of the three days of anesthesia and at PND 21. An open field test was carried out to assess spontaneous locomotion on PNDs 21, 28 and 35. Y maze performance was used to assess attention and working memory on PND 28. Sevoflurane induced upregulation of NR1 and NR2B in the PFC at the end of anesthesia. On PND 21, NR1 and NR2B receptors were significantly increased whereas NR2A receptors were significantly decreased in the PFC in group sevo. Sevoflurane-treated rats showed hyper-locomotion and impairment of

  2. (+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism

    PubMed Central

    Zhao, Jing; Mysona, Barbara A.; Qureshi, Azam; Kim, Lily; Fields, Taylor; Gonsalvez, Graydon B.; Smith, Sylvia B.; Bollinger, Kathryn E.

    2016-01-01

    Purpose To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)-pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. Methods Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1−/− (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)-pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. Results N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. Conclusions Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases. PMID:26868747

  3. GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice.

    PubMed

    Oliveira-Pinto, Juliana; Paes-Branco, Danielle; Cristina-Rodrigues, Fabiana; Krahe, Thomas E; Manhães, Alex C; Abreu-Villaça, Yael; Filgueiras, Cláudio C

    2015-01-01

    Both NMDA receptor blockade and GABAA receptor overactivation during the brain growth spurt may contribute to the hyperactivity phenotype reminiscent of attention-deficit/hyperactivity disorder. Here, we evaluated the effects of exposure to MK801 (a NMDA antagonist) and/or to muscimol (a GABAA agonist) during the brain growth spurt on locomotor activity of juvenile Swiss mice. This study was carried out in two separate experiments. In the first experiment, pups received a single i.p. injection of either saline solution (SAL), MK801 (MK, 0.1, 0.3 or 0.5 mg/kg) or muscimol (MU, 0.02, 0.1 or 0.5 mg/kg) at the second postnatal day (PND2), and PNDs 4, 6 and 8. In the second experiment, we investigated the effects of a combined injection of MK (0.1 mg/kg) and MU (doses: 0.02, 0.1 or 0.5 mg/kg) following the same injection schedule of the first experiment. In both experiments, locomotor activity was assessed for 15 min at PND25. While MK promoted a dose-dependent increase in locomotor activity, exposure to MU failed to elicit significant effects. The combined exposure to the highest dose of MU and the lowest dose of MK induced marked hyperactivity. Moreover, the combination of the low dose of MK and the high dose of MU resulted in a reduced activity in the center of the open field, suggesting an increased anxiety-like behavior. These findings suggest that, during the brain growth spurt, the blockade of NMDA receptors induces juvenile locomotor hyperactivity whereas hyperactivation of GABAA receptors does not. However, GABAA overactivation during this period potentiates the effects of NMDA blockade in inducing locomotor hyperactivity.

  4. A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice.

    PubMed

    Poleszak, Ewa; Wlaź, Piotr; Szewczyk, Bernadeta; Wlaź, Aleksandra; Kasperek, Regina; Wróbel, Andrzej; Nowak, Gabriel

    2011-11-01

    Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and D: -cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and D: -cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or D: -cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and D: -cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by D: -serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.

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

    PubMed

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

    2015-12-01

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

  6. Lack of NMDA-AMPA interaction in antidepressant-like effect of CGP 37849, an antagonist of NMDA receptor, in the forced swim test.

    PubMed

    Dybała, Małgorzata; Siwek, Agata; Poleszak, Ewa; Pilc, Andrzej; Nowak, Gabriel

    2008-11-01

    The NMDA receptor antagonist, CGP 37849-induced reduction in immobility time in the forced swim test in mice was not antagonized by pre-treatment with the AMPA receptor antagonist NBQX. This is the first demonstration of the antidepressant effect of the NMDA antagonist not being dependent on the AMPA transmission.

  7. Glutamatergic NMDA Receptor as Therapeutic Target for Depression.

    PubMed

    Réus, Gislaine Z; Abelaira, Helena M; Tuon, Talita; Titus, Stephanie E; Ignácio, Zuleide M; Rodrigues, Ana Lúcia S; Quevedo, João

    2016-01-01

    Major depressive disorder (MDD) affects approximately 121 million individuals globally and poses a significant burden to the healthcare system. Around 50-60% of patients with MDD respond adequately to existing treatments that are primarily based on a monoaminergic system. However, the neurobiology of MDD has not been fully elucidated; therefore, it is possible that other biochemical alterations are involved. The glutamatergic system and its associated receptors have been implicated in the pathophysiology of MDD. In fact, the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor, is a binding or modulation site for both classical antidepressants and new fast-acting antidepressants. Thus, this review aims to present evidence describing the effect of antidepressants that modulate NMDA receptors and the mechanisms that contribute to the antidepressant response.

  8. NMDA receptor modulation of incidental learning in Pavlovian context conditioning.

    PubMed

    Stote, Deborah L; Fanselow, Michael S

    2004-02-01

    Rats exposed to a footshock show conditional fear when reexposed to the shock context. Immediate presentation of shock after placement in the context significantly reduces this fear. Preexposure to the context in the absence of shock, coupled with a minimum preshock interval during training, overcomes this immediate shock deficit. Because rats learn about the context during preexposure and express that learning after being reinforced, the context preexposure effect is an aversive analogue of latent learning. The authors examined the effect of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphovalerate (APV) on the facilitatory effect of context preexposure. Rats were preexposed to a chamber after APV administration. The next day they were placed in the same chamber without drug and received shock 35 s later. APV blocked the facilitatory effect of preexposure. Therefore NMDA receptors are important for contextual latent learning.

  9. Efficacies of treatments for anti-NMDA receptor encephalitis.

    PubMed

    Wang, Hsiuying

    2016-01-01

    Treatments for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis include immunotherapy with steroids, intravenous immunoglobulin, plasma exchange, or plasmapheresis as first-line treatments, immunotherapy with rituximab or cyclophosphamide as second-line treatments, and tumor removal. In this systematic review, we evaluated previous studies and examined the association between certain microRNAs and anti-NMDA receptor encephalitis to investigate the performance of different treatment combinations. The efficacies of different combinations of treatments classified into the following four categories were compared: (I) intravenous immunoglobulin administration, (II) plasmapheresis or plasma exchange, (III) treatment with rituximab or cyclophosphamide and (IV) tumor removal. Statistical analyses showed that treatment combinations including at least two of these categories resulted in higher efficacy rates than treatment with a single form of therapy. These findings suggest that if a patient is not recovering, converting to other therapies is more likely to result in early recovery than continuing on the original therapy.

  10. 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.

  11. Subunit-dependent effects of nickel on NMDA receptor channels.

    PubMed

    Marchetti, Carla; Gavazzo, Paola

    2003-10-07

    Nickel (Ni2+) is a transition metal that affects different neuronal ionic channels. We investigated its effects on glutamate channels of the NMDA-type in the presence of saturating concentration of glutamate or NMDA (50 microM), in 0 external Mg and in the continuous presence of saturating glycine (30 microM). In neonatal rat cerebellar granule cells, Ni2+ inhibited the current evoked by NMDA at -60 mV with an IC50 close to 40 microM. The inhibition was weakly voltage-dependent and the current at +40 mV was inhibited with IC50=86 microM. Wash out of the metal unmasked a stimulatory effect which persisted for a few seconds. In HEK293 cells transiently transfected with recombinant NR1a-NR2A receptors, Ni2+ inhibited the current elicited by glutamate with an IC50=52 microM at -60 mV and 90 microM at +40 mV. In HEK293 expressing NR1a-NR2B receptors, 0.1-100 microM Ni2+ caused a potentiation of the current, with EC50=4 microM, while with 300 microM, a voltage-dependent block became apparent (IC50=170 microM). As previously reported, the current through both classes of recombinant receptors was steeply dependent on external pH, and in both cases the protonic block had an IC50 close to pH 7.2. Application of Ni2+ showed that stimulation of NR1a-NR2B receptor channels was dependent on external pH, while voltage-independent inhibition of NR1a-NR2A was less sensitive to pH change. These results indicate that Ni2+ has multiple and complex effects on NMDA channels, which are largely dependent on the NR2 subunit.

  12. NMDA receptor antagonists extend the sensitive period for imprinting.

    PubMed

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

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

    PubMed

    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.

  14. 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

  15. 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.

  16. 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

  17. Mauthner cell-initiated electromotor behavior is mediated via NMDA and metabotropic glutamatergic receptors on medullary pacemaker neurons in a gymnotid fish.

    PubMed

    Curti, S; Falconi, A; Morales, F R; Borde, M

    1999-10-15

    Weakly electric fish generate meaningful electromotor behaviors by specific modulations of the discharge of their medullary pacemaker nucleus from which the rhythmic command for each electric organ discharge (EOD) arises. Certain electromotor behaviors seem to involve the activation of specific neurotransmitter receptors on particular target cells within the nucleus, i.e., on pacemaker or on relay cells. This paper deals with the neural basis of the electromotor behavior elicited by activation of Mauthner cells in Gymnotus carapo. This behavior consists of an abrupt and prolonged increase in the rate of the EOD. The effects of specific glutamate agonists and antagonists on basal EOD frequency and on EOD accelerations induced by Mauthner cell activation were assessed. Injections of both ionotropic (AMPA, kainate, and NMDA) and metabotropic (trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid) glutamate agonists induced increases in EOD rate that were maximal when performed close to the soma of pacemaker cells. In contrast, injections in the proximity of relay cells were ineffective. Therefore, pacemaker neurons are probably endowed with diverse glutamate receptor subtypes, whereas relay cells are probably not. The Mauthner cell-evoked electromotor behavior was suppressed by injections of AP-5 and (+/-)-amino-4-carboxy-methyl-phenylacetic acid, NMDA receptor and metabotropic glutamate receptor antagonists, respectively. Thus, this electromotor behavior relies on the activation of the NMDA and metabotropic glutamate receptor subtypes of pacemaker cells. Our study gives evidence for the synergistic effects of NMDA and metabotropic receptor activation and shows how a simple circuit can produce specific electromotor outputs.

  18. Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors.

    PubMed

    Paquette, Melanie A; Martinez, Alex A; Macheda, Teresa; Meshul, Charles K; Johnson, Steven W; Berger, S Paul; Giuffrida, Andrea

    2012-11-01

    Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.

  19. Identification of potential Gly/NMDA receptor antagonists by cheminformatics approach: a combination of pharmacophore modelling, virtual screening and molecular docking studies.

    PubMed

    Ugale, V G; Bari, S B

    2016-01-01

    The Gly/NMDA receptor has become known as potential target for the management of neurodegenerative diseases. Discovery of Gly/NMDA antagonists has thus attracted much attention in recent years. In the present research, a cheminformatics approach has been used to determine structural requirements for Gly/NMDA antagonism and to identify potential antagonists. Here, 37 quinoxaline derivatives were selected to develop a significant pharmacophore model with good certainty. The selected model was validated by leave-one-out cross-validation, an external test set, decoy set and Y-randomization test. Applicability domain was verified by the standardization approach. The validated 3D-QSAR model was used to screen virtual hits from the ZINC database by pharmacophore mapping. Molecular docking was used for assessment of receptor-ligand binding modes and binding affinities. The GlideScore and molecular interactions with critical amino acids were considered as crucial features to identify final hits. Furthermore, hits were analysed for in silico pharmacokinetic parameters and Lipinski's rule of five, demonstrating their potential as drug-like candidates. The PubChem and SciFinder search tools were used to authenticate the novelty of leads retrieved. Finally, five different leads have been suggested as putative novel candidates for the exploration of potent Gly/NMDA receptor antagonists.

  20. Anti-NMDA Receptor antibody encephalitis with concomitant detection of Varicella zoster virus.

    PubMed

    Solís, Natalia; Salazar, Lucrecia; Hasbun, Rodrigo

    2016-10-01

    The typical presentation of anti-NMDA (N-Methyl-d-Aspartate) receptor encephalitis involves young women with psychiatric, neurologic and autonomic symptoms; it is often associated with mature ovarian teratomas. NMDA receptor encephalitis has been described following Herpes simplex virus (HSV) encephalitis. This case describes a classic presentation of anti-NMDA receptor encephalitis with the concomitant presence of Varicella zoster virus in the cerebrospinal fluid.

  1. The parvalbumin-positive interneurons in the mouse dentate gyrus express GABAA receptor subunits α1, β2, and δ along their extrasynaptic cell membrane.

    PubMed

    Milenkovic, I; Vasiljevic, M; Maurer, D; Höger, H; Klausberger, T; Sieghart, W

    2013-12-19

    Neuronal circuitries in the hippocampus are involved in navigation and memory and are controlled by major networks of GABAergic interneurons. Parvalbumin (PV)-expressing interneurons in the dentate gyrus (DG) are identified as fast-spiking cells, playing a crucial role in network oscillation and synchrony. The inhibitory modulation of these interneurons is thought to be mediated mainly through GABAA receptors, the major inhibitory neurotransmitter receptors in the brain. Here we show that all PV-positive interneurons in the granular/subgranular layer (GL/SGL) of the mouse DG express high levels of the GABAA receptor δ subunit. PV-containing interneurons in the hilus and the molecular layer, however, express the δ subunit to a lower extent. Only 8% of the somatostatin-containing interneurons express the δ subunit, whereas calbindin- or calretinin-containing interneurons in the DG seem not to express the GABAA receptor δ subunit at all. Hence, these cells receive a GABAergic control different from that of PV-containing interneurons in the GL/SGL. Experiments investigating a possible co-expression of GABAA receptor α1, α2, α3, α4, α5, β1, β2, β3, or γ2 subunits with PV and δ subunits indicated that α1 and β2 subunits are co-expressed with δ subunits along the extrasynaptic membranes of PV-interneurons. These results suggest a robust tonic GABAergic control of PV-containing interneurons in the GL/SGL of the DG via δ subunit-containing receptors. Our data are important for better understanding of the neuronal circuitries in the DG and the role of specific cell types under pathological conditions.

  2. Proteomic analysis of the mice hippocampus after preconditioning induced by N-methyl-D-aspartate (NMDA).

    PubMed

    do Amaral e Silva Müller, Gabrielle; Vandresen-Filho, Samuel; Tavares, Carolina Pereira; Menegatti, Angela C O; Terenzi, Hernán; Tasca, Carla Inês; Severino, Patricia Cardoso

    2013-05-01

    Preconditioning induced by N-methyl-D-aspartate (NMDA) has been used as a therapeutic tool against later neuronal insults. NMDA preconditioning affords neuroprotection against convulsions and cellular damage induced by the NMDA receptor agonist, quinolinic acid (QA) with time-window dependence. This study aimed to evaluate the molecular alterations promoted by NMDA and to compare these alterations in different periods of time that are related to the presence or lack of neuroprotection. Putative mechanisms related to NMDA preconditioning were evaluated via a proteomic analysis by using a time-window study. After a subconvulsant and protective dose of NMDA administration mice, hippocampi were removed (1, 24 or 72 h) and total protein analyzed by 2DE gels and identified by MALDI-TOF. Differential protein expression among the time induction of NMDA preconditioning was observed. In the hippocampus of protected mice (24 h), four proteins: HSP70(B), aspartyl-tRNA synthetase, phosphatidylethanolamine binding protein and creatine kinase were found to be up-regulated. Two other proteins, HSP70(A) and V-type proton ATPase were found down-regulated. Proteomic analysis showed that the neuroprotection induced by NMDA preconditioning altered signaling pathways, cell energy maintenance and protein synthesis and processing. These events may occur in a sense to attenuate the excitotoxicity process during the activation of neuroprotection promoted by NMDA preconditioning.

  3. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis.

    PubMed

    Wandinger, Klaus-Peter; Saschenbrecker, Sandra; Stoecker, Winfried; Dalmau, Josep

    2011-02-01

    Anti-NMDA-receptor encephalitis is a severe, treatable and potentially reversible disorder presenting with memory deficits, psychiatric symptoms and seizures. Initially described in young patients with ovarian teratoma, the disease is meanwhile increasingly recognized also in women without tumours, in men and in children. The presence of anti-glutamate receptor (type NMDA) autoantibodies in serum or cerebrospinal fluid is specific for this novel and widely underdiagnosed disorder. Early recognition is crucial since prognosis largely depends on adequate immunotherapy and, in paraneoplastic cases, complete tumour removal. Indirect immunofluorescence using NMDA-type glutamate receptors recombinantly expressed in human cells is a highly competent method for diagnosing anti-NMDA-receptor encephalitis.

  4. Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor

    PubMed Central

    Olmos, Gabriel; DeGregorio-Rocasolano, Nuria; Regalado, M Paz; Gasull, Teresa; Boronat, M Assumpció; Trullas, Ramón; Villarroel, Alvaro; Lerma, Juan; García-Sevilla, Jesús A

    1999-01-01

    This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells.Exposure (30 min) of energy deprived cells to L-glutamate (1–100 μM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 μM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine).Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 μM (EC100) L-glutamate with the rank order (EC50 in μM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole] (101)>RX821002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors.Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding.In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10–12 μM at 0 mV.It is concluded that imidazol(ine) drugs and agmatine are

  5. 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

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

    PubMed

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

    2014-10-01

    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.

  7. Topiramate antagonizes NMDA- and AMPA-induced seizure-like activity in planarians.

    PubMed

    Rawls, Scott M; Thomas, Timmy; Adeola, Mobilaji; Patil, Tanvi; Raymondi, Natalie; Poles, Asha; Loo, Michael; Raffa, Robert B

    2009-10-01

    The mechanism of anticonvulsant action of topiramate includes inhibition of glutamate-activated ion channels. The evidence is most convincing for direct inhibitory action at the ionotropic AMPA (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2S,3S,4S)-3-(Carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid) glutamate receptor subtypes. Less direct connection has been made to the NMDA (N-Methyl-d-aspartate) subtype. In the present study, we demonstrate that NMDA and AMPA produce concentration-dependent seizure-like activity in planarians, a type of flatworm which possesses mammalian-like neurotransmitters. In contrast, planarians exposed to the inhibitory amino acid, glycine, did not display pSLA. For combination experiments, topiramate significantly reduced planarian seizure-like activity (pSLA) produced by NMDA or AMPA. Additionally, NMDA-induced pSLA was antagonized by either an NMDA receptor antagonist (MK-801) or AMPA receptor antagonist (DNQX), thus suggesting that NMDA-induced pSLA was mediated by NMDA and non-NMDA receptors. The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology.

  8. Glutamatergic Dysbalance and Oxidative Stress in In Vivo and In Vitro Models of Psychosis Based on Chronic NMDA Receptor Antagonism

    PubMed Central

    Genius, Just; Geiger, Johanna; Dölzer, Anna-Lena; Benninghoff, Jens; Giegling, Ina; Hartmann, Annette M.; Möller, Hans-Jürgen; Rujescu, Dan

    2013-01-01

    Background The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia. Methods The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats. Results Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/− 10.4% S.E.M of control; p = 0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro. Conclusion The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia. PMID:23869202

  9. Roles of presynaptic NMDA receptors in neurotransmission and plasticity

    PubMed Central

    Banerjee, Abhishek; Larsen, Rylan S.; Philpot, Benjamin D.; Paulsen, Ole

    2015-01-01

    Presynaptic NMDA receptors (preNMDARs) play pivotal roles in excitatory neurotransmission and synaptic plasticity. They facilitate presynaptic neurotransmitter release and modulate mechanisms controlling synaptic maturation and plasticity during formative periods of brain development. There is an increasing understanding of the roles of preNMDARs in experience-dependent synaptic and circuit-specific computation. In this review, we summarize the latest understanding of compartment-specific expression and function of preNMDARs, and how they contribute to synapse-specific and circuit-level information processing. PMID:26726120

  10. A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity

    PubMed Central

    Yoon, Seo-Yeon; Kwon, Soon-Gu; Kim, Yong Ho; Yeo, Ji-Hee; Ko, Hyoung-Gon; Roh, Dae-Hyun; Kaang, Bong-Kiun; Beitz, Alvin J; Lee, Jang-Hern

    2017-01-01

    Background Self-injurious behaviors (SIBs) are devastating traits in autism spectrum disorder (ASD). Although deficits in pain sensation might be one of the contributing factors underlying the development of SIBs, the mechanisms have yet to be addressed. Recently, the Shank2 synaptic protein has been considered to be a key component in ASD, and mutations of SHANK2 gene induce the dysfunction of N-methyl-D-aspartate (NMDA) receptors, suggesting a link between Shank2 and NMDA receptors in ASD. Given that spinal NMDA receptors play a pivotal role in pain hypersensitivity, we investigated the possible role of Shank2 in nociceptive hypersensitivity by examining changes in spontaneous pain following intrathecal NMDA injection in Shank2−/− (Shank2 knock-out, KO) mice. Results Intrathecal NMDA injection evoked spontaneous nociceptive behaviors. These NMDA-induced nociceptive responses were significantly reduced in Shank2 KO mice. We also observed a significant decrease of NMDA currents in the spinal dorsal horn of Shank2 KO mice. Subsequently, we examined whether mitogen-activated protein kinase or AKT signaling is involved in this reduced pain behavior in Shank2 KO mice because the NMDA receptor is closely related to these signaling molecules. Western blotting and immunohistochemistry revealed that spinally administered NMDA increased the expression of a phosphorylated form of extracellular signal-regulated kinase (p-ERK) which was significantly reduced in Shank2 KO mice. However, p38, JNK, or AKT were not changed by NMDA administration. The ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in a dose-dependent manner in wild-type mice. Moreover, it was found that the NMDA-induced increase in p-ERK was primarily colocalized with Shank2 proteins in the spinal cord dorsal horn. Conclusion Shank2 protein is involved in spinal NMDA receptor-mediated pain, and mutations of Shank2 may suppress NMDA-ERK signaling in spinal pain transmission. This study

  11. Effects of an NMDA antagonist on the auditory mismatch negativity response to transcranial direct current stimulation.

    PubMed

    Impey, Danielle; de la Salle, Sara; Baddeley, Ashley; Knott, Verner

    2016-09-13

    Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which uses a weak constant current to alter cortical excitability and activity temporarily. tDCS-induced increases in neuronal excitability and performance improvements have been observed following anodal stimulation of brain regions associated with visual and motor functions, but relatively little research has been conducted with respect to auditory processing. Recently, pilot study results indicate that anodal tDCS can increase auditory deviance detection, whereas cathodal tDCS decreases auditory processing, as measured by a brain-based event-related potential (ERP), mismatch negativity (MMN). As evidence has shown that tDCS lasting effects may be dependent on N-methyl-D-aspartate (NMDA) receptor activity, the current study investigated the use of dextromethorphan (DMO), an NMDA antagonist, to assess possible modulation of tDCS's effects on both MMN and working memory performance. The study, conducted in 12 healthy volunteers, involved four laboratory test sessions within a randomised, placebo and sham-controlled crossover design that compared pre- and post-anodal tDCS over the auditory cortex (2 mA for 20 minutes to excite cortical activity temporarily and locally) and sham stimulation (i.e. device is turned off) during both DMO (50 mL) and placebo administration. Anodal tDCS increased MMN amplitudes with placebo administration. Significant increases were not seen with sham stimulation or with anodal stimulation during DMO administration. With sham stimulation (i.e. no stimulation), DMO decreased MMN amplitudes. Findings from this study contribute to the understanding of underlying neurobiological mechanisms mediating tDCS sensory and memory improvements.

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

    PubMed

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

    2007-04-03

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

  13. Mechanical stress activates NMDA receptors in the absence of agonists.

    PubMed

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

    2017-01-03

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca(2+) entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca(2+) influx. Extracellular Mg(2+) at 2 mM did not significantly affect the shear induced Ca(2+) influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

  14. Mechanical stress activates NMDA receptors in the absence of agonists

    PubMed Central

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

    2017-01-01

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca2+ influx. Extracellular Mg2+ at 2 mM did not significantly affect the shear induced Ca2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI. PMID:28045032

  15. A kinetic model of NMDA ion channel under varying noise

    NASA Astrophysics Data System (ADS)

    Wang, Rubin; Chen, Hao; Zhang, Zhikang

    2004-05-01

    It is well known that when transmitters are applied to the postsynaptic membrane, the resulting depolarization is noisy that is due to the random opening and closing of the ion channels activated by the transmitters[1]. In other words, the energy of noise is associated with changes in ion channels. On the base of these ideas, we explore a model of relationship between NMDA (n-methyl-D-aspartate) ion channels and LTP (long-term synaptic potentiation). We have proved that NMDA ion channel and calcium-dependent protein kinases, which are the triggers for the inducement of LTP, could be regarded as "molecular machines". In this system all of these molecules require energy and the energy of the system is supplied from the random motion of water molecules generated through heat energy of ATP hydrolysis[2]. So the appropriate framework to describe them comes from bioenergetics. Models of LTP previously reported are all on the macroscopic level [3-7]. Instead, we research a model at the molecular level by applying energy parameters [8].

  16. 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.

  17. TAAR1 Modulates Cortical Glutamate NMDA Receptor Function.

    PubMed

    Espinoza, Stefano; Lignani, Gabriele; Caffino, Lucia; Maggi, Silvia; Sukhanov, Ilya; Leo, Damiana; Mus, Liudmila; Emanuele, Marco; Ronzitti, Giuseppe; Harmeier, Anja; Medrihan, Lucian; Sotnikova, Tatyana D; Chieregatti, Evelina; Hoener, Marius C; Benfenati, Fabio; Tucci, Valter; Fumagalli, Fabio; Gainetdinov, Raul R

    2015-08-01

    Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.

  18. TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

    PubMed Central

    Espinoza, Stefano; Lignani, Gabriele; Caffino, Lucia; Maggi, Silvia; Sukhanov, Ilya; Leo, Damiana; Mus, Liudmila; Emanuele, Marco; Ronzitti, Giuseppe; Harmeier, Anja; Medrihan, Lucian; Sotnikova, Tatyana D; Chieregatti, Evelina; Hoener, Marius C; Benfenati, Fabio; Tucci, Valter; Fumagalli, Fabio; Gainetdinov, Raul R

    2015-01-01

    Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions. PMID:25749299

  19. Association between genetic variations of NMDA receptor NR3 subfamily genes and heroin addiction in male Han Chinese.

    PubMed

    Xie, Xiaohu; Liu, Huifen; Zhang, Jianbing; Chen, Weisheng; Zhuang, Dingding; Duan, Shiwei; Zhou, Wenhua

    2016-09-19

    Growing amounts of evidence suggest that N-Methyl-d-aspartate (NMDA) receptor mediated glutamate neurotransmission may be involved in the pathophysiology of drug dependence. The NMDA receptor consists of three subfamilies (NR1, NR2, and NR3). The ability of subunit NR3 to negatively modulate the NMDA receptor function makes it an attractive candidate gene of heroin addiction. The purpose of this study is to explore the association between four single nucleotide polymorphisms (SNPs) of NR3 gene and heroin addiction. Genotyping of two SNPs (rs3739722 and rs17189632) in GRIN3A and two SNPs (rs4807399 and rs2240158) in GRIN3B was performed using TaqMan SNP genotyping method. The association between heroin addiction and these SNPs was assessed among 332 male heroin dependent patients and 400 male normal control subjects. The results showed the genotype and allele frequencies of rs17189632 and rs2240158 were significantly different between the cases and the controls (nominal P values were 0.0284, 0.0136 for rs17189632; 0.0048, 0.0013 for rs2240158, respectively). After Bonferroni correction, rs2240158 of GRIN3B was still found to be associated with heroin addiction. The frequencies of haplotype C-A at GRIN3A (rs3739722-rs17189632) and of C-C and C-T at GRIN3B (rs4807399-rs2240158) differed significantly between the cases and the controls. The genotype and allele distributions of rs3739722 and rs4807399 were not significantly different between in the cases and in the controls (P>0.05). These results suggest that GRIN3A rs17189632 and GRIN3B rs2240158 may contribute to the susceptibility of heroin addiction.

  20. Involvement of peripheral NMDA and non-NMDA receptors in development of persistent firing of spinal wide-dynamic-range neurons induced by subcutaneous bee venom injection in the cat.

    PubMed

    Chen, J; Li, H; Luo, C; Li, Z; Zheng, J

    1999-10-09

    To study the roles of peripheral excitatory amino acids receptor subtypes N-methyl-D-aspartate (NMDA) and non-NMDA receptors in persistent nociception, extracellular single unit recording technique was used to assess the effects of a single dose NMDA and non-NMDA receptor antagonists, AP(5) (5-aminophosphonovaleric acid) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) or DNQX (6,7-dinitroquinoxaline-2,3-dione), on s.c. bee venom-induced increase in firing of wide-dynamic-range (WDR) neurons in the spinal dorsal horn of the urethane-chloralose anesthetized cats. Subcutaneous bee venom injection into the cutaneous receptive field resulted in a single phase of increased firing of WDR neurons over the background activity for more than 1 h. Local pre-administration of AP(5) (200 microg/100 microl) or CNQX (8.3 microg/100 microl) into the bee venom injection site produced 94% (1.01+/-0.96 spikes/s, n=5) or 76% (2.97+/-0.58 spikes/s, n=4) suppression of the increased neuronal firing when compared with local saline (16.32+/-4.55 spikes/s, n=10) or dimethyl sulfoxide (DMSO) (12.37+/-6.36 spikes/s, n=4) pre-treated group, respectively. Local post-administration of the same dose of AP(5) produced a similar result to the pre-treatment group with a 67% inhibition of the mean firing rate, however, the same treatment with CNQX and even a higher dose of DNQX (100 microg/100 microl) did not produce any inhibition of the neuronal firing induced by s.c. bee venom injection (DNQX vs. DMSO: 23.91+/-0. 25 vs. 22.14+/-0.04 spikes/s, P=0.0298, n=5). In the control experiments, local pre-administration of the same dose of AP(5) or CNQX into a region on the contralateral hindpaw symmetrical to the bee venom injection site produced no significant influence on the increased firing of the WDR neurons [contralateral AP(5) vs. saline: 14.17+/-6.27 spikes/s (n=5) vs. 16.32+/-4.55 spikes/s (n=10), P0.05; contralateral CNQX vs. DMSO: 12.85+/-6.38 spikes/s (n=4) vs. 12. 37+/-6.36 spikes/s (n=4), P0

  1. Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons.

    PubMed

    Noh, Ji-Hyun; Gwag, Byoung-Joo; Chung, Jun-Mo

    2006-01-01

    Sulfasalazine (SULFA), of anti-inflammatory drugs, shows a protective action against NMDA-induced neuronal toxicity. Here, we used an electrophysiological study of the pharmacological effects of SULFA on NMDA receptors to examine the molecular mechanisms underlying the neuroprotective role of SULFA. The drug acted as a typical noncompetitive inhibitor with neither agonist- nor use-dependency, and antagonized NMDA-evoked responses in a voltage-independent manner, suggesting that SULFA is not an open channel blocker. Noise and single channel analyses showed that SULFA-blocked NMDA responses by reducing the number of NMDA channels available for activation, and also reduced the channel open probability without changing single channel conductance. Moreover, SULFA accelerated NMDA desensitization without affecting the affinity of the receptor for NMDA or glutamate. Taken together, these data indicate that SULFA blocks the NMDA response by reducing the number of NMDA channels available for activation. This appears to occur via a SULFA-induced decrease in the channel open probability, and a concomitant acceleration of the desensitization response, which is likely associated with a reduced affinity for glycine. SULFA indeed decreased the glycine-potentiated NMDA response without binding directly to the glycine site. Our results suggest that SULFA acts as a noncompetitive NMDA receptor antagonist with an allosteric glycine modulation.

  2. 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.

  3. Further insights into the anti-aggregating activity of NMDA in human platelets

    PubMed Central

    Franconi, Flavia; Miceli, Mauro; Alberti, Luisa; Seghieri, Giuseppe; De Montis, M Graziella; Tagliamonte, Alessandro

    1998-01-01

    In the present study the effect of N-methyl-D-aspartate (NMDA) on thromboxane B2 synthesis and on [Ca2+]i was studied in human platelets.NMDA (10−7 M) completely inhibited the synthesis of thromboxane B2 from exogenous arachidonic acid (AA), while it did not interfere with the aggregating effect of the thromboxane A2 receptor agonist U-46619.NMDA (0.1 μM–10 μM) dose-dependently increased intracellular calcium in washed platelets pre-loaded with fura 2 AM, and this effect was not additive with that of AA.NMDA shifted the dose-response curve of AA to the right. At the highest AA concentrations platelet aggregation was not inhibited.The antiaggregating effect of NMDA was not antagonized by NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase (NOS) inhibitor.Finally, NMDA (0.01 nM–100 nM) associated with either aspirin or indomethacin significantly potentiated the antiaggregating activity of both cyclo-oxygenase inhibitors.It was concluded that NMDA is a potent inhibitor of platelet aggregation and thromboxane B2 synthesis in human platelet rich plasma (PRP). PMID:9630340

  4. Kinetic Contributions to Gating by Interactions Unique to N-methyl-d-aspartate (NMDA) Receptors*

    PubMed Central

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

    2015-01-01

    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

  5. Neuroprotective Effect of Lutein on NMDA-Induced Retinal Ganglion Cell Injury in Rat Retina.

    PubMed

    Zhang, Chanjuan; Wang, Zhen; Zhao, Jiayi; Li, Qin; Huang, Cuiqin; Zhu, Lihong; Lu, Daxiang

    2016-05-01

    Lutein injection is a possible therapeutic approach for retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate its protective effects in retinal ganglion cells (RGCs) against N-methyl-D-aspartate (NMDA)-induced retinal damage in vivo. Retinal damage was induced by intravitreal NMDA injection in rats. Each animal was given five daily intraperitoneal injections of Lutein or vehicle along with intravitreal NMDA injections. Electroretinograms were recorded. The number of viable RGCs was quantified using the retinal whole-mount method by immunofluorescence. Proteins were measured by Western blot assays. Lutein reduced the retinal damage and improved the response to light, as shown by an animal behavior assay (the black-and-white box method) in rats. Furthermore, Lutein treatment prevented the NMDA-induced reduction in phNR wave amplitude. Lutein increased RGC number after NMDA-induced retina damage. Most importantly, Bax, cytochrome c, p-p38 MAPK, and p-c-Jun were all upregulated in rats injected with NMDA, but these expression patterns were reversed by continuous Lutein uptake. Bcl-2, p-GSK-3β, and p-Akt in the Lutein-treated eyes were increased compared with the NMDA group. Lutein has neuroprotective effects against retinal damage, its protective effects may be partly mediated by its anti-excitability neurotoxicity, through MAPKs and PI3K/Akt signaling, suggesting a potential approach for suppressing retinal neural damage.

  6. Glycine decreases desensitization of N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes and is required for NMDA responses.

    PubMed

    Lerma, J; Zukin, R S; Bennett, M V

    1990-03-01

    In Xenopus oocytes injected with rat brain mRNA, as in neurons, glycine greatly potentiated responses of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. Injected oocytes generated a partially desensitizing inward current in response to NMDA with 30 nM added glycine. As the added glycine concentration was increased from 30 nM to 1 microM, the NMDA response was increased and exhibited less desensitization. The relationship between the NMDA peak response and added glycine concentration indicated a single component response with apparent affinity of 0.29 microM and a Hill coefficient of 0.77. The desensitized response was also fit by the Hill relation with a lower affinity but similar coefficient. The time course of desensitization at 500 microM NMDA was exponential with a time constant (350 msec) that was independent of glycine concentration between 0.03 and 0.3 microM. At higher glycine concentration a slower component of decay (tau = 1.4 sec) was observed. This component was enhanced by increasing the extracellular Ca2+. NMDA without added glycine evoked a small transient response. However this response was suppressed completely by prewashing with the glycine antagonist 7-chlorokynurenic acid, suggesting that it may have been due to glycine contamination. The dose-response relation for low concentrations of glycine indicated that the measured level of glycine contamination accounted for these responses. These results indicate that glycine has at least two actions at the NMDA receptor: it enables channel opening by the agonist and decreases desensitization.

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

    PubMed Central

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

    2014-01-01

    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 (p75NTR), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75NTR 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 Tyr1472 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 an Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. PMID:24611998

  8. Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice.

    PubMed

    Blue, Mary E; Kaufmann, Walter E; Bressler, Joseph; Eyring, Charlotte; O'driscoll, Cliona; Naidu, Sakkubai; Johnston, Michael V

    2011-10-01

    Our previous postmortem study of girls with Rett Syndrome (RTT), a development disorder caused by MECP2 mutations, found increases in the density of N-Methyl-D-aspartate (NMDA) receptors in the prefrontal cortex of 2-8-year-old girls, whereas girls older than 10 years had reductions in NMDA receptors compared with age-matched controls (Blue et al., Ann Neurol 1999b;45:541-545). Using [(3)H]-CGP to label NMDA-type glutamate receptors in 2- and 7-week old wild-type (WT), Mecp2-null, and Mecp2-heterozygous (HET) mice (Bird model), we found that frontal areas of the brain also exhibited a bimodal pattern in NMDA expression, with increased densities of NMDA receptors in Mecp2-null mice at 2 weeks of age but decreased densities at 7 weeks of age. Visual cortex showed a similar pattern, while other cortical regions only exhibited changes in NMDA receptor densities at 2 weeks (retrosplenial granular) or 7 weeks (somatosensory). In thalamus of null mice, NMDA receptors were increased at 2 and 7 weeks. No significant differences in density were found between HET and WT mice at both ages. Western blots for NMDAR1 expression in frontal brain showed higher levels of expression in Mecp2-null mice at 2 weeks of age but not at 1 or 7 weeks of age. Our mouse data support the notion that deficient MeCP2 function is the primary cause of the NMDA receptor changes we observed in RTT. Furthermore, the findings of regional and temporal differences in NMDA expression illustrate the importance of age and brain region in evaluating different genotypes of mice.

  9. Role of NMDA receptors in the lateralized potentiation of amygdala afferent and efferent neural transmission produced by predator stress.

    PubMed

    Adamec, Robert; Blundell, Jacqueline; Burton, Paul

    2005-09-15

    The present study investigated the role of NMDA receptors in behavioral and neuroplastic changes in amygdala efferent (central amygdala to periaqueductal gray-ACE-PAG) and amygdala afferent (ventral angular bundle to basolateral amygdala-VAB-BLA) pathways in response to predator stress. Effects on brain and behavioral response to predator stress of competitive block of NMDA receptors with a dose of 10 mg/kg of CPP (3-(2-carboxypiperazin4-yl)propyl-l-phosphonic acid) were studied. Behavioral response to stress was tested with hole board, elevated plus maze, light/dark box, social interaction and acoustic startle tests. CPP was administered i.p. 30 min prior to predator stress and blocked the effects of predator on some but not all behaviors measured 8-9 days later. Effects of predator stress and CPP on potentials evoked in the PAG by single pulse stimulation of the ACE and in the BLA by single pulse stimulation of VAB were assessed 10-11 days after predator stress. Predator stress potentiated ACE-PAG evoked potentials in the right but not the left hemisphere, replicating previous work. Predator stress potentiated VAB-BLA transmission in both hemispheres 10-11 days after predator stress. Right hemisphere VAB-BLA potentiation replicated and extended past studies showing right hemisphere potentiation at 1 and 9 days after stress. Left VAB-BLA potentiation effects differed from the long term depression seen in VAB-BLA at 1 and 9 days after stress in previous studies. CPP blocked predator stress-induced potentiation of ACE-PAG and VAB-BLA evoked potentials in the right hemisphere. CPP did not block left VAB-BLA potentiation, rather CPP amplified it. Left hemisphere effects of CPP were interpreted as reflecting block of NMDA dependent long term depression, which unmasked a non-NMDA dependent potentiation. Taken together, the findings add to a body of evidence suggesting that a syndrome of behavioral changes follows predator stress. Components of this syndrome likely

  10. EXTREME DELTA BRUSH EEG PATTERN IN A CASE WITH ANTI-NMDA RECEPTOR ENCEPHALITIS.

    PubMed

    Söylemez, Elif; Güveli, Betül Tekin; Atakli, Dilek; Yatmazoğlu, Merve; Atay, Turan; Dayan, Cengiz

    2015-09-30

    Anti-N-methyl-D-aspartate receptor NMDA-R encephalitis is caused by antibodies against the NMDA-R and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. This disorder is often accompanied with malignancies, especially ovarian teratoma. Some patients' EEGs show a different pattern similar to the waveforms of premature infants and this pattern is specifically named as extreme delta brush (EDB). We report a 24-year-old female having anti-NMDA receptor encephalitis and EDB patern.

  11. The NMDA receptor as a target for cognitive enhancement

    PubMed Central

    Collingridge, Graham L.; Volianskis, Arturas; Bannister, Neil; France, Grace; Hanna, Lydia; Mercier, Marion; Tidball, Patrick; Fang, Guangyu; Irvine, Mark W.; Costa, Blaise M.; Monaghan, Daniel T.; Bortolotto, Zuner A.; Molnár, Elek; Lodge, David; Jane, David E.

    2015-01-01

    NMDA receptors (NMDAR) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events. PMID:22796429

  12. 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

  13. 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

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

    PubMed Central

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

    2014-01-01

    The effects of 28 days of heavy resistance training while ingesting the alleged testosterone-boosting supplement, NMDA, were determined on body composition, muscle strength, serum cortisol, prolactin, and hormones associated with the hypothalamo-pituitary- gonadal (HPG) axis. Twenty resistance-trained males engaged in 28 days of resistance training 4 times/wk while orally ingesting daily either 1.78 g of placebo (PLAC) or NMDA. Data were analyzed with separate 2 x 2 ANOVA (p < 0.05). Criterion measures involved body composition, muscle strength, serum cortisol, prolactin, and gonadal hormone levels [free and total testosterone, luteininzing hormome (LH), gonadotrophin releasing hormone (GnRH), estradiol], and were assessed before (Day 0) and after (Day 29) resistance training and supplementation. No changes were noted for total body water and fat mass in response to resistance training (p > 0.05) or supplementation (p > 0.05). In regard to total body mass and fat-free mass, however, each was significantly increased in both groups in response to resistance training (p < 0.05), but were not affected by supplementation (p > 0.05). In both groups, lower-body muscle strength was significantly increased in response to resistance training (p < 0.05); however, supplementation had no effect (p > 0.05). All serum hormones (total and free testosterone, LH, GnRH, estradiol, cortisol, prolactin) were unaffected by resistance training (p > 0.05) or supplementation (p > 0.05). The gonadal hormones and cortisol and prolactin were unaffected by 28 days of NMDA supplementation and not associated with the observed increases in muscle strength and mass. At the dose provided, NMDA had no effect on HPG axis activity or ergogenic effects in skeletal muscle. Key Points In response to 28 days of heavy resistance training and NMDA supplementation, similar increases in muscle mass and strength in both groups occurred; however, the increases were not different between supplement groups. The

  15. Disruption of Performance in the 5-Choice Serial Reaction Time Task Induced by Administration of NMDA Receptor Antagonists: Relevance to Cognitive Dysfunction in Schizophrenia

    PubMed Central

    Amitai, Nurith; Markou, Athina

    2010-01-01

    Schizophrenia patients suffer from cognitive impairments that are not satisfactorily treated by currently available medications. Cognitive dysfunction in schizophrenia encompasses deficits in several cognitive modalities that can be differentially responsive to different medications and are likely to be mediated by different neurobiological substrates. Translational animal models of cognitive deficits with relevance to schizophrenia are critical for gaining insights into the mechanisms underlying these impairments and developing more effective treatments. The 5-choice serial reaction time task (5-CSRTT) is a cognitive task used in rodents that allows simultaneous assessment of several cognitive modalities, including attention, response inhibition, cognitive flexibility, and processing speed. Administration of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists disrupts multiple 5-CSRTT performance measures in a way that mirrors various cognitive deficits exhibited by schizophrenia patients. Some of these disruptions are partially attenuated by antipsychotic medications that exhibit partial effectiveness on cognitive dysfunction in schizophrenia, suggesting that the model has predictive validity. Examination of the effects of pharmacological manipulations on 5-CSRTT performance disruptions induced by NMDA antagonists have implicated a range of brain regions, neurotransmitter systems, and specific receptor subtypes in schizophrenia-like impairment of different cognitive modalities. Thus, disruption of 5-CSRTT performance by NMDA antagonists represents a valuable tool for exploring the neurobiological bases of cognitive dysfunction in schizophrenia. PMID:20488434

  16. The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine

    PubMed Central

    Zhang, Hai Xia; Hyrc, Krzysztof; Thio, Liu Lin

    2009-01-01

    Sarcosine is an amino acid involved in one-carbon metabolism and a promising therapy for schizophrenia because it enhances NMDA receptor (NMDAR) function by inhibiting glycine uptake. The structural similarity between sarcosine and glycine led us to hypothesize that sarcosine is also an agonist like glycine. We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons. We found that sarcosine is an NMDAR co-agonist at the glycine binding site. However, sarcosine differed from glycine because less NMDAR desensitization occurred with sarcosine than with glycine as the co-agonist. This finding led us to examine whether the physiological effects of NMDAR activation with these two co-agonists are the same. The difference in desensitization probably accounts for rises in intracellular Ca2+, as assessed by the fluorescent indicator fura-FF, being larger when NMDAR activation occurred with sarcosine than with glycine. In addition, Ca2+-activated K+ currents following NMDAR activation were larger with sarcosine than with glycine. Compared to glycine, NMDAR-mediated autaptic currents decayed faster with sarcosine suggesting that NMDAR deactivation also differs with these two co-agonists. Despite these differences, NMDAR-dependent neuronal death as assessed by propidium iodide was similar with both co-agonists. The same was true for neuronal bursting. Thus, sarcosine may enhance NMDAR function by more than one mechanism and may have different effects from other NMDAR co-agonists. PMID:19433577

  17. Ethanol inhibits epileptiform activity and NMDA receptor-mediated synaptic transmission in rat amygdaloid slices

    SciTech Connect

    Gean, P.W. )

    1992-02-26

    The effect of ethanol on the epileptiform activity induced by Mg{sup ++}-free solution was studied in rat amygdalar slices using intracellular recording techniques. The spontaneous and evoked epileptiform discharges consisting of an initial burst followed by afterdischarges were observed 20-30 min after switching to Mg{sup ++}-free medium. Superfusion with ethanol reversibly reduced the duration of spontaneous and evoked bursting discharges in a concentration-dependent manner. Synaptic response mediated by N-methyl-D-aspartate (NMDA) receptor activation was isolated by application of a solution containing the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and either in Mg{sup ++}-free solution or in the presence of 50 {mu}M bicuculline. Application of ethanol reversibly suppressed the duration of NMDA receptor-mediated synaptic response. These results suggest that intoxicating concentrations of ethanol possess anticonvulsant activity through blocking the NMDA receptor-mediated synaptic excitation.

  18. The antiparkinsonian drugs budipine and biperiden are use-dependent (uncompetitive) NMDA receptor antagonists.

    PubMed

    Jackisch, R; Kruchen, A; Sauermann, W; Hertting, G; Feuerstein, T J

    1994-10-24

    N-Methyl-D-aspartate- (NMDA-) evoked [3H]acetylcholine release in rabbit caudate nucleus slices was inhibited by the antiparkinsonian drugs budipine (1-tert-butyl-4,4-diphenylpiperidine) and biperiden (1-bicyclo[2.2.1.]hept-5-en-2-yl-1-phenyl-3-piperidino propanol) yielding functional Ki values of 4.6 and 8.8 microM. In contrast to the competitive antagonist 2-amino-5-phosphonopentaonate, budipine and biperidene significantly reduced both the apparent KD and the Emax value of NMDA. Moreover, they displaced [3H]MK-801 specifically bound to membranes of the same tissue, although with low affinity (IC50: 38 and 92 microM). It is concluded that budipine and biperiden are use-dependent (uncompetitive) antagonists at the NMDA receptor, binding to the receptor-linked ion channel, but probably not to the MK-801 binding site. NMDA antagonism may contribute to the antiparkinsonian effects of budipine.

  19. Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity

    PubMed Central

    Chen, Yong; Khan, Reas S.; Cwanger, Alyssa; Song, Ying; Steenstra, Katie; Bang, Sookhee; Cheah, Jaime H.; Dunaief, Joshua; Shindler, Kenneth S.; Snyder, Solomon H.; Kim, Sangwon F.

    2013-01-01

    Dexras1, a small G-protein localized predominantly to the brain, is transcriptionally upregulated by the synthetic glucocorticoid dexamethasone. It has close homology to the Ras subfamily, but differs in that Dexras1 contains an extended 7 kDa C-terminal tail. Previous studies in our laboratory showed that NMDA receptor activation, via NO and Dexras1, physiologically stimulates DMT1, the major iron importer. A membrane permeable iron chelator substantially reduces NMDA-excitotoxicity suggesting that Dexras1-mediated iron influx plays a crucial role in NMDA/NO-mediated cell death. We here report that iron influx is elicited by nitric oxide but not by other pro-apoptotic stimuli such as H2O2 or staurosporine. Deletion of Dexras1 in mice attenuates NO-mediated cell death in dissociated primary cortical neurons and retinal ganglion cells in vivo. Thus Dexras1 appears to mediate NMDA-elicited neurotoxicity via NO and iron influx. PMID:23426685

  20. [Clinical diagnosis and treatment of anti-NMDA (N-methyl-D-aspartate) receptor encephalitis].

    PubMed

    Kamei, Satoshi

    2013-05-01

    Recent clinical management of anti-NMDA receptor encephalitis is reviewed. This illness is required the management of the neurological emergency. Typical symptoms of anti-NMDA receptor encephalitis develop in several stages that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and respiratory instability. The diagnosis is depended on the detection of the NMDA receptor antibody in CSF or serum under the above characteristic symptoms of encephalitis. The disorder predominantly affects children and young adults, occurs with or without tumor association. The presence of a tumor (usually an ovarian teratoma) is dependent on age and sex, being more frequent in women older than 18 years. Anti-NMDA receptor encephalitis should be treated with tumor resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) responded faster to treatment and less frequently needed second-line immunotherapy (cyclophosphamide or rituximab, or both).

  1. 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

    2015-08-27

    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.

  2. 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

  3. Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test.

    PubMed

    Haj-Mirzaian, Arya; Ostadhadi, Sattar; Kordjazy, Nastaran; Dehpour, Ahmad Reza; Ejtemaei Mehr, Shahram

    2014-07-15

    Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression.

  4. 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

  5. CGX-1007 prevents excitotoxic cell death via actions at multiple types of NMDA receptors.

    PubMed

    Alex, Anitha B; Saunders, Gerald W; Dalpé-Charron, Alexandre; Reilly, Christopher A; Wilcox, Karen S

    2011-08-01

    Glutamate induced excitotoxic injury through over-activation of N-methyl-D-aspartate receptors (NMDARs) plays a critical role in the development of many neurodegenerative diseases. The present study was undertaken to evaluate the role of CGX-1007 (Conantokin G) as a neuroprotective agent against NMDA-induced excitotoxicity. Conantokin G, a cone snail peptide isolated from Conus geographus is reported to selectively inhibit NR2B containing NMDARs with high specificity and is shown to have potent anticonvulsant and antinociceptive effects. CGX-1007 significantly reduced the excitotoxic cell death induced by NMDA in organotypic hippocampal brain slice cultures in a concentration-dependent manner. In contrast, ifenprodil, another NR2B specific antagonist failed to offer neuroprotection against NMDA-induced excitotoxicity. We further determined that the neuroprotection observed is likely due to the action of CGX-1007 at multiple NMDA receptor subtypes. In a series of electrophysiology experiments, CGX-1007 inhibited NMDA-gated currents in human embryonic kidney (HEK) 293 cells expressing NMDA receptors containing either NR1a/NR2B or NR1a/NR2A subunit combinations. CGX-1007 produced a weak inhibition at NR1a/NR2C receptors, whereas it had no effect on NR1a/NR2D receptors. Further, the inhibition of NMDA receptors by CGX-1007 was voltage-dependent with greater inhibition seen at hyperpolarized membrane potentials. The voltage-dependence of CGX-1007 activity was also observed in recordings of NMDA-gated currents evoked in native receptors expressed in cortical neurons in culture. Based on our results, we conclude that CGX-1007 is a potent neuroprotective agent that acts as an antagonist at both NR2A and NR2B containing receptors.

  6. Neuroprotection Profile of the High Affinity NMDA Receptor Antagonist Conantokin-G

    DTIC Science & Technology

    2002-01-01

    ABSTRACT Conantokin-G (Con-G or CGX-1007), a potent NR2B subunit selective NMDA receptor antagonist, was evaluated for its neuroprotective properties...protection against staurosporine-induced apoptotic injury (Pɘ.01, n = 12/group), which was linked to the NR2B subunit. For in vivo brain injury...CGX-1007), a potent NR2B subunit selective NMDA receptor antagonist, was evaluated for its neuroprotective properties in experimental models of

  7. Exaggerated NMDA Mediated LTD in a Mouse Model of Down Syndrome and Pharmacological Rescuing by Memantine

    ERIC Educational Resources Information Center

    Scott-McKean, Jonah J.; Costa, Alberto C. S.

    2011-01-01

    The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 [mu]M NMDA for 3 min and 50 [mu]M DHPG for 5 min, respectively. We found that Ts65Dn mice…

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

    PubMed

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

    2010-12-02

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

  9. Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA Receptors in Dopamine Neurons

    PubMed Central

    Castagna, Candace; Mrejeru, Ana; Lizardi-Ortiz, José E.; Klein, Zoe; Lindsley, Craig W.

    2013-01-01

    NMDA receptor activity is involved in shaping synaptic connections throughout development and adulthood. We recently reported that brief activation of NMDA receptors on cultured ventral midbrain dopamine neurons enhanced their axon growth rate and induced axonal branching. To test whether this mechanism was relevant to axon regrowth in adult animals, we examined the reinnervation of dorsal striatum following nigral dopamine neuron loss induced by unilateral intrastriatal injections of the toxin 6-hydroxydopamine. We used a pharmacological approach to enhance NMDA receptor-dependent signaling by treatment with an inhibitor of glycine transporter-1 that elevates levels of extracellular glycine, a coagonist required for NMDA receptor activation. All mice displayed sprouting of dopaminergic axons from spared fibers in the ventral striatum to the denervated dorsal striatum at 7 weeks post-lesion, but the reinnervation in mice treated for 4 weeks with glycine uptake inhibitor was approximately twice as dense as in untreated mice. The treated mice also displayed higher levels of striatal dopamine and a complete recovery from lateralization in a test of sensorimotor behavior. We confirmed that the actions of glycine uptake inhibition on reinnervation and behavioral recovery required NMDA receptors in dopamine neurons using targeted deletion of the NR1 NMDA receptor subunit in dopamine neurons. Glycine transport inhibitors promote functionally relevant sprouting of surviving dopamine axons and could provide clinical treatment for disorders such as Parkinson's disease. PMID:24133278

  10. DOPAMINE RECEPTOR ACTIVATION REVEALS A NOVEL, KYNURENATE-SENSITIVE COMPONENT OF STRIATAL NMDA NEUROTOXICITY

    PubMed Central

    Poeggeler, Burkhard; Rassoulpour, Arash; Wu, Hui-Qiu; Guidetti, Paolo; Roberts, Rosalinda C.; Schwarcz, Robert

    2007-01-01

    The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in 2-3-fold increases in excitotoxic lesion size. Pre-treatment with kynurenine 3-hydroxylase inhibitors or dopamine receptor antagonists, two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum. PMID:17629627

  11. 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.

  12. Effects of Neural Morphology and Input Distribution on Synaptic Processing by Global and Focal NMDA-Spikes

    PubMed Central

    Poleg-Polsky, Alon

    2015-01-01

    Cortical neurons can respond to glutamatergic stimulation with regenerative N-Methyl-D-aspartic acid (NMDA)-spikes. NMDA-spikes were initially thought to depend on clustered synaptic activation. Recent work had shown however a new variety of a global NMDA-spike, which can be generated by randomly distributed inputs. Very little is known about the factors that influence the generation of these global NMDA-spikes, as well the potentially distinct rules of synaptic integration and the computational significance conferred by the two types of NMDA-spikes. Here I show that the input resistance (RIN) plays a major role in influencing spike initiation; while the classical, focal NMDA-spike depended upon the local (dendritic) RIN, the threshold of global NMDA-spike generation was set by the somatic RIN. As cellular morphology can exert a large influence on RIN, morphologically distinct neuron types can have dissimilar rules for NMDA-spikes generation. For example, cortical neurons in superficial layers were found to be generally prone to global NMDA-spike generation. In contrast, electric properties of cortical layer 5b cells clearly favor focal NMDA-spikes. These differences can translate into diverse synaptic integration rules for the different classes of cortical cells; simulated superficial layers neurons were found to exhibit strong synaptic interactions between different dendritic branches, giving rise to a single integrative compartment mediated by the global NMDA-spike. In these cells, efficiency of postsynaptic activation was relatively little dependent on synaptic distribution. By contrast, layer 5b neurons were capable of true multi-unit computation involving independent integrative compartments formed by clustered synaptic input which could trigger focal NMDA-spikes. In a sharp contrast to superficial layers neurons, randomly distributed synaptic inputs were not very effective in driving firing the layer 5b cells, indicating a possibility for different

  13. Striatopallidal Neuron NMDA Receptors Control Synaptic Connectivity, Locomotor, and Goal-Directed Behaviors

    PubMed Central

    Lambot, Laurie; Chaves Rodriguez, Elena; Houtteman, Delphine; Li, Yuquing; Schiffmann, Serge N.; Gall, David

    2016-01-01

    The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goal-directed learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected. SIGNIFICANCE STATEMENT The striatum controls habits, locomotion, and goal-directed behaviors by coordinated activation of two antagonistic pathways. Insofar as NMDA receptors (NMDA-Rs) play a key role in synaptic

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

    PubMed

    Guilarte, Tomás R; Chen, Ming-Kai

    2007-11-01

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

  15. Mitochondria and NMDA Receptor-Dependent Toxicity of Berberine Sensitizes Neurons to Glutamate and Rotenone Injury

    PubMed Central

    Kysenius, Kai; Brunello, Cecilia A.; Huttunen, Henri J.

    2014-01-01

    The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine. PMID:25192195

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

    PubMed

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

    2016-05-01

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

  17. How can an inert gas counterbalance a NMDA-induced glutamate release?

    PubMed

    Vallee, Nicolas; Rostain, Jean-Claude; Risso, Jean-Jacques

    2009-12-01

    Previous neurochemical studies performed in rats have revealed a decrease of striatal dopamine and glutamate induced by inert gas narcosis. We sought to establish the hypothetical role of glutamate and its main receptor, the N-methyl-d-aspartate (NMDA) receptor, in this syndrome. We aimed to counteract the nitrogen narcosis-induced glutamate and dopamine decreases by stimulating the NMDA receptor in the striatum. We used bilateral retrodialysis on awake rats, submitted to nitrogen under pressure (3 MPa). Continuous infusion of 2 mM of NMDA under normobaric conditions (0.01 MPa) (n = 8) significantly increased extracellular average levels of glutamate, aspartate, glutamine, and asparagine by 241.8%, 292.5%, 108.3%, and 195.3%, respectively. The same infusion conducted under nitrogen at 3 MPa (n = 6) revealed significant lower levels of these amino acids (n = 8/6, P > 0.001). In opposition, the NMDA-induced effects on dopamine, dihydrophenylacetic acid (DOPAC), and homovanillic acid (HVA) levels were statistically not affected by the nitrogen at 3 MPa exposure (n = 8/6, P > 0.05). Dopamine was increased by >240% on average. HVA was decreased (down to 40%), and there was no change in DOPAC levels, in both conditions. Results highlight that the NMDA receptor is not directly affected by nitrogen under pressure as indicated by the elevation in NMDA-induced dopamine release under hyperbaric nitrogen. On the other hand, the NMDA-evoked glutamate increase is counteracted by nitrogen narcosis. No improvement in motor and locomotor disturbances was observed with high striatal concentration in dopamine. Further experiments have to be done to specify why the striatal glutamate pathways, in association with the inhibition of its metabolism, only are affected by nitrogen narcosis in this study.

  18. NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus

    PubMed Central

    Colwell, Christopher S.

    2008-01-01

    A variety of evidence suggests that the effects of light on the mammalian circadian system are mediated by glutamatergic mechanisms and that the N-methyl-D-aspartate (NMDA) receptor plays an important role in this regulation. One of the fundamental features of circadian oscillators is that their response to environmental stimulation varies depending on the phase of the daily cycle when the stimuli are applied. For example, the same light treatment, which can produce phase shifts of the oscillator when applied during subjective night, has no effect when applied during the subjective day in animals held in constant darkness (DD). We examined the hypothesis that the effects of NMDA on neurons in the suprachiasmatic nucleus (SCN) also vary from day to night. Optical techniques were utilized to estimate NMDA-induced calcium (Ca2+) changes in SCN cells. The resulting data indicate that there was a daily rhythm in the magnitude and duration of NMDA-induced Ca2+ transients. The phase of this rhythm was determined by the light—dark cycle to which the rats were exposed with the Ca2+ transients peaking during the night. This rhythm continued when animals were held in DD. γ-Aminobutyric acid (GABA)ergic mechanisms modulated the NMDA response but were not responsible for the rhythm. Finally, there was a rhythm in NMDA-evoked currents in SCN neurons that also peaked during the night. This study provides the first evidence for a circadian oscillation in NMDA-evoked Ca2+ transients in SCN cells. This rhythm may play an important role in determining the periodic sensitivity of the circadian systems response to light. PMID:11298803

  19. 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

  20. 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

  1. Computationally Discovered Potentiating Role of Glycans on NMDA Receptors

    PubMed Central

    Sinitskiy, Anton V.; Stanley, Nathaniel H.; Hackos, David H.; Hanson, Jesse E.; Sellers, Benjamin D.; Pande, Vijay S.

    2017-01-01

    N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors. PMID:28378791

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

    PubMed Central

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

    2017-01-01

    Evidence from a large number of preclinical studies suggests that chronic exposure to drugs of abuse, such as psychostimulants or ethanol induces changes in glutamatergic transmission in key brain areas associated with reward and control of behavior. These changes include alterations in the expression of ionotropic glutamate receptors including N-methyl-D-aspartate receptors (NMDAR) that are important for regulating neuronal activity and synaptic plasticity. NMDA receptors are inhibited by ethanol and reductions in NMDA-mediated signaling are thought to trigger homestatic responses that limit ethanol's effects on glutamatergic transmission. Following repeated exposures to ethanol, these homeostatic responses may become unstable leading to an altered glutamatergic state that contributes to the escalations in drinking and cognitive deficits observed in alcohol-dependent subjects. An important unanswered question is whether ethanol-induced changes in NMDAR expression are modulated by the intrinsic sensitivity of the receptor to ethanol. In this study, we examined the effects of ethanol on NMDAR subunit expression in cortical (orbitofrontal, medial prefrontal), striatal (dorsal and ventral striatum) and limbic (dorsal hippocampus, basolateral amygdala) areas in mice genetically modified to express ethanol-resistant receptors (F639A mice). These mice have been previously shown to drink more ethanol than their wild-type counterparts and have altered behavioral responses to certain actions of ethanol. Following long-term voluntary drinking, F639A mice showed elevations in GluN2A but not GluN1 or GluN2B expression as compared to wild-type mice. Mice treated with repeated injections with ethanol (2–3.5 g/kg; i.p.) showed changes in NMDAR expression that varied in a complex manner with genotype, brain region, subunit type and exposure protocol all contributing to the observed response. F639A mice, but not wild-type mice, showed enhanced motor activity following repeated

  3. Visual dysfunction, but not retinal thinning, following anti-NMDA receptor encephalitis

    PubMed Central

    Oberwahrenbrock, Timm; Mikolajczak, Janine; Zimmermann, Hanna; Prüss, Harald; Paul, Friedemann; Finke, Carsten

    2016-01-01

    Objective: To assess structural and functional changes in the afferent visual system following anti-NMDA receptor (NMDAR) encephalitis. Methods: In this cross-sectional study including 31 patients after acute NMDAR encephalitis and matched healthy controls, visual function was assessed as high-contrast visual acuity using Early Treatment Diabetic Retinopathy Study charts and low-contrast sensitivity using Functional Acuity Contrast Test. Retinal changes were measured using optical coherence tomography with assessment of peripapillary retinal nerve fiber layer (pRNFL) and macular intraretinal layer thicknesses. Residual clinical impairment was described using the modified Rankin Scale. Results: High-contrast (logMAR 0.02 ± 0.14 vs −0.09 ± 0.14, p < 0.001) and low-contrast (area under the curve 1.89 ± 0.21 vs 2.00 ± 0.26, p = 0.039) visual acuity were reduced in patients in comparison to healthy controls. More severely affected patients performed worse in visual acuity testing than patients with good recovery (logMAR −0.02 ± 0.11 vs 0.08 ± 0.17, p = 0.030). In contrast, patients did not differ from matched healthy controls in pRNFL or in thickness of intraretinal layers, including the ganglion cell complex, the inner nuclear layer, the outer nuclear and plexiform layers, and the photoreceptor layer. Conclusions: After acute NMDAR encephalitis, patients have mild visual dysfunction in comparison to matched healthy controls, while retinal structure appears unaltered. These observations could point to an impairment of anterior or posterior visual pathway NMDAR function that is similar to dysfunction of NMDAR in cerebral cortex and subcortical structures. Alternatively, residual cognitive impairment might reduce visual function. PMID:26894203

  4. Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior.

    PubMed

    Adamec, R E; Burton, P; Shallow, T; Budgell, J

    Lasting increases in anxiety-like behavior (ALB) in the elevated plus-maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus-maze for up to 3 weeks after the exposure. The first study in this series demonstrated that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given systemically 30 min prior to exposure to a cat prevents the increase in ALB assessed 1 week later in the elevated plus-maze. To localize the site of action of systemic MK-801, MK-801 was injected in the amygdala 30 min prior to predator stress. Injections were given either unilaterally in either hemisphere, or bilaterally in both hemispheres. The target of the injection was the basolateral amygdala. The effects of injection depended on both the type of behavior and the hemisphere of injection. Injections of MK-801 in a variety of sites in the basolateral amygdala had no effect on the suppression of open-arm exploration produced by predator stress. Other amygdala nuclei or other limbic sites likely mediate the effects of systemically administered MK-801 on this behavior. In contrast, NMDA receptors in the left lateral amygdala mediate lasting suppression of risk assessment. MK-801, in a variety of sites in the left but not right lateral amygdala, blocked the effects of predator stress on risk assessment. This is clear evidence of separability of neural mechanisms controlling open-arm exploration and risk assessment. Different NMDA-dependent amygdala circuitry mediated effects of predator stress on unconditioned acoustic startle 1 week after cat exposure. The data indicate that integrity of the left lateral amygdala is necessary for potentiation of startle amplitude by predator stress, though NMDA receptors are not involved in this function. Nevertheless, NMDA receptors in the right, but not the left lateral amygdala, mediate initiation of changes in startle. The data also suggest that the right amygdala action is "downstream" from the left

  5. Altered Excitatory-Inhibitory Balance in the NMDA-Hypofunction Model of Schizophrenia

    PubMed Central

    Kehrer, Colin; Maziashvili, Nino; Dugladze, Tamar; Gloveli, Tengis

    2008-01-01

    Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDA-receptor subtype in the aetiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation–inhibition (E/I) balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed. PMID:18946539

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

    PubMed

    Sühs, Kurt-Wolfram; Wegner, Florian; Skripuletz, Thomas; Trebst, Corinna; Tayeb, Said Ben; Raab, Peter; Stangel, Martin

    2015-10-01

    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.

  7. NMDA receptor coagonist glycine site: evidence for a role in lateral hypothalamic stimulation of feeding.

    PubMed

    Stanley, B G; Butterfield, B S; Grewal, R S

    1997-08-01

    To investigate the role of the glycine coagonist binding site on the N-methyl-D-aspartate (NMDA) receptor in feeding control, we injected the glycine site antagonist 7-chlorokynurenic acid (7-CK) into the lateral hypothalamus (LH) of satiated rats before LH injection of NMDA, 7-CK (10-44 nmol) blocked the 6- to 10-g eating response elicited by NMDA. This block was reversed by LH pretreatment with glycine, arguing for a specific action at the glycine site. In contrast to the suppression produced by high doses, 7-CK at 0.1 nmol enhanced NMDA-elicited eating. For examination of behavioral specificity, 7-CK was injected into the LH before kainic acid (KA) or DL-alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). 7-CK at a dose of 0.1 nmol suppressed feeding elicited by KA or AMPA, but at 10 nmol it suppressed eating elicited by AMPA while enhancing eating elicited by KA. Finally, bilateral LH injection of 7-CK effectively suppressed eating produced by fasting. These findings support a role for the NMDA receptor coagonist glycine site in LH regulation of eating behavior.

  8. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  9. NMDA receptor blockade attenuates locomotion elicited by intrastriatal dopamine D1-receptor stimulation.

    PubMed

    Kreipke, Christian W; Walker, Paul D

    2004-07-01

    Previous behavioral studies suggest that the striatum mediates a hyperactive response to systemic NMDA receptor antagonism in combination with systemic D1 receptor stimulation. However, many experiments conducted at the cellular level suggest that inhibition of NMDA receptors should block D1 receptor-mediated locomotor activity. Therefore, we investigated the consequences of NMDA receptor blockade on the ability of striatal D1 receptors to elicit locomotor activity using systemic and intrastriatal injections of the NMDA antagonist MK-801 combined with intrastriatal injections of the D1 full agonist SKF 82958. Following drug treatment locomotor activity was measured via computerized activity monitors designed to quantify multiple parameters of rodent open-field behavior. Both systemic (0.1 mg/kg) and intrastriatal (1.0 microg) MK-801 pretreatments completely blocked locomotor and stereotypic activity elicited by 10 microg of SKF 82958 directly infused into the striatum. Further, increased activity triggered by intrastriatal SKF 82958 was attenuated by a posttreatment with intrastriatal infusion of 1 microg MK-801. These data suggest that D1-stimulated locomotor behaviors controlled by the striatum require functional NMDA channels.

  10. Scopolamine administration modulates muscarinic, nicotinic and NMDA receptor systems.

    PubMed

    Falsafi, Soheil Keihan; Deli, Alev; Höger, Harald; Pollak, Arnold; Lubec, Gert

    2012-01-01

    Studies on the effect of scopolamine on memory are abundant but so far only regulation of the muscarinic receptor (M1) has been reported. We hypothesized that levels of other cholinergic brain receptors as the nicotinic receptors and the N-methyl-D-aspartate (NMDA) receptor, known to be involved in memory formation, would be modified by scopolamine administration.C57BL/6J mice were used for the experiments and divided into four groups. Two groups were given scopolamine 1 mg/kg i.p. (the first group was trained and the second group untrained) in the multiple T-maze (MTM), a paradigm for evaluation of spatial memory. Likewise, vehicle-treated mice were trained or untrained thus serving as controls. Hippocampal levels of M1, nicotinic receptor alpha 4 (Nic4) and 7 (Nic7) and subunit NR1containing complexes were determined by immunoblotting on blue native gel electrophoresis.Vehicle-treated trained mice learned the task and showed memory retrieval on day 8, while scopolamine-treatment led to significant impairment of performance in the MTM. At the day of retrieval, hippocampal levels for M1, Nic7 and NR1 were higher in the scopolamine treated groups than in vehicle-treated groups.The concerted action, i.e. the pattern of four brain receptor complexes regulated by the anticholinergic compound scopolamine, is shown. Insight into probable action mechanisms of scopolamine at the brain receptor complex level in the hippocampus is provided. Scopolamine treatment is a standard approach to test cognitive enhancers and other psychoactive compounds in pharmacological studies and therefore knowledge on mechanisms is of pivotal interest.

  11. 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 ...

  12. Acute p38-mediated inhibition of NMDA-induced outward currents in hippocampal CA1 neurons by interleukin-1beta.

    PubMed

    Zhang, Ruoyu; Sun, Li; Hayashi, Yoshinori; Liu, Xia; Koyama, Susumu; Wu, Zhou; Nakanishi, Hiroshi

    2010-04-01

    Interleukin-1beta (IL-1beta) is a potent pro-inflammatory cytokine that is primarily produced by microglia in the brain. IL-1beta inhibits N-methyl-d-aspartate (NMDA)-induced outward currents (I(NMDA-OUT)) through IL-1 type I receptor (IL-1RI) in hippocampal CA1 neurons (Zhang, R., Yamada, J., Hayashi, Y., Wu, Z, Koyama, S., Nakanishi, H., 2008. Inhibition of NMDA-induced outward currents by interleukin-1beta in hippocampal neurons, Biochem. Biophys. Res. Commun. 372, 816-820). Although IL-1RI is associated with mitogen-activated protein kinases, their involvement in the effect of IL-1beta on I(NMDA-OUT) remains unclear. In the present study, we demonstrate that IL-1beta caused activation of p38 mitogen-activated protein kinase and that the p38 inhibitor SB203580 significantly blocked the effect of IL-1beta on I(NMDA-OUT) in hippocampal CA1 neurons. Furthermore, the intracellular perfusion of active recombinant p38alpha significantly decreased the mean amplitude of I(NMDA-OUT). In neurons prepared from inflamed hippocampus, the mean amplitude of I(NMDA-OUT) was significantly reduced. In the inflamed hippocampus, IL-1beta and IL-1RI were expressed mainly in microglia and neurons, respectively. These results suggest that IL-1beta increases the excitability of hippocampal CA1 neurons in the p38-dependent inhibition of I(NMDA-OUT).

  13. NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death

    PubMed Central

    Poddar, Ranjana; Deb, Ishani; Mukherjee, Saibal; Paul, Surojit

    2011-01-01

    The present study examines the role of a neuron-specific tyrosine phosphatase (STEP) in excitotoxic cell death. Our findings demonstrate that p38 MAPK, a stress-activated kinase that is known to play a role in the etiology of excitotoxic cell death is a substrate of STEP. Glutamate-mediated NMDA receptor stimulation leads to rapid but transient activation of p38 MAPK, which is primarily dependent on NR2A-NMDA receptor activation. Conversely, activation of NR2B-NMDA receptors leads to dephosphorylation and subsequent activation of STEP, which in turn leads to inactivation of p38 MAPK. Thus during transient NMDA receptor stimulation, increases in STEP activity appears to limit the duration of activation of p38 MAPK and improves neuronal survival. However, if NR2B-NMDA receptor stimulation is sustained, protective effects of STEP activation are lost, as these stimuli cause significant degradation of active STEP, leading to secondary activation of p38 MAP kinase. Consistent with this observation, a cell transducible TAT-STEP peptide that constitutively binds to p38 MAPK attenuated neuronal cell death caused by sustained NMDA receptor stimulation. The findings imply that the activation and levels of STEP are dependent on the duration and magnitude of NR2B-NMDA receptor stimulation and STEP serves as a modulator of NMDA receptor dependent neuronal injury, through its regulation of p38 MAPK. PMID:21029094

  14. 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

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

    PubMed

    Kyuhou, Shin-ichi; Gemba, Hisae

    2007-04-27

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

  16. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo

    PubMed Central

    Ultanir, Sila K.; Kim, Ji-Eun; Hall, Benjamin J.; Deerinck, Thomas; Ellisman, Mark; Ghosh, Anirvan

    2007-01-01

    Dendritic spines are the major sites of excitatory synaptic transmission in the CNS, and their size and density influence the functioning of neuronal circuits. Here we report that NMDA receptor signaling plays a critical role in regulating spine size and density in the developing cortex. Genetic deletion of the NR1 subunit of the NMDA receptor in the cortex leads to a decrease in spine density and an increase in spine head size in cortical layer 2/3 pyramidal neurons. This process is accompanied by an increase in the presynaptic axon bouton volume and the postsynaptic density area, as well as an increase in the miniature excitatory postsynaptic current amplitude and frequency. These observations indicate that NMDA receptors regulate synapse structure and function in the developing cortex. PMID:18048342

  17. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo.

    PubMed

    Ultanir, Sila K; Kim, Ji-Eun; Hall, Benjamin J; Deerinck, Thomas; Ellisman, Mark; Ghosh, Anirvan

    2007-12-04

    Dendritic spines are the major sites of excitatory synaptic transmission in the CNS, and their size and density influence the functioning of neuronal circuits. Here we report that NMDA receptor signaling plays a critical role in regulating spine size and density in the developing cortex. Genetic deletion of the NR1 subunit of the NMDA receptor in the cortex leads to a decrease in spine density and an increase in spine head size in cortical layer 2/3 pyramidal neurons. This process is accompanied by an increase in the presynaptic axon bouton volume and the postsynaptic density area, as well as an increase in the miniature excitatory postsynaptic current amplitude and frequency. These observations indicate that NMDA receptors regulate synapse structure and function in the developing cortex.

  18. 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.

  19. 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.

  20. A Case of Anti-NMDA Receptor Encephalitis Treated with ECT.

    PubMed

    Jones, Kristin C; Schwartz, Ann C; Hermida, Adriana P; Kahn, David A

    2015-09-01

    We describe the case of a 17-year-old male who presented with acute onset of seizures and malignant catatonia with psychosis, agitation, and hypermetabolism, who responded to electroconvulsive therapy (ECT). Soon after he began to respond, he was diagnosed with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis and then given immunosuppressive therapy. Anti-NMDA receptor encephalitis is an increasingly recognized autoimmune disorder that often presents with neuropsychiatric symptoms. The mainstays for treatment have been early diagnosis, tumor work-up and removal if found, and initiation of immunosuppressive therapy. Treatment response is often slow and residual symptoms common. In this case, ECT produced clinical stabilization before the underlying diagnosis of anti-NMDA receptor encephalitis was made and standard treatment initiated. We suggest that ECT may be highly beneficial for stabilizing life-threatening neuropsychiatric symptoms in this syndrome and should be considered as a potentially additive treatment to immunotherapy when rapid relief is sought.

  1. Control of Proton Sensitivity of the NMDA Receptor by RNA Splicing and Polyamines

    NASA Astrophysics Data System (ADS)

    Traynelis, Stephen F.; Hartley, Melissa; Heinemann, Stephen F.

    1995-05-01

    The function of the N-methyl-D-aspartate (NMDA)-preferring glutamate receptor can be regulated by extracellular pH, a process that may be important during ischemia in the brain or during seizures. Protons inhibit NMDA receptor function by 50 percent at pH 7.3 through interactions with the NR1 subunit, and both polyamines and NR1 exon 5 potentiate receptor function through relief of the tonic proton inhibition present at physiological pH. A single amino acid (lysine 211) was identified that mediates the effects of exon 5 in the rat brain. Electroneutral substitutions at this position restored pH sensitivity and, consequently, polyamine relief of tonic inhibition. This effect, together with the structural similarities between polyamines and the surface loop encoded by exon 5, suggest that exon 5 may act as a tethered pH-sensitive constitutive modulator of NMDA receptor function.

  2. Reconsolidation of Reminder-Induced Amnesia: Role of NMDA and AMPA Glutamate Receptors.

    PubMed

    Nikitin, V P; Kozyrev, S A; Solntseva, S V

    2015-11-01

    We studied the role of glutamate receptors and reminder in the mechanisms of amnesia maintenance caused by disruption of conditioned food aversion reconsolidation with an antagonist of NMDA glutamate receptor in snails. At the early stage of amnesia (day 3 after induction), injection or NMDA of AMPA glutamate receptor antagonists prior to reminder (presentation of the conditioned food stimulus) led to memory recovery. Reminder alone or injection of antagonists without reminder or after reminder was ineffective. At the late stage of amnesia (day 10), antagonists/reminder had no effect on amnesia maintenance. It was hypothesized that reminder at the early stage of amnesia led to reactivation and reconsolidation of the molecular processes of amnesia including activation NMDA and AMPA glutamate receptors. Injection of antagonists of these receptors prior to reminder led to disruption of reactivation/reconsolidation of amnesia and recovery of the conditioned food aversion memory.

  3. The Rehabilitation of Children with Anti-NMDA-Receptor Encephalitis: A Case Series

    PubMed Central

    Houtrow, Amy J.; Bhandal, Manjit; Pratini, Napala R.; Davidson, Loren; Neufeld, Jacob A.

    2012-01-01

    Anti-N-methyl-D-aspartate (NMDA)-receptor encephalitis is a serious, complex, and potentially fatal disease in children. Children with this condition frequently present with altered mental status, rapid functional deterioration, and seizures. Despite aggressive treatment with immune therapy such as corticosteroids, intravenous immunoglobin (IVIG), and plasmapheresis, children often need extensive rehabilitative services and can be left with lasting deficits. In this case series we report on six known consecutive pediatric cases of NMDA-receptor antibody encephalitis in Northern California requiring comprehensive inpatient rehabilitation. The children presented with a variety of symptoms and had waxing and waning clinical courses. All children progressed well through their rehabilitation programs, but were discharged home with persistent functional deficits. At follow-up, all but one child had lasting deficits. Because of the complicated management and extensive rehabilitation needs of children with anti-NMDA-receptor encephalitis, physiatrists and other rehabilitation providers should be knowledgeable about this complex condition. PMID:22415341

  4. 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

  5. The NMDA Agonist D-Cycloserine Facilitates Fear Memory Consolidation in Humans

    PubMed Central

    Holt, Beatrice; Petrovic, Predrag; De Martino, Benedetto; Klöppel, Stefan; Büchel, Christian; Dolan, Raymond J.

    2009-01-01

    Animal research suggests that the consolidation of fear and extinction memories depends on N-methyl D-aspartate (NMDA)-type glutamate receptors. Using a fear conditioning and extinction paradigm in healthy normal volunteers, we show that postlearning administration of the NMDA partial agonist D-cycloserine (DCS) facilitates fear memory consolidation, evidenced behaviorally by enhanced skin conductance responses, relative to placebo, for presentations of a conditioned stimulus (CS) at a memory test performed 72 h later. DCS also enhanced CS-evoked neural responses in a posterior hippocampus/collateral sulcus region and in the medial prefrontal cortex at test. Our data suggest a role for NMDA receptors in regulating fear memory consolidation in humans. PMID:18477687

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

    PubMed

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

    2005-10-03

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

  7. The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition

    PubMed Central

    Zanos, Panos; Piantadosi, Sean C.; Wu, Hui-Qiu; Pribut, Heather J.; Dell, Matthew J.; Can, Adem; Snodgrass, H. Ralph; Zarate, Carlos A.; Schwarcz, Robert

    2015-01-01

    Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pretreatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channel-blocking NMDA receptor antagonists. PMID:26265321

  8. Aberrant NMDA-dependent LTD after perinatal ethanol exposure in young adult rat hippocampus.

    PubMed

    Kervern, Myriam; Silvestre de Ferron, Benoît; Alaux-Cantin, Stéphanie; Fedorenko, Olena; Antol, Johann; Naassila, Mickael; Pierrefiche, Olivier

    2015-08-01

    Irreversible cognitive deficits induced by ethanol exposure during fetal life have been ascribed to a lower NMDA-dependent synaptic long-term potentiation (LTP) in the hippocampus. Whether NMDA-dependent long-term depression (LTD) may also play a critical role in those deficits remains unknown. Here, we show that in vitro LTD induced with paired-pulse low frequency stimulation is enhanced in CA1 hippocampus field of young adult rats exposed to ethanol during brain development. Furthermore, single pulse low frequency stimulation, ineffective at this age (LFS600), induced LTD after ethanol exposure accompanied with a stronger response than controls during LFS600, thus revealing an aberrant form of activity-dependent plasticity at this age. Blocking NMDA receptor or GluN2B containing NMDA receptor prevented both the stronger response during LFS600 and LTD whereas Zinc, an antagonist of GluN2A containing NMDA receptor, was ineffective on both responses. In addition, LFS600-induced LTD was revealed in controls only with a reduced-Mg(2+) medium. In whole dissected hippocampus CA1 field, perinatal ethanol exposure increased GluN2B subunit expression in the synaptic compartment whereas GluN2A was unaltered. Using pharmacological tools, we suggest that LFS600 LTD was of synaptic origin. Altogether, we describe a new mechanism by which ethanol exposure during fetal life induces a long-term alteration of synaptic plasticity involving NMDA receptors, leading to an aberrant LTD. We suggest this effect of ethanol may reflect a delayed maturation of the synapse and that aberrant LTD may also participates to long-lasting cognitive deficits in fetal alcohol spectrum disorder.

  9. Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex.

    PubMed

    De-May, C L; Ali, A B

    2013-01-03

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings - combined with biocytin labelling - were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II-V of rat (postnatal days 17-22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(-)-2-amino-5-phosphonopentanoic acid (d-AP5) (50μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow.

  10. Separation of domain contacts is required for heterotetrameric assembly of functional NMDA receptors

    PubMed Central

    Farina, Anthony N.; Blain, Katherine Y.; Maruo, Tomohiko; Kwiatkowski, Witek; Choe, Senyon; Nakagawa, Terunaga

    2011-01-01

    The precise knowledge of the subunit assembly process of NMDA receptors (NMDA-Rs) is essential to understand the receptor architecture and underlying mechanism of channel function. Because NMDA-Rs are obligatory heterotetramers requiring the GluN1 subunit, it is critical to investigate how GluN1 and GluN2 type subunits co-assemble into tetramers. By combining approaches in cell biology, biochemistry, single particle electron microscopy, and X-ray crystallography, we report the mechanisms and phenotypes of mutant GluN1 subunits that are defective in receptor maturation. The T110A mutation in the N-terminal domain (NTD) of the GluN1 promotes heterodimerization between the NTDs of GluN1 and GluN2, whereas the Y109C mutation in the adjacent residue stabilizes the homodimer of the NTD of GluN1. The crystal structure of the NTD of GluN1 revealed the mechanism underlying the biochemical properties of these mutants. Effects of these mutations on the maturation of heteromeric NMDA-Rs were investigated using a receptor trafficking assay. Our results suggest that the NTDs of the GluN1 subunit initially form homodimers and the subsequent dimer dissociation is critical for forming heterotetrameric NMDA-Rs containing GluN2 subunits, defining a molecular determinant for receptor assembly. The domain arrangement of the dimeric NTD of GluN1 is unique among the ionotropic glutamate receptors and predicts that the structure and mechanism around the NTDs of NMDA-Rs are different from those of the homologous AMPA and kainate receptors. PMID:21389213

  11. Sodium channel activation augments NMDA receptor function and promotes neurite outgrowth in immature cerebrocortical neurons

    PubMed Central

    George, Joju; Dravid, Shashank M.; Prakash, Anand; Xie, Jun; Peterson, Jennifer; Jabba, Sairam V.; Baden, Daniel G.; Murray, Thomas F.

    2009-01-01

    A range of extrinsic signals, including afferent activity, affect neuronal growth and plasticity. Neuronal activity regulates intracellular Ca2+ and activity-dependent calcium signaling has been shown to regulate dendritic growth and branching (Konur and Ghosh, 2005). NMDA receptor (NMDAR) stimulation of Ca2+/calmodulin-dependent protein kinase signaling cascades has moreover been demonstrated to regulate neurite/axonal outgrowth (Wayman et al., 2004). We used a sodium channel activator, brevetoxin (PbTx-2), to explore the relationship between intracellular [Na+] and NMDAR-dependent development. PbTx-2 alone, at a concentration of 30 nM, did not affect Ca2+ dynamics in DIV-2 cerebrocortical neurons; however, this treatment robustly potentiated NMDA-induced Ca2+ influx. The 30 nM PbTx-2 treatment produced a maximum [Na+]i of 16.9 ± 1.5 mM representing an increment of 8.8 ± 1.8 mM over basal. The corresponding membrane potential change produced by 30 nM PbTx-2 was modest and therefore insufficient to relieve the voltage-dependent Mg2+ block of NMDARs. To unambiguously demonstrate the enhancement of NMDA receptor function by PbTx-2, we recorded single-channel currents from cell-attached patches. PbTx-2 treatment was found to increase both the mean open time and open probability of NMDA receptors. These effects of PbTx-2 on NMDA receptor function were dependent on extracellular Na+ and activation of Src kinase. The functional consequences of PbTx-2-induced enhancement of NMDAR function were evaluated in immature cerebrocortical neurons. PbTx-2 concentrations between 3 and 300 nM enhanced neurite outgrowth. Voltage-gated sodium channel activators may accordingly represent a novel pharmacologic strategy to regulate neuronal plasticity through an NMDA receptor and Src family kinase-dependent mechanism. PMID:19279266

  12. Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models.

    PubMed

    Kim, Youngkyung; Cho, Hwi-young; Ahn, Young Ju; Kim, Junesun; Yoon, Young Wook

    2012-05-01

    N-Methyl-d-aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000nmol) and Ro25-6981 (20, 50, 100, 200nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25-6981 increased the mechanical nociceptive threshold in a dose-dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1-2 and L4-5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain.

  13. Scaffolding protein Homer1a protects against NMDA-induced neuronal injury

    PubMed Central

    Wang, Y; Rao, W; Zhang, C; Zhang, C; Liu, M-d; Han, F; Yao, L-b; Han, H; Luo, P; Su, N; Fei, Z

    2015-01-01

    Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca2+ influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a−/−) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a+/+). Additionally, Homer1a overexpression in the cortex of Homer1a−/− mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs. PMID:26247728

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

    PubMed

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

    2005-01-11

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

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

    PubMed

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

    2011-10-31

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

  16. Unilateral predominance of abnormal movements: A characteristic feature of the pediatric anti-NMDA receptor encephalitis?

    PubMed

    Benjumea-Cuartas, Vanessa; Eisermann, Monika; Simonnet, Hina; Hully, Marie; Nabbout, Rima; Desguerre, Isabelle; Kaminska, Anna

    2017-01-01

    Anti-NMDA receptor encephalitis is a treatable autoimmune disease characterized by cognitive, motor and psychiatric features that primarily affects young adults and children. We present a case of a 7-year-old boy with asymmetrical (mainly right hemibody) and abnormal polymorphic movements without concomitant scalpictal EEG changes but had background slowing predominating over the left hemisphere. This report illustrates previous descriptions of asymmetric presentation of abnormal movements in pediatric anti-NMDA receptor encephalitis and emphasizes the importance of video-EEG interpreted within the overall clinical context, to differentiate epileptic from non-epileptic abnormal movements in patients with autoimmune encephalitis.

  17. 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.

  18. Anti-NMDA receptor encephalitis: a neurological disease in psychiatric disguise.

    PubMed

    Sharma, Bhawna; Handa, Rahul; Prakash, Swayam; Nagpal, Kadam; Gupta, Pankaj

    2014-02-01

    Anti-NMDA receptor encephalitis was first described in 2005 when psychiatric features, memory loss and altered consciousness were found in four women with ovarian teratoma. We report a case of anti-NMDA receptor encephalitis in a 16-year-old female who presented with psychiatric features followed by autonomic dysfunction and orofacial dyskinesias that showed drastic improvement to intravenous immunoglobulin. As many patients of anti-NMDAR encephalitis initially present with psychiatric features, it is important for psychiatrists to have high index of suspicion for this disease and thus avoid the delay in diagnosing this treatable condition which may be otherwise fatal.

  19. Anti-NMDA encephalitis: an uncommon, autoimmune mediated form of encephalitis.

    PubMed

    Azizyan, Avetis; Albrektson, Joshua R; Maya, Marcel M; Pressman, Barry D; Moser, Franklin

    2014-08-01

    We report an interesting case of a 19 year old female with findings on MRI suggestive of viral encephalitis. An extensive workup was negative for infectious causes and she was subsequently diagnosed with anti-NMDA encephalitis. Anti-NMDA encephalitis is a highly lethal but treatable form of autoimmune encephalitis that has recently been characterized. It is frequently found in young women and associated with an underlying teratoma. Although rare, this diagnosis should be considered in young females for whom a rapid onset of encephalitis cannot be explained by more common causes.

  20. Anti-NMDA receptor encephalitis: an easily missed diagnosis in older patients.

    PubMed

    Rainey, Katie; Gholkar, Bethan; Cheesman, Mark

    2014-09-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an important, treatable cause of encephalitis which remains under-recognised despite a growing body of the literature [1]. It is an immune-mediated syndrome which presents with a variety of neurological symptoms including headache, fever, personality change and seizures. Most case reports to date are of young adults, it is much less frequently reported in older adults. The syndrome has been associated with ovarian teratomas. The prognosis is good with early recognition and treatment, though may relapse. We present a case of NMDA encephalitis in an elderly patient who responded well to immunosuppressive therapy.

  1. Anti-NMDA receptor encephalitis: psychiatric presentation and diagnostic challenges from psychosomatic medicine perspective.

    PubMed

    Gulyayeva, Nataliya A; Massie, Mary Jane; Duhamel, Katherine N

    2014-04-01

    We describe two cases of confirmed anti-NMDA receptor encephalitis; one patient initially presented with a clinical picture that resembled delirium and later appeared to present with a conversion reaction and the second patient presented with a first psychotic break followed by the clinical picture of neuroleptic malignant syndrome with catatonia. Neither patient had a previous history of psychiatric illness or recreational drug use. These cases illustrate the diagnostic and treatment challenges associated with this neuropsychiatric condition and underscore the role of psychosomatic medicine psychiatrists in diagnosing anti-NMDA receptor encephalitis.

  2. NMDA potentiation by visible light in the presence of a fluorescent neurosteroid analogue.

    PubMed

    Eisenman, Lawrence N; Shu, Hong-Jin; Wang, Cunde; Aizenman, Elias; Covey, Douglas F; Zorumski, Charles F; Mennerick, Steven

    2009-06-15

    N-Methyl-D-aspartate (NMDA) receptors are widely studied because of their importance in synaptic plasticity and excitotoxic cell death. Here we report a novel method of potentiating NMDA receptors with fluorescence excited by blue (480 nm) light. In the presence of 300 nM of a (7-nitro-2,1,3-benzoxadiazol-4-yl) amino (NBD)-tagged neuroactive steroid carrier C2-NBD-(3alpha,5alpha)-3-hydroxypregnan-20-one (C2-NBD 3alpha5alphaP), responses of cultured hippocampal neurons to 10 microM NMDA were potentiated to 219.2 +/- 9.2% of the baseline response (100%) by a 30 s exposure to 480 nm light. The potentiation decayed back to baseline with a time constant of 80.6 s. Responses to 1 microM and 100 microM NMDA were potentiated to 147.9 +/- 9.6% and 174.1 +/- 15.6% of baseline, respectively, suggesting that visible-light potentiation is relatively insensitive to NMDA concentration. Peak autaptic NMDA responses were potentiated to 178.9 +/- 22.4% of baseline. Similar potentiation was seen with 10 microM NBD-lysine, suggesting that visible-light potentiation is not a steroid effect. Potentiation was also seen with a steroid analogue in which the NBD was replaced with fluorescein, suggesting that NBD is not the only fluorophore capable of supporting visible-light potentiation. UV light and redox potentiation of NMDA receptors largely occluded subsequent blue light potentiation (127.7 +/- 7.4% and 120.2 +/- 6.2% of baseline, respectively). The NR1a(C744A,C798A) mutant that is insensitive to redox and UV potentiation was also largely unaffected by visible-light potentiation (135.0 +/- 10.0% of baseline). Finally, we found that the singlet oxygen scavenger furfuryl alcohol decreased visible-light potentiation. Collectively, these data suggest that visible-light potentiation of NMDA receptors by fluorescence excitation shares mechanisms with UV and redox potentiation and may involve singlet oxygen production.

  3. 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

  4. Sleep-Dependent Declarative Memory Consolidation—Unaffected after Blocking NMDA or AMPA Receptors but Enhanced by NMDA Coagonist D-Cycloserine

    PubMed Central

    Feld, Gordon B; Lange, Tanja; Gais, Steffen; Born, Jan

    2013-01-01

    Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors. PMID:23887151

  5. Blockade of NMDA receptors in the dorsomedial striatum prevents action-outcome learning in instrumental conditioning.

    PubMed

    Yin, Henry H; Knowlton, Barbara J; Balleine, Bernard W

    2005-07-01

    Although there is consensus that instrumental conditioning depends on the encoding of action-outcome associations, it is not known where this learning process is localized in the brain. Recent research suggests that the posterior dorsomedial striatum (pDMS) may be the critical locus of these associations. We tested this hypothesis by examining the contribution of N-methyl-D-aspartate receptors (NMDARs) in the pDMS to action-outcome learning. Rats with bilateral cannulae in the pDMS were first trained to perform two actions (left and right lever presses), for sucrose solution. After the pre-training phase, they were given an infusion of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (APV, 1 mg/mL) or artificial cerebral spinal fluid (ACSF) before a 30-min session in which pressing one lever delivered food pellets and pressing the other delivered fruit punch. Learning during this session was tested the next day by sating the animals on either the pellets or fruit punch before assessing their performance on the two levers in extinction. The ACSF group selectively reduced responding on the lever that, in training, had earned the now devalued outcome, whereas the APV group did not. Experiment 2 replicated the effect of APV during the critical training session but found no effect of APV given after acquisition and before test. Furthermore, Experiment 3 showed that the effect of APV on instrumental learning was restricted to the pDMS; infusion into the dorsolateral striatum did not prevent learning. These experiments provide the first direct evidence that, in instrumental conditioning, NMDARs in the dorsomedial striatum are involved in encoding action-outcome associations.

  6. Sos2 is dispensable for NMDA-induced Erk activation and LTP induction

    PubMed Central

    Arai, Junko A.; Li, Shaomin; Feig, Larry A.

    2009-01-01

    N-methyl-D-aspartate (NMDA) receptor-induced activation of extracellular signal-related protein kinase (Erk) plays important roles in various neuronal functions including long-term potentiation (LTP). Son of sevenless (Sos) proteins have been implicated in NMDA-induced Erk activation in neurons of young mice. However, contribution of each of the two Sos isoforms, Sos1 and Sos2, has not been clarified. In this study, Sos2 involvement in NMDA-induced Erk activation was examined. We observed no defect in Erk phosphorylation induced by NMDA treatment of cortical neuronal cultures from Sos2-/- newborn mice. Moreover, theta-burst induced LTP induction in the hippocampus of Sos2-/- mice was also normal. Finally, Erk activation by either depolarization or BDNF treatment was also normal in cultured neurons from Sos2 knockout mice. These results imply that Sos1 is the major regulator of these well-known neuronal Sos functions and suggest that a novel function for Sos2 in neurons remains to be determined. PMID:19429099

  7. 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...

  8. Differential role of insular cortex muscarinic and NMDA receptors in one-trial appetitive taste learning.

    PubMed

    Parkes, Shauna L; De la Cruz, Vanesa; Bermúdez-Rattoni, Federico; Coutureau, Etienne; Ferreira, Guillaume

    2014-12-01

    Our current understanding of the neurobiology of taste learning and memory has been greatly facilitated by the use of a reliable behavioural model, conditioned taste aversion (CTA). This model has revealed that the insular cortex (IC), specifically muscarinic and N-methyl-d-aspartate (NMDA) receptor activation in the IC, is critical for the formation of aversive taste memories. In contrast, current models of appetitive taste learning are less adequate, relying on the use of neophobic tastes (attenuation of neophobia) or on the integration of appetitive and aversive taste memories (latent inhibition of CTA). While these models have implicated IC muscarinic receptors, the involvement of NMDA receptors in the IC remains unclear. Here, we examined the role of both muscarinic and NMDA receptors in appetitive taste learning using a simple paradigm that is independent of neophobic and aversive components. First, we demonstrated that a single exposure to a novel taste, saccharin 0.1%, is sufficient to promote an appetitive taste memory as revealed by an increase in saccharin consumption during the second presentation. This increase was blocked by bilateral infusion in the IC of the muscarinic receptor antagonist, scopolamine. In contrast, infusion of the NMDA receptor antagonist, AP5, did not block appetitive taste learning but did abolish CTA. Therefore, common and distinct molecular substrates within the IC mediate appetitive versus aversive learning about the same taste.

  9. 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

  10. The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity.

    PubMed

    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

    2013-12-01

    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.

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

    PubMed

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

    2015-09-01

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

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

    SciTech Connect

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K. )

    1990-01-01

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

  13. 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

  14. Surface Expression of NMDA Receptor Changes during Memory Consolidation in the Crab "Neohelice granulata"

    ERIC Educational Resources Information Center

    Hepp, Yanil; Salles, Angeles; Carbo-Tano, Martin; Pedreira, Maria Eugenia; Freudenthal, Ramiro

    2016-01-01

    The aim of the present study was to analyze the surface expression of the NMDA-like receptors during the consolidation of contextual learning in the crab "Neohelice granulata". Memory storage is based on alterations in the strength of synaptic connections between neurons. The glutamatergic synapses undergo various forms of…

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

    PubMed

    Castro-Alamancos, Manuel A; Favero, Morgana

    2015-06-01

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

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

    SciTech Connect

    Tao-Cheng, Jung-Hwa; Yang, Yijung; Bayer, K. Ulrich; Reese, Thomas S.; Dosemeci, Ayse

    2014-07-18

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

  17. Atypical effect of dopamine in modulating the functional inhibition of NMDA receptors of cultured retina cells.

    PubMed

    Do Nascimento, J L; Kubrusly, R C; Reis, R A; De Mello, M C; De Mello, F G

    1998-02-05

    Cultured retina cells released accumulated [3H]GABA (gamma-aminobutyric acid) when stimulated by L-glutamate, N-methyl-D-aspartate (NMDA) and kainate. In the absence of Mg2+, dopamine at 200 microM (IC50 60 microM), inhibited in more than 50% the release of [3H]GABA induced by L-glutamate and NMDA, but not by kainate. This effect was not blocked by the D1-like dopamine receptor antagonist, R-(+)-7-chloro-8-hydroxy-3-methyl- -phenyl-2,3,4,5-tetrahydro- H-3-benzazepine hydrochloride (SCH 23390), neither by haloperidol nor spiroperidol (dopamine D2-like receptor antagonists). The dopamine D1-like receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,diol hydrochloride (SKF 38393) at 50 microM, but not its enantiomer, also inhibited the release of [3H]GABA induced by NMDA, but not by kainate; an effect that was not prevented by the antagonists mentioned above. (+/-)-6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin e hydrobromide (SKF 812497) had no effect. Neither 8BrcAMP (5 mM) nor forskolin (10 microM) inhibited the release of [3H]GABA. Our results suggest that dopamine and (+)-SKF 38393 inhibit the glutamate and NMDA-evoked [3H]GABA release through mechanisms that seem not to involve known dopaminergic receptor systems.

  18. 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…

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

    PubMed

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

    2010-01-01

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

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

    PubMed Central

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

    2016-01-01

    NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation. PMID:27807405

  1. Cytisine confers neuronal protection against excitotoxic injury by down-regulating GluN2B-containing NMDA receptors.

    PubMed

    Li, Yu-Jiao; Yang, Qi; Zhang, Kun; Guo, Yan-Yan; Li, Xu-Bo; Yang, Le; Zhao, Ming-Gao; Wu, Yu-Mei

    2013-01-01

    Cytisine (CYT), one of the principal bioactive components derived from the seeds of Cytisus laborinum L, has been widely used for central nervous system (CNS) diseases treatment. The present study investigated the protective effect of CYT on cultured cortical neural injury induced by N-methyl-d-aspartate (NMDA). Our data showed that CYT conferred protective effect against loss of cellular viability induced by brief exposure to 200 μM NMDA in a concentration-dependent manner. CYT significantly inhibited the neuronal apoptosis induced by NMDA exposure by reversing intracellular Ca(2+) overload and balancing Bcl-2 and Bax expression levels. Furthermore, CYT significantly reversed the up-regulation of GluN2B-containing NMDA receptors by exposure to NMDA, but it did not affect the level of GluN2A-containing NMDA receptors. These findings suggest that CYT protects cortical neurons, at least partially, by inhibiting the level of GluN2B-containing NMDA receptors and regulating Bcl-2 family.

  2. The NMDA receptor complex: a long and winding road to therapeutics.

    PubMed

    Wood, Paul L

    2005-03-01

    Advances in our basic understanding of inhibitory and excitatory amino acid neurotransmission have provided the foundation for directed drug discovery programs to modulate inhibitory GABAergic and excitatory N-methyl-D-aspartate (NMDA) receptor-mediated synapses. Gamma-Amino butyric acid (GABA(A)) and NMDA receptors are complex ion channels formed by multiple protein subunits that act as binding sites for transmitter amino acids and as allosteric regulatory binding sites to regulate ion channel activity. In the case of the NMDA receptor complex, one such allosteric site binds the obligatory glycine and/or d-serine co-agonist. Historical data from preclinical and clinical studies of GABAergic agents have clearly demonstrated that direct receptor modulators lack sufficient therapeutic indices to warrant clinical utility. However, pharmacological modulation of allosteric sites of the GABA multimeric receptor has resulted in the clinical development of safe and efficacious agents, exemplified by the benzodiazepines. Research has also revealed a similar outcome for the NMDA receptor, with allosteric modulators demonstrating improved safety profiles in the modulation of excitatory amino acid (EAA) transmission compared with direct NMDA receptor antagonists. First-generation EAA drugs were low affinity channel blockers of the NMDA multimeric receptor complex and included the anesthetic agent ketamine and the Alzheimer's drug memantine. As predicted by preclinical studies, direct NMDA receptor antagonists (eg, selfotel (Novartis AG) and high-affinity channel blockers (eg, dizocilpine) failed in the clinic as a result of narrow therapeutic indices. More recent efforts have focused on glycine/d-serine co-agonist function. These approaches include partial glycine agonists, in their agonist dose-range, for cognitive improvement and for treating schizophrenia. Such partial glycine agonists are also being advanced for the treatment of neuropathic pain in the antagonist dose

  3. Activation of the ζ receptor 1 suppresses NMDA responses in rat retinal ganglion cells.

    PubMed

    Zhang, X-J; Liu, L-L; Jiang, S-X; Zhong, Y-M; Yang, X-L

    2011-03-17

    The sigma receptor 1 (σR1) has been shown to modulate the activity of several voltage- and ligand-gated channels. Using patch-clamp techniques in rat retinal slice preparations, we demonstrated that activation of σR1 by SKF10047 (SKF) or PRE-084 suppressed N-methyl-D-aspartate (NMDA) receptor-mediated current responses from both ON and OFF type ganglion cells (GCs), dose-dependently, and the effect could be blocked by the σR1 antagonist BD1047 or the σR antagonist haloperidol. The suppression by SKF of NMDA currents was abolished with pre-incubation of the G protein inhibitor GDP-β-S or the Gi/o activator mastoparan. We further explored the intracellular signaling pathway responsible for the SKF-induced suppression of NMDA responses. Application of either cAMP/the PKA inhibitor Rp-cAMP or cGMP/the PKG inhibitor KT5823 did not change the SKF-induced effect, suggesting the involvement of neither cAMP/PKA nor cGMP/PKG pathway. In contrast, suppression of NMDA responses by SKF was abolished by internal infusion of the phosphatidylinostiol-specific phospholipase C (PLC) inhibitor U73122, but not by the phosphatidylcholine-PLC inhibitor D609. SKF-induced suppression of NMDA responses was dependent on intracellular Ca2+ concentration ([Ca2+]i), as evidenced by the fact that the effect was abolished when [Ca2+]i was buffered with 10 mM BAPTA. The SKF effect was blocked by xestospongin-C/heparin, IP3 receptor antagonists, but unchanged by ryanodine/caffeine, ryanodine receptor modulators. Furthermore, application of protein kinase C inhibitors Bis IV and Gö6976 eliminated the SKF effect. These results suggest that the suppression of NMDA responses of rat retinal GCs caused by the activation of σR1 may be mediated by a distinct [Ca2+]i-dependent PLC-PKC pathway. This effect of SKF could help ameliorate malfunction of GCs caused by excessive stimulation of NMDA receptors under pathological conditions.

  4. Modulation of NMDA receptor expression in the rat spinal cord by peripheral nerve injury and adrenal medullary grafting.

    PubMed

    Hama, A T; Unnerstall, J R; Siegan, J B; Sagen, J

    1995-07-31

    Excessive activation of N-methyl-D-aspartate (NMDA) receptors in the spinal cord consequent to peripheral injury has been implicated in the initiation of neuropathologic events leading to a state of chronic hyperexcitability and persistence of exaggerated sensory processing. In other CNS disease or injury states, NMDA-mediated neurotoxic damage is associated with a loss of NMDA receptors, and outcome may be improved by agents reducing NMDA activation. Previous findings in our laboratory have demonstrated that the transplantation of adrenal medullary tissue into the spinal subarachnoid space can alleviate sensory abnormalities and reduce the induction of a putative nitric oxide synthase consequent to peripheral nerve injury. In order to determine changes in NMDA receptor expression in the spinal cord following peripheral nerve injury and adrenal medullary grafting, NMDA receptor binding using a high-affinity competitive NMDA receptor antagonist, CGP-39653, and NMDAR1 subunit distribution using immunocytochemistry were investigated. Two weeks following peripheral nerve injury by loose ligation of the right sciatic nerve, either adrenal medullary or striated muscle (control) tissue pieces were implanted in the spinal subarachnoid space. Binding studies revealed a marked reduction in [3H]CGP-39653 binding at L4-L5 levels ipsilateral to peripheral nerve injury in control transplanted animals. In contrast, NMDA binding was normalized in adrenal medullary grafted animals. In addition, NMDAR1 immunoreactivity was reduced in both the dorsal horn neuropil and motor neurons of the ventral horn in animals with peripheral nerve injury, while levels in adrenal medullary grafted animals appeared similar to intact controls. These results suggest that adrenal medullary transplants reduce abnormal sensory processing resulting from peripheral injury by intervening in the spinal NMDA-excitotoxicity cascade.

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

    PubMed

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

    2015-04-01

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

  6. 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

  7. 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.

  8. [NMDA receptor encephalitis in the course of recurrent CNS demyelinating disorders: a case report].

    PubMed

    Yamamoto, Masanari; Kokubun, Norito; Watanabe, Yuka; Okabe, Ryuta; Nakamura, Toshiki; Hirata, Koichi

    2013-01-01

    We present the case of a 31-year-old woman who developed N-methyl-d-aspartate (NMDA) receptor encephalitis during the course of relapsing and remitting multiple brain lesions. The patient developed a tingling sensation in the left upper and lower extremities, and was first admitted to our hospital at age 27. She was tentatively diagnosed with multiple sclerosis on the basis of multiple lesions with Gd-enhancement in the brainstem, and 2 separate clinical relapses by age 28. At age 31, she developed a headache and pyrexia, followed by confusion and abnormal behavior. Her symptoms acutely progressed to stupor, and subsequently, she developed oral dyskinesia and athetosis-like involuntary movement of the left arm. The stupor state continued over 2 months. However, she had completely recovered by 3 months after the onset of psychiatric symptoms. Her serum and CSF samples tested positive for anti-NMDA receptor antibodies, and she was diagnosed with NMDA receptor encephalitis. Her serum was negative for anti-AQP4 antibody, but showed weak positivity for antinuclear antibody. Between ages 32 and 34, she experienced 2 clinical relapses, including right-hand clumsiness, confusion, aphasia, and dysphagia. FLAIR images showed a high-intensity area in the brain stem, thalamus, and subcortical white matter. No tumors were found throughout the course. A clinical entity of NMDA receptor encephalitis can include various neurologic disorders, such as the development of recurrent demyelinating brain lesions. Further investigation is required to clarify the pathophysiological role of anti-NMDA receptor antibody in our patient.

  9. 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

  10. 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.

  11. Voltage-dependent inhibition of recombinant NMDA receptor-mediated currents by 5-hydroxytryptamine

    PubMed Central

    Kloda, Anna; Adams, David J

    2005-01-01

    The effect of 5-HT and related indolealkylamines on heteromeric recombinant NMDA receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp recording technique. In the absence of external Mg2+ ions, 5-HT inhibited NMDA receptor-mediated currents in a concentration-dependent manner. The inhibitory effect of 5-HT was independent of the NR1a and NR2 subunit combination. The inhibition of glutamate-evoked currents by 5-HT was use- and voltage-dependent. The voltage sensitivity of inhibition for NR1a+NR2 subunit combinations by 5-HT was similar, exhibiting an e-fold change per ∼20 mV, indicating that 5-HT binds to a site deep within the membrane electric field. The inhibition of the open NMDA receptor by external Mg2+ and 5-HT was not additive, suggesting competition between Mg2+ and 5-HT for a binding site in the NMDA receptor channel. The concentration-dependence curves for 5-HT and 5-methoxytryptamine (5-MeOT) inhibition of NMDA receptor-mediated currents are shifted to the right in the presence of external Mg2+. The related indolealkylamines inhibited glutamate-evoked currents with the following order of inhibitory potency: 5-MeOT=5-methyltryptamine>tryptamine>7-methyltryptamine>5-HT≫tryptophan=melatonin. Taken together, these data suggest that 5-HT and related compounds can attenuate glutamate-mediated excitatory synaptic responses and may provide a basis for drug treatment of excitoxic neurodegeneration. PMID:15655527

  12. Evaluation of age-dependent response to NMDA receptor antagonism in zebrafish.

    PubMed

    Menezes, Fabiano Peres; Kist, Luiza Wilges; Bogo, Maurício Reis; Bonan, Carla Denise; Da Silva, Rosane Souza

    2015-04-01

    Imbalances in glutamatergic signaling have been proposed as the cause of several neurological disturbances. The use of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, to mimic features of these neurological disorders is effective both in mammals and in fish. However, the variability of the subunits comprising the NMDA receptor during development alters the pharmacokinetic properties of the receptor and leads to different responses to this drug. Here, we evaluated the locomotor response of zebrafish to MK-801 (1, 5, and 20 μM) through the development (30 days postfertilization [dpf] to 2 years postfertilization [ypf]). The NMDA receptor subunit gene expression was also analyzed through the development (7 dpf to 2 ypf). Zebrafish displayed an age-related response to MK-801 with a higher response at 60 and 120 dpf. The magnitude of hyperlocomotion promoted by MK-801 seems to be less powerful for zebrafish in relation to rodents. The verification of expression levels in zebrafish NMDA receptor subunits shows that NR1.1 had a slight reduction throughout the development, while the NR2 subunits, especially NR2A.2 and NR2C.1, vary their expression levels according to the stage of development. The time-specific locomotor response to MK-801 through the development could be a consequence of differential NMDA receptor subunit expression. This result of developmental response to MK-801 is a crucial component in the consolidation of zebrafish as a suitable model to study glutamatergic neurotransmission in early phases.

  13. Autoantibodies to NR2A Peptide of the Glutamate/NMDA Receptor in Patients with Seizure Disorders in Neuropsychiatric Systemic Lupus Erythematosus

    PubMed Central

    Wang, Xue-er; Mei, Qing-hua; Jiang, Wen-qing

    2017-01-01

    Objective. Seizure disorders are one of the most disabling, life-threatening, and the least understood syndromes associated with neuropsychiatric SLE (NPSLE). N-Methyl-D-aspartate (NMDA) receptors are a subgroup of the glutamate receptor family, whose NR2A subunit was found on neuronal cells (anti-NR2A) in NPSLE patients with different types of epilepsy. The present study was conducted to determine the serum levels of anti-NR2A antibodies in a large group of SLE patients, to investigate the possible correlation between the presence of the NR2A specific antibodies and NPSLE-related seizure disorders. Methods and Results. The study population consisted of 107 SLE patients and 43 age- and sex-matched healthy controls. 73 SLE patients had active disease. 36 of these had NPSLE. NMDA levels were measured by ELISA. Clinical and serological parameters were assessed according to routine procedures. The levels of anti-NR2A antibodies were significantly higher in NPSLE patients, compared with non-NPSLE patients and healthy controls. Furthermore, the levels of NPSLE in patients with seizure disorders were shown to be higher than in those with cognitive dysfunction and other CNS symptoms, however, without significance. Increase in serum anti-NR2A antibodies levels correlated to anti-dsDNA antibody and SLEDAI as well as complement levels. Conclusion. We suggest that anti-NR2A antibodies play a role in the pathogenesis of NPSLE with seizure disorders. PMID:28154472

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

    PubMed

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

    2011-02-01

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

  15. Loss of NMDA receptors in dopamine neurons leads to the development of affective disorder-like symptoms in mice

    PubMed Central

    Jastrzębska, Kamila; Walczak, Magdalena; Cieślak, Przemysław Eligiusz; Szumiec, Łukasz; Turbasa, Mateusz; Engblom, David; Błasiak, Tomasz; Parkitna, Jan Rodriguez

    2016-01-01

    The role of changes in dopamine neuronal activity during the development of symptoms in affective disorders remains controversial. Here, we show that inactivation of NMDA receptors on dopaminergic neurons in adult mice led to the development of affective disorder-like symptoms. The loss of NMDA receptors altered activity and caused complete NMDA-insensitivity in dopamine-like neurons. Mutant mice exhibited increased immobility in the forced swim test and a decrease in social interactions. Mutation also led to reduced saccharin intake, however the preference of sweet taste was not significantly decreased. Additionally, we found that while mutant mice were slower to learn instrumental tasks, they were able to reach the same performance levels, had normal sensitivity to feedback and showed similar motivation to exert effort as control animals. Taken together these results show that inducing the loss of NMDA receptor-dependent activity in dopamine neurons is associated with development of affective disorder-like symptoms. PMID:27853270

  16. 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

  17. Synaptic excitation of individual rat cerebellar granule cells in situ: evidence for the role of NMDA receptors.

    PubMed Central

    D'Angelo, E; De Filippi, G; Rossi, P; Taglietti, V

    1995-01-01

    1. Current-clamp recordings were made in whole-cell patch-clamp configuration from ninety-one granule cells in parasagittal cerebellar slices obtained from 21- to 31-day-old rats. Recordings were performed at 30 degrees C. 2. Resting membrane potential was -58 +/- 6 mV (n = 43). The membrane voltage response to step current injection showed inward rectification consistent with increasing input resistance during membrane depolarization. Over -35 +/- 7 mV (n = 14) repetitive firing with little or no adaptation was activated. Spike frequency increased nearly linearly with injected current. 3. Unitary EPSPs obtained by stimulating the mossy fibre bundle had an amplitude of 11.4 +/- 2.1 mV (n = 22, holding potential = -75 mV). Synchronous activation of greater than one to two mossy fibres was needed to elicit action potentials. Antidromic stimulation elicited antidromic spikes and also EPSPs, presumably through a mossy fibre 'axon reflex'. 4. EPSPs were brought about by NMDA and non-NMDA receptor activation, accounting for about 70 and 30%, respectively, of peak amplitude at the holding potential of -70 mV. The EPSP decay conformed to passive membrane discharge after blocking the NMDA receptors. 5. No appreciable correlation was found between the time-to-peak and decay time constant of the EPSPs, consistent with the compact electrotonic structure of these neurons. 6. During membrane depolarization EPSP amplitude increased transiently, due to both a voltage-dependent increase of the NMDA component and inward rectification. In addition, EPSPs slowed down due to a slowdown of the NMDA component. 7. Temporal summation during high-frequency stimulation was sustained by NMDA receptors, whose contribution to depolarization tended to prevail over that of non-NMDA receptors during the trains. A block of the NMDA receptors resulted in reduced depolarization and output spike frequency. 8. This study, as well as extending previous knowledge to the intracellular level in vivo

  18. Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse.

    PubMed

    Gocel, James; Larson, John

    2012-09-27

    Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.

  19. Inducible Nitric Oxide Inhibitors Block NMDA Antagonist-Stimulated Motoric Behaviors and Medial Prefrontal Cortical Glutamate Efflux

    PubMed Central

    Bergstrom, Hadley C.; Darvesh, Altaf S.; Berger, S. P.

    2015-01-01

    Nitric oxide (NO) plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA)-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS) for studying the neurobehavioral effects of non-competitive NMDA-antagonist stimulants such as dizocilpine (MK-801) and phencyclidine (PCP). This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS) aminoguanidine (AG) and (-)-epigallocatechin-3-gallate (EGCG) in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG, or vehicle prior to receiving NMDA antagonists MK-801, PCP, or a conventional psychostimulant (cocaine) and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex (mPFC) was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated mPFC glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in “green tea” and chocolate) may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia. PMID:26696891

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

    PubMed Central

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

    2015-01-01

    ABSTRACT 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

  1. Intermingled modulatory and neurotoxic effects of thimerosal and mercuric ions on electrophysiological responses to GABA and NMDA in hippocampal neurons.

    PubMed

    Wyrembek, P; Szczuraszek, K; Majewska, M D; Mozrzymas, J W

    2010-12-01

    The organomercurial, thimerosal, is at the center of medical controversy as a suspected factor contributing to neurodevelopmental disorders in children. Many neurotoxic effects of thimerosal have been described, but its interaction with principal excitatory and inhibitory neurotransmiter systems is not known. We examined, using electrophysiological recordings, thimerosal effects on GABA and NMDA-evoked currents in cultured hippocampal neurons. After brief (3 to 10 min) exposure to thimerosal at concentrations up to 100 μM, there was no significant effect on GABA or NMDA-evoked currents. However, following exposure for 60-90 min to 1 or 10 μM thimerosal, there was a significant decrease in NMDA-induced currents (p<0.05) and GABAergic currents (p<0.05). Thimerosal was also neurotoxic, damaging a significant proportion of neurons after 60-90 min exposure; recordings were always conducted in the healthiest looking neurons. Mercuric chloride, at concentrations 1 μM and above, was even more toxic, killing a large proportion of cells after just a few minutes of exposure. Recordings from a few sturdy cells revealed that micromolar mercuric chloride markedly potentiated the GABAergic currents (p<0.05), but reduced NMDA-evoked currents (p<0.05). The results reveal complex interactions of thimerosal and mercuric ions with the GABA(A) and NMDA receptors. Mercuric chloride act rapidly, decreasing electrophysiological responses to NMDA but enhancing responses to GABA, while thimerosal works slowly, reducing both NMDA and GABA responses. The neurotoxic effects of both mercurials are interwoven with their modulatory actions on GABA(A) and NMDA receptors, which most likely involve binding to these macromolecules.

  2. 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.

  3. 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

  4. Agmatine enhances the antidepressant-like effect of lithium in mouse forced swimming test through NMDA pathway.

    PubMed

    Mohseni, Gholmreza; Ostadhadi, Sattar; Imran-Khan, Muhammad; Norouzi-Javidan, Abbas; Zolfaghari, Samira; Haddadi, Nazgol-Sadat; Dehpour, Ahmad-Reza

    2017-04-01

    Depression is one the world leading global burdens leading to various comorbidities. Lithium as a mainstay in the treatment of depression is still considered gold standard treatment. Similar to lithium another agent agmatine has also central protective role against depression. Since, both agmatine and lithium modulate various effects through interaction with NMDA receptor, therefore, in current study we aimed to investigate the synergistic antidepressant-like effect of agmatine with lithium in mouse force swimming test. Also to know whether if such effect is due to interaction with NMDA receptor. In our present study we found that when potent dose of lithium (30mg/kg) was administered, it significantly decreased the immobility time. Also, when subeffective dose of agmatine (0.01mg/kg) was coadministered with subeffective dose of lithium (3mg/kg), it potentiated the antidepressant-like effect of subeffective dose of lithium. For the involvement of NMDA receptor in such effect, we administered NMDA receptor antagonist MK-801 (0.05mg/kg) with a combination of subeffective dose of lithium (3mg/kg) and agmatine (0.001mg/kg). A significant antidepressant-like effect was observed. Furthermore, when subeffective dose (50 and 75mg/kg) of NMDA was given it inhibited the synergistic effect of agmatine (0.01mg/kg) with lithium (3mg/kg). Hence, our finding demonstrate that agmatine have synergistic effect with lithium which is mediated by NMDA receptor pathway.

  5. Aloe-emodin suppressed NMDA-induced apoptosis of retinal ganglion cells through regulation of ERK phosphorylation.

    PubMed

    Lin, Hui-Ju; Chao, Pei-Dawn Lee; Huang, Shiuan-Yi; Wan, Lai; Wu, Chen-Ju; Tsai, Fuu-Jen

    2007-11-01

    A high concentration of glutamate in the vitreous body and optic nerves of the eyes activates N-methyl-D-aspartate (NMDA) receptors and is toxic to retina ganglion cells (RGCs) in glaucomatous patients. Aloe-emodin sulfates/glucuronides (s/g), the major metabolites of aloe-emodin, was found to be effective in decreasing NMDA-induced apoptosis in RGCs. In order to elucidate the mechanisms, an in vitro optic neuropathy model adding NMDA to N18 RGCs was used in this study. The phosphorylation level of extra-cellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 kinase (cytokines-suppressive antiinflammatory drug binding protein kinase) were measured by western blotting and luciferase reporter assay. The results showed that aloe-emodin metabolites significantly decreased the activation of three major mitogen-activated protein (MAP) kinase pathways and the activation of downstream genes in nucleus induced by NMDA, which were verified by the addition of the respective inhibitors. Comparing the effect of the inhibitors of the three MAP kinase pathways, the ERK pathway was found to be the major route of aloe-emodin metabolites in decreasing the apoptosis of NMDA-treated RGCs. Besides, cfos rather then cjun was the target downstream gene. Aloe-emodin emodin metabolites could regulate the phosphorylation of ERK kinases and it was a promising candidate for NMDA-induced apoptosis of RGCs.

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

    PubMed

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

    2015-05-01

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

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

    PubMed

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

    2006-08-01

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

  8. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction

    PubMed Central

    2010-01-01

    Background A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R) was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown. Methods We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats. Results Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF. Conclusion These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder. PMID:21110857

  9. NMDA/glutamate mechanism of antidepressant-like action of magnesium in forced swim test in mice.

    PubMed

    Poleszak, Ewa; Wlaź, Piotr; Kedzierska, Ewa; Nieoczym, Dorota; Wróbel, Andrzej; Fidecka, Sylwia; Pilc, Andrzej; Nowak, Gabriel

    2007-12-01

    Antidepressant-like activity of magnesium in forced swim test (FST) was demonstrated previously. Also, enhancement of such activity by joint administration of magnesium and antidepressants was shown. However, the mechanism(s) involved in such activity remain to be established. In the present study we examined the involvement of NMDA/glutamate pathway in the magnesium activity in FST in mice. In the present study we investigated the effect of NMDA agonists on magnesium-induced activity in FST and the influence of NMDA antagonists with sub-effective doses of magnesium in this test. Magnesium-induced antidepressant-like activity was antagonized by N-methyl-d-aspartic acid (NMDA). Moreover, low, ineffective doses of NMDA antagonists (CGP 37849, L-701,324, d-cycloserine, and MK-801) administered together with low and ineffective doses of magnesium exhibit significant reduction of immobility time in FST. The active in FST doses of examined agents did not alter the locomotor activity (with an exception of increased activity induced by MK-801). The present study indicates the involvement of NMDA/glutamate pathway in the antidepressant-like activity of magnesium in mouse FST and further suggests antidepressant properties of magnesium.

  10. Heterosynaptic GABAergic plasticity bidirectionally driven by the activity of pre- and postsynaptic NMDA receptors

    PubMed Central

    Gandolfi, Daniela; Vilella, Antonietta; Zoli, Michele; Bigiani, Albertino

    2016-01-01

    Dynamic changes of the strength of inhibitory synapses play a crucial role in processing neural information and in balancing network activity. Here, we report that the efficacy of GABAergic connections between Golgi cells and granule cells in the cerebellum is persistently altered by the activity of glutamatergic synapses. This form of plasticity is heterosynaptic and is expressed as an increase (long-term potentiation, LTPGABA) or a decrease (long-term depression, LTDGABA) of neurotransmitter release. LTPGABA is induced by postsynaptic NMDA receptor activation, leading to calcium increase and retrograde diffusion of nitric oxide, whereas LTDGABA depends on presynaptic NMDA receptor opening. The sign of plasticity is determined by the activation state of target granule and Golgi cells during the induction processes. By controlling the timing of spikes emitted by granule cells, this form of bidirectional plasticity provides a dynamic control of the granular layer encoding capacity. PMID:27531957

  11. Requirement for hippocampal CA3 NMDA receptors in associative memory recall.

    PubMed

    Nakazawa, Kazu; Quirk, Michael C; Chitwood, Raymond A; Watanabe, Masahiko; Yeckel, Mark F; Sun, Linus D; Kato, Akira; Carr, Candice A; Johnston, Daniel; Wilson, Matthew A; Tonegawa, Susumu

    2002-07-12

    Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.

  12. GHB-Induced Cognitive Deficits During Adolescence and the Role of NMDA Receptor.

    PubMed

    Sircar, R; Wu, L-C; Reddy, K; Sircar, D; Basak, A K

    2011-03-01

    We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex.

  13. GHB–Induced Cognitive Deficits During Adolescence and the Role of NMDA Receptor

    PubMed Central

    Sircar, R; Wu, L-C; Reddy, K; Sircar, D; Basak, A.K

    2011-01-01

    We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex. PMID:21886597

  14. Thalamocortical NMDA conductances and intracortical inhibition can explain cortical temporal tuning

    NASA Technical Reports Server (NTRS)

    Krukowski, A. E.; Miller, K. D.

    2001-01-01

    Cells in cerebral cortex fail to respond to fast-moving stimuli that evoke strong responses in the thalamic nuclei innervating the cortex. The reason for this behavior has remained a mystery. We study an experimentally motivated model of the thalamic input-recipient layer of cat primary visual cortex that accounts for many aspects of cortical orientation tuning. In this circuit, inhibition dominates over excitation, but temporal modulations of excitation and inhibition occur out of phase with one another, allowing excitation to transiently drive cells. We show that this circuit provides a natural explanation of cortical low-pass temporal frequency tuning, provided N-methyl-D-aspartate (NMDA) receptors are present in thalamocortical synapses in proportions measured experimentally. This suggests a new and unanticipated role for NMDA conductances in shaping the temporal response properties of cortical cells, and suggests that common cortical circuit mechanisms underlie both spatial and temporal response tuning.

  15. Increased phosphorylation of the NR1 subunit of the NMDA receptor following cerebral ischemia.

    PubMed

    Cheung, H H; Teves, L; Wallace, M C; Gurd, J W

    2001-09-01

    The effects of transient cerebral ischemia on phosphorylation of the NR1 subunit of the NMDA receptor by protein kinase C (PKC) and protein kinase A (PKA) were investigated. Adult rats received 15 min of cerebral ischemia followed by various times of recovery. Phosphorylation was examined by immunoblotting hippocampal homogenates with antibodies that recognized NR1 phosphorylated on the PKC phosphorylation sites Ser890 and Ser896, the PKA phosphorylation site Ser897, or dually phosphorylated on Ser896 and Ser897. The phosphorylation of all sites examined increased following ischemia. The increase in phosphorylation by PKC was greater than by PKA. The ischemia-induced increase in phosphorylation was predominantly associated with the population of NR1 that was insoluble in 1% deoxycholate. Enhanced phosphorylation of NR1 by PKC and PKA may contribute to alterations in NMDA receptor function in the postischemic brain.

  16. The participation of NMDA receptors, PKC, and MAPK in Lymnaea memory extinction.

    PubMed

    Rosenegger, David; Lukowiak, Ken

    2013-02-01

    The aerial respiratory behavior of Lymnaea can be operantly conditioned to form a long-term memory (LTM) that will persist for >24h. LTM formation is dependent on altered gene activity and new protein synthesis, with the N-methyl-D-aspartate (NMDA) receptors, mitogen activated protein kinase (MAPK), and protein kinase C (PKC) pathways playing a critical role. LTM can also undergo extinction, whereby the original memory is temporarily masked by a new memory. Here we investigate if the formation of an extinction memory uses similar molecular pathways to those required for LTM formation. We find that the formation of the extinction memory can be blocked by inhibitors of NMDA receptors, PKC, and MAPK suggesting that extinction memory formation uses similar mechanisms to that of 'normal' memory formation.

  17. Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid.

    PubMed

    Severino, Patricia Cardoso; Muller, Gabriele do Amaral Silva; Vandresen-Filho, Samuel; Tasca, Carla Inês

    2011-10-10

    The search for novel, less invasive therapeutic strategies to treat neurodegenerative diseases has stimulated scientists to investigate the mechanisms involved in preconditioning. Preconditioning has been report to occur in many organs and tissues. In the brain, the modulation of glutamatergic transmission is an important and promising target to the use of effective neuroprotective agents. The glutamatergic excitotoxicity is a factor common to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury and epilepsy. In this review we focus on the neuroprotection and preconditioning by chemical agents. Specially, chemical preconditioning models using N-methyl-d-aspartate (NMDA) pre-treatment, which has demonstrated to lead to neuroprotection against seizures and damage to neuronal tissue induced by quinolinic acid (QA). Here we attempted to gather important results obtained in the study of cellular and molecular mechanisms involved in NMDA preconditioning and neuroprotection.

  18. The Role of NMDA Receptors in the Development of Brain Resistance through Pre- and Postconditioning

    PubMed Central

    Celso Constantino, Leandra; Tasca, Carla Inês; Boeck, Carina Rodrigues

    2014-01-01

    Brain tolerance or resistance can be achieved by interventions before and after injury through potential toxic agents used in low stimulus or dose. For brain diseases, the neuroprotection paradigm desires an attenuation of the resulting motor, cognitive, emotional, or memory deficits following the insult. Preconditioning is a well-established experimental and clinical translational strategy with great beneficial effects, but limited applications. NMDA receptors have been reported as protagonists in the adjacent cellular mechanisms contributing to the development of brain tolerance. Postconditioning has recently emerged as a new neuroprotective strategy, which has shown interesting results when applied immediately, i.e. several hours to days, after a stroke event. Investigations using chemical postconditioning are still incipient, but nevertheless represent an interesting and promising clinical strategy. In the present review pre- and postconditioning are discussed as neuroprotective paradigms and the focus of our attention lies on the participation of NMDA receptors proteins in the processes related to neuroprotection. PMID:25489494

  19. Attenuation of NMDA receptor activity and neurotoxicity by nitroxyl anion, NO-.

    PubMed

    Kim, W K; Choi, Y B; Rayudu, P V; Das, P; Asaad, W; Arnelle, D R; Stamler, J S; Lipton, S A

    1999-10-01

    Recent evidence indicates that the NO-related species, nitroxyl anion (NO), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (NOS), superoxide dismutase, and S-nitrosothiols (SNOs), which have recently been identified in brain. However, the chemical biology of NO- remains largely unknown. Here, we show that NO- -unlike NO*, but reminiscent of NO+ transfer (or S-nitrosylation)- -reacts mainly with Cys-399 in the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of NO- closely resembles that of NOS, which also downregulates NMDA receptor activity under similar conditions in culture.

  20. Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

    PubMed Central

    Corlew, Rebekah; Brasier, Daniel J.; Feldman, Daniel E.; Philpot, Benjamin D.

    2009-01-01

    Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the last 10 years demonstrates that NMDARs also exist presynaptically, and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here we review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. We discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology. PMID:19029059

  1. NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice

    SciTech Connect

    Dekundy, Andrzej . E-mail: andrzej.dekundy@merz.de; Kaminski, Rafal M.; Zielinska, Elzbieta; Turski, Waldemar A.

    2007-03-15

    Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures.

  2. Glycine transporters type 1 inhibitor promotes brain preconditioning against NMDA-induced excitotoxicity.

    PubMed

    Pinto, Mauro Cunha Xavier; Lima, Isabel Vieira de Assis; da Costa, Flávia Lage Pessoa; Rosa, Daniela Valadão; Mendes-Goulart, Vânia Aparecida; Resende, Rodrigo Ribeiro; Romano-Silva, Marco Aurélio; de Oliveira, Antônio Carlos Pinheiro; Gomez, Marcus Vinícius; Gomez, Renato Santiago

    2015-02-01

    Brain preconditioning is a protective mechanism, which can be activated by sub-lethal stimulation of the NMDA receptors (NMDAR) and be used to achieve neuroprotection against stroke and neurodegenerative diseases models. Inhibitors of glycine transporters type 1 modulate glutamatergic neurotransmission through NMDAR, suggesting an alternative therapeutic strategy of brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by NFPS, a GlyT1 inhibitor, against NMDA-induced excitotoxicity in mice hippocampus, as well as to study its neurochemical mechanisms. C57BL/6 mice (male, 10-weeks-old) were preconditioned by intraperitoneal injection of NFPS at doses of 1.25, 2.5 or 5.0 mg/kg, 24 h before intrahippocampal injection of NMDA. Neuronal death was evaluated by fluoro jade C staining and neurochemical parameters were evaluated by gas chromatography-mass spectrometry, scintillation spectrometry and western blot. We observed that NFPS preconditioning reduced neuronal death in CA1 region of hippocampus submitted to NMDA-induced excitotoxicity. The amino acids (glycine and glutamate) uptake and content were increased in hippocampus of animals treated with NFPS 5.0 mg/kg, which were associated to an increased expression of type-2 glycine transporter (GlyT2) and glutamate transporters (EAAT1, EAAT2 and EAAT3). The expression of GlyT1 was reduced in animals treated with NFPS. Interestingly, the preconditioning reduced expression of GluN2B subunits of NMDAR, whereas did not change the expression of GluN1 or GluN2A in all tested doses. Our study suggests that NFPS preconditioning induces resistance against excitotoxicity, which is associated with neurochemical changes and reduction of GluN2B-containing NMDAR expression.

  3. Protons trap NR1/NR2B NMDA receptors in a nonconducting state.

    PubMed

    Banke, Tue G; Dravid, Shashank M; Traynelis, Stephen F

    2005-01-05

    NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H+. We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 x 10(9) m(-1) sec(-1) and 110-196 sec(-1), respectively (K(d) corresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.

  4. Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function

    PubMed Central

    Braun, Urs; Schäfer, Axel; Rausch, Franziska; Schweiger, Janina I.; Bilek, Edda; Erk, Susanne; Romanczuk-Seiferth, Nina; Grimm, Oliver; Geiger, Lena S.; Haddad, Leila; Otto, Kristina; Mohnke, Sebastian; Heinz, Andreas; Zink, Mathias; Walter, Henrik; Schwarz, Emanuel; Meyer-Lindenberg, Andreas; Tost, Heike

    2016-01-01

    Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation–inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified “network flexibility,” a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia. PMID:27791105

  5. Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

    PubMed

    Braun, Urs; Schäfer, Axel; Bassett, Danielle S; Rausch, Franziska; Schweiger, Janina I; Bilek, Edda; Erk, Susanne; Romanczuk-Seiferth, Nina; Grimm, Oliver; Geiger, Lena S; Haddad, Leila; Otto, Kristina; Mohnke, Sebastian; Heinz, Andreas; Zink, Mathias; Walter, Henrik; Schwarz, Emanuel; Meyer-Lindenberg, Andreas; Tost, Heike

    2016-11-01

    Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.

  6. A calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression.

    PubMed

    Jurado, Sandra; Biou, Virginie; Malenka, Robert C

    2010-09-01

    AKAP79/150 is a protein scaffold that is thought to position specific kinases (protein kinase A and C) and phosphatases (calcineurin) in appropriate synaptic domains so that their activities can regulate excitatory synaptic strength. Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin.

  7. Enhancing and impairing extinction of habit memory through modulation of NMDA receptors in the dorsolateral striatum.

    PubMed

    Goodman, Jarid; Ressler, Reed L; Packard, Mark G

    2017-04-02

    The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder).

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

    PubMed

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

    2016-04-01

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

  9. EM colocalization of AMPA and NMDA receptor subunits at synapses in rat cerebral cortex.

    PubMed

    Kharazia, V N; Phend, K D; Rustioni, A; Weinberg, R J

    1996-05-24

    Electrophysiology and light microscopy suggest that a single excitatory synapse may use both amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Using immunogold electron microscopy, we here provide direct evidence for colocalization at individual synapses in sensorimotor cortex of adult rats. Colocalization was most commonly observed on dendritic spines; subunits of the two classes of receptors seemed to be independently distributed within the synaptic active zone.

  10. Non-tumor-Associated Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis in Chinese Girls With Positive Anti-thyroid Antibodies.

    PubMed

    Guan, Wenjuan; Fu, Zhenqiang; Zhang, Hui; Jing, Lijun; Lu, Jingjing; Zhang, Jing; Lu, Hong; Teng, Junfang; Jia, Yanjie

    2015-10-01

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a new category of autoimmune encephalitis associated with anti-NMDA receptor antibodies. The disease was first described in 2007, and it predominantly affects young women with or without ovarian teratomas. Most patients typically present with seizures, a decreased consciousness level, dyskinesia, autonomic dysfunction, and psychiatric symptoms. The presence of anti-thyroid antibodies in non-tumor-associated anti-NMDA receptor encephalitis was first described in 2010. Additionally, anti-thyroid antibodies were found in teratoma-associated anti-NMDA receptor encephalitis. We report the cases of 3 Chinese girls with non-tumor-associated anti-NMDA receptor encephalitis with positive anti-thyroid antibodies. We followed up the details of their titers and suggest that anti-thyroid antibodies were an indicator of autoimmune predisposition in the development of non-tumor-associated anti-NMDA receptor encephalitis.

  11. Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex.

    PubMed

    López-Avila, Alberto; Coffeen, Ulises; Ortega-Legaspi, J Manuel; del Angel, Rosendo; Pellicer, Francisco

    2004-09-01

    The anterior cingulate cortex (ACC) plays a key role in pain processing. It has been reported that increased activity of glutamatergic projections into the ACC intensifies nociception; whereas dopaminergic projections inhibit it. The aim of this study was to evaluate the role of dopaminergic and NMDA systems of the ACC in the modulation of long-term nociception elicited by sciatic denervation in the rat. Score, onset and incidence of long-term nociception were measured by the autotomy behavior. The effects of a single microinjection into the ACC of different doses of dopamine (100 nM, 100 microM and 100 mM), a NMDA receptor antagonist (MK801 200 nM and 9.34 mM) and amantadine, a dopamine agonist and NMDA receptor antagonist (10, 100 and 1000 microM) were tested on long-term nociception. Dopamine diminished autotomy behavior in an inverse dose-dependent manner, with dopamine 100 nM as most effective concentration. MK801 and amantadine elicited a significant reduction on autotomy score. Prior injections of D1 and D2 receptor antagonists blocked the antinociceptive effects of amantadine on long-term nociceptive behavior. The present study suggests an interaction between dopaminergic and glutamatergic systems within the ACC in the genesis and maintenance of long-term nociception.

  12. 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

  13. Reduction of inflammatory pain in female rats after NR2B NMDA cortical antagonism.

    PubMed

    Vasquez, Carol; Sánchez, Melany; Herrera, Jairo; Quintero, Gabriel

    2012-05-01

    Studies have shown that N-methyl-D-aspartate (NMDA) receptors play a critical role in pain processing at different levels of the central nervous system. In this study, we used female adult Wistar rats to examine the effects of antagonizing the NR2B subunit of the NMDA receptor in phasic and tonic pain processes. All the rats underwent stereotaxic surgery for cortical cannula implantation and after at least one week of recovery, rats performed behavioral tests. For evaluating the effects of drugs on motor coordination rats were tested in the rotarod apparatus. Moreover, rats were evaluated in the paw withdrawal latency (PWL) to a noxious thermal stimulus. Furthermore, rats were tested in the formalin-pain test. Rats that received the NR2B antagonist Ro 25-6981 before and after formalin injection showed significantly reduced pain responses in the formalin test, as compared with female control rats (p<0.05). In contrast, no differences among groups were found in the phasic pain test (Hargreaves) and the rotarod test. Taken together, these results suggest that cortical antagonism of the NR2B subunit of NMDA receptors is able to reduce inflammatory pain levels not only before, but after the formalin injection in females at different phases of the estrous cycle.

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

    PubMed

    Rammsayer, Thomas H

    2003-05-01

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

  15. 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

  16. Remodeling of striatal NMDA receptors by chronic A(2A) receptor blockade in Huntington's disease mice.

    PubMed

    Martire, Alberto; Ferrante, Antonella; Potenza, Rosa Luisa; Armida, Monica; Ferretti, Roberta; Pézzola, Antonella; Domenici, Maria Rosaria; Popoli, Patrizia

    2010-01-01

    Excitotoxicity plays a major role in the pathogenesis of Huntington disease (HD), a fatal neurodegenerative disorder. Adenosine A(2A) receptors (A(2A)Rs) modulate excitotoxicity and have been suggested to play a pathogenetic role in HD. The main aim of this study was to evaluate the effect of A(2A)R blockade on the expression and functions of NMDA receptors in the striatum of HD mice (R6/2). We found that 3 weeks' treatment with SCH 58261 (0.01 mg/kg/day i.p. from the 8th week of age) modified NR1 and NR2A/NR2B expression in the striatum of R6/2 (Western blotting) while had no effect on NMDA-induced toxicity in corticostriatal slices (electrophysiological experiments). In conclusion, in vivo A(2A)R blockade induced a remodeling of NMDA receptors in the striatum of HD mice. Even though the functional relevance of the above effect remains to be fully elucidated, these results add further evidence to the modulatory role of A(2A)Rs in HD.

  17. Novel Fluorine-Containing NMDA Antagonists for Brain Imaging: In Vitro Evaluation

    SciTech Connect

    Alvarado, M.; Biegon, A.

    2001-01-01

    The NMDA receptor has been implicated in neuronal death following stroke, brain injury and neurodegenerative disorders (e.g. Alzheimer's, Parkinson's and Huntington's disease) and in physiological functions (e.g. memory and cognition). Non-competitive antagonists, such as MK- 801 and CNS-1102, that block the action of glutamate at the NMDA receptor have been shown to be neuroprotective by blocking the influx of calcium into the cells. As a result, they are being considered as therapeutic agents for the above mentioned diseases. Several Fluorine-containing novel analogs of NMDA channel blockers have been synthesized and evaluated in search of a compound suitable for 18F labeling and Positron Emission Tomography (PET). Based on in vitro binding assay studies on rat brain membranes, the novel compounds examined displayed a range of affinities. Preliminary analyses indicated that chlorine is the best halogen on the ring, and that ethyl fluoro derivatives are more potent than methyl-fluoro compounds. Further analysis based on autoradiography will be needed to examine the regional binding characteristics of the novel compounds examined in this study. Labeling with 18F will allow the use of these compounds in humans, generating new insights into mechanisms and treatment of diseases involving malfunction of the glutamatergic system in the brain.

  18. 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.

  19. Steroid unresponsive anti-NMDA receptor encephalitis during pregnancy successfully treated with plasmapheresis.

    PubMed

    Shahani, Lokesh

    2015-04-29

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune disorder resulting in neurological and psychiatric symptoms. It is rare during pregnancy and treatment is extremely challenging as little data exist to guide management. A 26-year-old woman presented at 22 weeks of gestation with intermittent headache and an acute episode of bizarre behaviour and grandiose delusions resulting in hospitalisation. The patient was worked up for encephalitis and was found to have anti-NMDA receptor antibody in cerebrospinal fluid as well as in serum. She was initially treated with high-dose steroids but failed to improve clinically and serologically. She was then treated with plasmapheresis and showed clinical and serological response. She had a successful delivery at 37 weeks and the baby did not show serological evidence of disease. This case adds to the sparse literature of anti-NMDA receptor encephalitis during pregnancy and adds to the differential diagnosis of new onset psychiatric symptoms during pregnancy.

  20. Progressive Brain Damage, Synaptic Reorganization and NMDA Activation in a Model of Epileptogenic Cortical Dysplasia

    PubMed Central

    Colciaghi, Francesca; Finardi, Adele; Nobili, Paola; Locatelli, Denise; Spigolon, Giada; Battaglia, Giorgio Stefano

    2014-01-01

    Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity. PMID:24587109

  1. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

    PubMed Central

    2011-01-01

    Background Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments. Results We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7. Conclusions These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. PMID:22182308

  2. 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.

  3. Downregulation of the spinal NMDA receptor NR2B subunit during electro-acupuncture relief of chronic visceral hyperalgesia.

    PubMed

    Liu, Hongping; Zhang, Yuhua; Qi, Debo; Li, Weimin

    2017-01-01

    The involvement of spinal NR2B, a N-methyl-D-aspartate (NMDA) receptor subunit, in the therapeutic effect of electro-acupuncture (EA) on chronic visceral hyperalgesia was investigated. Chronic visceral hyperalgesia was induced using an irritable bowel syndrome (IBS) model in rats. Graded colorectal distention (CRD) stimuli at strengths of 20, 40, 60 and 80 mmHg were applied, and behavioral tests were performed to measure the abdominal withdrawal reflex (AWR) in response to the CRD stimuli and assess the severity of the visceral hyperalgesia. Rats were randomly divided into four groups: normal intact (control) group, IBS model (model) group, EA-treated IBS rats (EA) group and sham EA-treated IBS rats (sham EA) group. For the EA treatment, electric stimuli were applied through needles inserted into two acupoints [Zu-san-li (ST-36) and Shang-ju-xu (ST-37)] in both hind limbs, while the sham EA treatment consisted of only the insertion of needles into these same acupoints without an application of electric stimuli. Our results showed that AWR scores of the model group responding to CRD stimuli of 20, 40, 60 and 80 mmHg were significantly increased. These increased scores subsequently decreased following EA treatment (P < 0.05) compared with those for the other groups. The expression of NR2B in the superficial laminae (SDH, laminae I and II), nucleus proprius (NP, laminae III and IV), neck of the dorsal horn (NECK, laminae V and VI) and central canal region (lamina X) at thoracolumbar (T13-L2) and lumbosacral (L6-S2) segmental level significantly increased in the model group versus the control group (P < 0.05) and significantly decreased after EA treatment (P < 0.05). There were no significant changes in neither AWR scores nor expression of the NR2B subunit in these spinal regions after the sham EA treatment. These results confirm that EA can relieve chronic visceral hyperalgesia in IBS model rats and suggest that such an effect is possibly mediated through the

  4. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone.

    PubMed

    Liu, Tiemin; Kong, Dong; Shah, Bhavik P; Ye, Chianping; Koda, Shuichi; Saunders, Arpiar; Ding, Jun B; Yang, Zongfang; Sabatini, Bernardo L; Lowell, Bradford B

    2012-02-09

    AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.

  5. Voltage-clamp frequency domain analysis of NMDA-activated neurons.

    PubMed

    Moore, L E; Hill, R H; Grillner, S

    1993-02-01

    1. Voltage and current-clamp steps were added to a sum of sine waves to measure the tetrodotoxin-insensitive membrane properties of neurons in the intact lamprey spinal cord. A systems analysis in the frequency domain was carried out on two types of cells that have very different morphologies in order to investigate the structural dependence of their electrophysiological properties. The method explicitly takes into account the geometrical shapes of (i) nearly spherical dorsal cells with one or two processes and (ii) motoneurons and interneurons that have branched dendritic structures. Impedance functions were analysed to obtain the cable properties of these in situ neurons. These measurements show that branched neurons are not isopotential and, therefore, a conventional voltage-clamp analysis is not valid. 2. The electrophysiological data from branched neurons were curve-fitted with a lumped soma-equivalent cylinder model consisting of eight equal compartments coupled to an isopotential cell body to obtain membrane parameters for both passive and active properties. The analysis provides a quantitative description of both the passive electrical properties imposed by the geometrical structure of neurons and the voltage-dependent ionic conductances determined by ion channel kinetics. The model fitting of dorsal cells was dominated by a one-compartment resistance and capacitance in parallel (RC) corresponding to the spherical, non-branched shape of these cells. Branched neurons required a model that contained both an RC compartment and a cable that reflected the structure of the cells. At rest, the electrotonic length of the cable was about two. Uniformly distributed voltage-dependent ionic conductance sites were adequate to describe the data at different membrane potentials. 3. The frequency domain admittance method in conjunction with a step voltage clamp was used to control and measure the oscillatory behavior induced by N-methyl-D-aspartate (NMDA) on lamprey spinal

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

    PubMed

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

    2008-11-13

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

  7. Modulation of cholestasis-induced antinociception in rats by two NMDA receptor antagonists: MK-801 and magnesium sulfate.

    PubMed

    Hasanein, Parisa; Parviz, Mohsen; Keshavarz, Mansoor; Javanmardi, Kazem; Allahtavakoli, Mohammad; Ghaseminejad, Majid

    2007-01-12

    Acute cholestasis is associated with increased activity of the endogenous opioid system that results to changes including analgesia. N-methyl-d-aspartate (NMDA) receptors are involved in the nociceptive pathway and play a major role in the development of morphine induced analgesia. The magnesium acts as a non-competitive NMDA receptor antagonist by blocking the NMDA receptor channel. Considering the reported antinociceptive effect of magnesium sulfate as a NMDA receptor antagonist and the existence of close functional links between NMDA receptor antagonists and magnesium with the opioid system, we studied the effect of acute and chronic administration of MK-801 as a NMDA antagonist and magnesium sulfate on modulation of nociception in an experimental model of elevated endogenous opioid tone, acute cholestasis, using the tail-flick paradigm. Cholestasis was induced by ligation of the main bile duct using two ligatures and then transsection of the duct at the midpoint between them. A significant increase (P<0.001) in nociception threshold was observed in bile duct ligated rats compared to unoperated and sham-operated animals. In acute treatment, MK-801 (0.1 mg/kg, b.i.d), but not magnesium (150 mg/kg magnesium sulfate, i.e. 30 mg/kg of Mg(+2), i.p., b.i.d.) increased antinociception in cholestatic rats compared to saline treated cholestatics (P<0.05). In chronic treatment, administration of MK-801 or magnesium sulfate for 7 consecutive days, increased tail-flick latency (P<0.05, P<0.01) in cholestatic animals compared to saline treated cholestatics. These data showed that NMDA receptor pathway is involved in modulation of cholestasis-induced antinociception in rats and that repeated dosages of magnesium sulfate similar to MK-801 is able to modulate nociception in cholestasis.

  8. 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

  9. Protective effect of magnesium acetyltaurate against NMDA-induced retinal damage involves restoration of minerals and trace elements homeostasis.

    PubMed

    Jafri, Azliana Jusnida Ahmad; Arfuzir, Natasha Najwa Nor; Lambuk, Lidawani; Iezhitsa, Igor; Agarwal, Renu; Agarwal, Puneet; Razali, Norhafiza; Krasilnikova, Anna; Kharitonova, Maria; Demidov, Vasily; Serebryansky, Evgeny; Skalny, Anatoly; Spasov, Alexander; Yusof, Ahmad Pauzi Md; Ismail, Nafeeza Mohd

    2017-01-01

    Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL(-1)). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL(-1)) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0

  10. Interferon-gamma potentiates NMDA receptor signaling in spinal dorsal horn neurons via microglia–neuron interaction

    PubMed Central

    Sonekatsu, Mayumi; Yamanaka, Manabu; Nishio, Naoko; Tsutsui, Shunji; Yamada, Hiroshi; Yoshida, Munehito; Nakatsuka, Terumasa

    2016-01-01

    Background Glia–neuron interactions play an important role in the development of neuropathic pain. Expression of the pro-inflammatory cytokne →cytokine Interferon-gamma (IFNγ) is upregulated in the dorsal horn after peripheral nerve injury, and intrathecal IFNγ administration induces mechanical allodynia in rats. A growing body of evidence suggests that IFNγ might be involved in the mechanisms of neuropathic pain, but its effects on the spinal dorsal horn are unclear. We performed blind whole-cell patch-clamp recording to investigate the effect of IFNγ on postsynaptic glutamate-induced currents in the substantia gelatinosa neurons of spinal cord slices from adult male rats. Results IFNγ perfusion significantly enhanced the amplitude of NMDA-induced inward currents in substantia gelatinosa neurons, but did not affect AMPA-induced currents. The facilitation of NMDA-induced current by IFNγ was inhibited by bath application of an IFNγ receptor-selective antagonist. Adding the Janus activated kinase inhibitor tofacitinib to the pipette solution did not affect the IFNγ-induced facilitation of NMDA-induced currents. However, the facilitatory effect of IFNγ on NMDA-induced currents was inhibited by perfusion of the microglial inhibitor minocycline. These results suggest that IFNγ binds the microglial IFNγ receptor and enhances NMDA receptor activity in substantia gelatinosa neurons. Next, to identify the effector of signal transmission from microglia to dorsal horn neurons, we added an inhibitor of G proteins, GDP-β-S, to the pipette solution. In a GDP-β-S–containing pipette solution, IFNγ-induced potentiation of the NMDA current was significantly suppressed after 30 min. In addition, IFNγ-induced potentiation of NMDA currents was blocked by application of a selective antagonist of CCR2, and its ligand CCL2 increased NMDA-induced currents. Conclusion Our findings suggest that IFNγ enhance the amplitude of NMDA-induced inward currents in substantia

  11. Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory

    PubMed Central

    Martel, Guillaume; Uchida, Shusaku; Hevi, Charles; Chévere-Torres, Itzamarie; Fuentes, Ileana; Park, Young Jin; Hafeez, Hannah; Yamagata, Hirotaka; Watanabe, Yoshifumi

    2016-01-01

    Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG. SIGNIFICANCE STATEMENT In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an

  12. Neurotoxicity of NMDA antagonists: a glutamatergic theory of schizophrenia based on selective impairment of local inhibitory feedback circuits

    PubMed Central

    Grunze, Heinz; Bender, Andreas; Wendhof, Stefan; Schäfer, Martin; Rujescu, Dan

    2000-01-01

    Modulation of recurrent inhibition is critical not only for the normal function of highly excitable regions of the brain, especially the limbic system, but may also be a primary determining factor for the viability of neurons in these regions. Standard extracellular and intracellular recordings from in vitro brain slices of rat hippocampi were employed to show that recurrent inhibition onto CA1 neurons can be modulated by N-methyl-D-aspartate (NMDA) antagonists. Besides reducing the amplitude of inhibitory postsynaptic potentials (IPSPs) at resting membrane potential conditions, different NMDA antagonists, including the endogenous substance N-acetyl-L-aspartyl-L-glutamic acid (NAAG), are able to block long-term potentiation (LIP) of recurrent inhibition completely at concentrations that are not sufficient to block LTP of the excitatory drive onto pyramidal neurons. This LTP of recurrent inhibition may play a significant role in stimulus discrimination and learning, as simulated in a biophysical computer model of a basic neuronal circuit. Both the amplitude of the IPSP and LTP of the recurrent inhibitory circuit also undergo developmental changes showing their highest expression and vulnerability to chronic NMDA antagonist injections in juvenile rats. Finally, blocking NMDA receptor-dependent transmission in the recurrent inhibition loop may lead to an overall increased excitability of the neuronal network. This may resemble the positive schizophrenic symptoms observed in man, presumably caused by elevated levels of the endogenous NMDA antagonist NAAG. PMID:22033472

  13. Receptor to glutamate NMDA-type: the functional diversity of the nr1 isoforms and pharmacological properties.

    PubMed

    Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Escoto-Delgadillo, Martha; Ureña-Guerrero, Mónica Elisa; Camins, Antoni; Beas-Zarate, Carlos

    2013-01-01

    Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system, and interacts with two classes of receptor: metabotropic and ionotropic receptors. Ionotropic receptors are divided according to the affinity of their specific agonists: Nmethyl- D-aspartate (NMDA), amino acid-3-hydroxy-5-methyl-4-isoxazole acid (AMPA) and kainic acid (KA). NMDA receptors (NMDA-R) are macromolecular structures that are formed by different combinations of subunits: NMDAR1 (NR1), NMDAR2 (NR2) and NMDAR3 (NR3). The study of this receptor has aroused great interest, partly due to its role in synaptic plasticity but mainly because of its permeability to the Ca(2+) ion. This review examines the molecular composition of NMDA-R and the variants of NR1 subunit editing in association with NR2 subunit dimers, which form the main components of this receptor. Their composition, structure, function and distinct temporal and spatial expression patterns demonstrate the versatility and diversity of functionally different isoforms of NR1 subunits and the various pharmacological properties of the NR2 subunit. Finally, the involvement of NMDA-R in the excitotoxicity phenomenon, as well as, its expression changes under these conditions as neuronal response are also discussed.

  14. Overexpression of EphB2 in hippocampus rescues impaired NMDA receptors trafficking and cognitive dysfunction in Alzheimer model.

    PubMed

    Hu, Rui; Wei, Pan; Jin, Lu; Zheng, Teng; Chen, Wen-Yu; Liu, Xiao-Ya; Shi, Xiao-Dong; Hao, Jing-Ru; Sun, Nan; Gao, Can

    2017-03-30

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, which affects more and more people. But there is still no effective treatment for preventing or reversing the progression of the disease. Soluble amyloid-beta (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs) play an important role in AD. Synaptic activity and cognition critically depend on the function of glutamate receptors. Targeting N-methyl-D-aspartic acid (NMDA) receptors trafficking and its regulation is a new strategy for AD early treatment. EphB2 is a key regulator of synaptic localization of NMDA receptors. Aβ oligomers could bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. Here we identified that overexpression of EphB2 with lentiviral vectors in dorsal hippocampus improved impaired memory deficits and anxiety or depression-like behaviors in APPswe/PS1-dE9 (APP/PS1) transgenic mice. Phosphorylation and surface expression of GluN2B-containing NMDA receptors were also improved. Overexpression of EphB2 also rescued the ADDLs-induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons. These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in hippocampus may be a promising strategy for AD treatment.

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

    PubMed Central

    Kumagai, Ayako; Fujita, Akira; Yokoyama, Tomoki; Nonobe, Yuki; Hasaba, Yasuhiro; Sasaki, Tsutomu; Itoh, Yumi; Koura, Minako; Suzuki, Osamu; Adachi, Shigeki; Ryo, Haruko; Kohara, Arihiro; Tripathi, Lokesh P.; Sanosaka, Masato; Fukushima, Toshiki; Takahashi, Hiroyuki; Kitagawa, Kazuo; Nagaoka, Yasuo; Kawahara, Hidehisa; Mizuguchi, Kenji; Nomura, Taisei; Matsuda, Junichiro; Tabata, Toshihide; Takemori, Hiroshi

    2014-01-01

    Memantine is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds. PMID:25513882

  16. PhTx3-4, a Spider Toxin Calcium Channel Blocker, Reduces NMDA-Induced Injury of the Retina

    PubMed Central

    Binda, Nancy Scardua; Porto Petruceli Carayon, Charles; Agostini, Rafael Mourão; do Nascimento Pinheiro, Ana Cristina; Nascimento Cordeiro, Marta; Romano Silva, Marco Aurélio; Figueira Silva, Juliana; Rita Pereira, Elizete Maria; da Silva Junior, Claudio Antonio; de Castro Junior, Célio José; Sena Guimarães, Andre Luiz; Gomez, Marcus Vinicius

    2016-01-01

    The in vivo neuroprotective effect of PhTx3-4, a spider toxin N-P/Q calcium channel blocker, was studied in a rat model of NMDA-induced injury of the retina. NMDA (N-Methyl-d-Aspartate)-induced retinal injury in rats reduced the b-wave amplitude by 62% ± 3.6%, indicating the severity of the insult. PhTx3-4 treatment increased the amplitude of the b-wave, which was almost equivalent to the control retinas that were not submitted to injury. The PhTx3-4 functional protection of the retinas recorded on the ERG also was observed in the neuroprotection of retinal cells. NMDA-induced injury reduced live cells in the retina layers and the highest reduction, 84%, was in the ganglion cell layer. Notably, PhTx3-4 treatment caused a remarkable reduction of dead cells in the retina layers, and the highest neuroprotective effect was in the ganglion cells layer. NMDA-induced cytotoxicity of the retina increased the release of glutamate, reactive oxygen species (ROS) production and oxidative stress. PhTx3-4 treatment reduced glutamate release, ROS production and oxidative stress measured by malondialdehyde. Thus, we presented for the first time evidence of in vivo neuroprotection from NMDA-induced retinal injury by PhTx3-4 (-ctenitoxin-Pn3a), a spider toxin that blocks N-P/Q calcium channels. PMID:26978403

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

    PubMed

    Han, Zhao; Yang, Jin-Long; Jiang, Susan X; Hou, Sheng-Tao; Zheng, Rong-Yuan

    2013-01-01

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

  18. 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

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

    PubMed

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

    2008-07-01

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

  20. 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…

  1. [Reversible cortical atrophy secondary to anti-NMDA receptor antibody encephalitis].

    PubMed

    Bravo-Oro, Antonio; Acosta-Yebra, Danae; Grimaldo-Zapata, Ilse P; Reyes-Vaca, Guillermo

    2015-05-16

    Introduccion. La encefalitis por anticuerpos antirreceptor de N-metil-D-aspartato (NMDA) inicialmente se describio como un sindrome paraneoplasico asociado a teratoma de ovario, pero cada vez con mas frecuencia se han ido publicando casos en mujeres jovenes y niños como un cuadro encefalopatico autoinmune secundario en el 40-50% de los casos a un proceso viral. Clinicamente, se caracteriza por un cuadro progresivo de manifestaciones psiquiatricas, crisis convulsivas, discinesias y disautonomias. Un hallazgo neurorradiologico poco comunicado es la atrofia cortical reversible, de la cual se desconoce su mecanismo. Caso clinico. Niña que a los 6 años comenzo con crisis convulsivas focales, con electroencefalograma epileptogeno y tomografia de craneo inicial normal. Se inicio tratamiento anticonvulsionante. A las tres semanas aparecieron nuevas crisis convulsivas, manifestaciones psiquiatricas y alteraciones en el ciclo de sueño-vigilia. Ante la sospecha de encefalitis por anticuerpos antirreceptor de NMDA, estos se determinaron en el suero y el liquido cefalorraquideo con resultado positivo. Resonancia magnetica durante el ingreso con atrofia cortical generalizada. Oncologia Pediatrica descarto asociacion a tumores. A los dos años del cuadro, con la paciente libre de crisis convulsivas, una valoracion neuropsicologica mostro la afectacion de funciones ejecutivas y una resonancia magnetica de control evidencio la recuperacion de la atrofia cortical. Conclusion. El mecanismo de la atrofia cortical reversible se desconoce, pero en pacientes con encefalitis por anticuerpos antirreceptor de NMDA podria ser directamente proporcional a la cantidad de anticuerpos circulantes y el tiempo de exposicion a estos en la corteza cerebral. Es muy importante el diagnostico temprano y el inicio de inmunomodulacion.

  2. Anti-NMDA-R encephalitis: Should we consider extreme delta brush as electrical status epilepticus?

    PubMed

    Chanson, Eve; Bicilli, Élodie; Lauxerois, Michel; Kauffmann, Sophie; Chabanne, Russell; Ducray, François; Honnorat, Jérome; Clavelou, Pierre; Rosenberg, Sarah

    2016-02-01

    Seizures are common clinical manifestations in anti-N-methyl-d-aspartate receptor (anti-NMDA-R) encephalitis, among other neurological and psychiatric symptoms. During the course of the disease, some specific EEG patterns have been described: generalized rhythmic delta activity (GRDA) and extreme delta brush (EDB). In comatose patients, the association of these EEG abnormalities with subtle motor manifestations can suggest ongoing non-convulsive status epilepticus (NCSE). We report the case of a 28-year-old woman admitted for a clinical presentation typical of anti-NMDA-R encephalitis, which was confirmed by CSF analysis. She was rapidly intubated because of severe dysautonomia and disturbed consciousness. Clinical examination revealed subtle paroxysmal and intermittent myoclonic and tonic movements, correlated on video-EEG with GRDA and/or EDB. NCSE was then suspected, but electroclinical manifestations persisted despite many anti-epileptic drugs combinations, or reappeared when barbiturate anesthesia was decreased. In order to confirm or dismiss the diagnosis, intracranial pressure (ICP) and surface video-EEG monitoring were performed simultaneously and revealed no ICP increase, thus being strongly against a diagnosis of seizures. Sedation was progressively weaned, and clinical condition as well as EEG appearance progressively improved. Literature review revealed 11 similar cases, including 2 with focal NCSE. Of the nine other cases, NCSE diagnosis was finally excluded in 5 cases. NCSE diagnosis in association with anti-NMDA-R encephalitis is sometimes very difficult and its occurrence might be overestimated. Video-EEG is highly recommended and more invasive techniques may sometimes be necessary.

  3. Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus.

    PubMed

    Zhang, Xi; Zhang, Quanguang; Tu, Jingyi; Zhu, Ying; Yang, Fang; Liu, Bin; Brann, Darrell; Wang, Ruimin

    2015-03-01

    Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK-801. Further work revealed that the NR2A-type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A-preferring antagonist (NVP-A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B-preferring antagonist (Ro25) was without effect. Post C significantly up-regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca(2+) influx and activation/phosphorylation of CamKIIα at Thr(286), effects that were NR2A mediated as they were blocked by NVP-A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB-dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP-A. Taken as a whole, the current study provides evidence that NR2A-activation and downstream prosurvival signaling is a critical mediator of Post C-induced neuroprotection and cognitive enhancement following GCI.

  4. Social isolation-induced increase in NMDA receptors in the hippocampus exacerbates emotional dysregulation in mice.

    PubMed

    Chang, Chih-Hua; Hsiao, Ya-Hsin; Chen, Yu-Wen; Yu, Yang-Jung; Gean, Po-Wu

    2015-04-01

    Epidemiological studies have shown that early life adverse events have long-term effects on the susceptibility to subsequent stress exposure in adolescence, but the precise mechanism is unclear. In the present study, mice on postnatal day 21-28 were randomly assigned to either a group or isolated cages for 8 weeks. The socially isolated (SI) mice exhibited a higher level of spontaneous locomotor activity, a longer duration of immobility in the forced swimming test (FST), significantly less prepulse inhibition (PPI) and an increase in aggressive (but not attack) behavior. However, acute stress markedly exacerbated the attack counts of the SI mice but did not affect the group housing (GH) mice. SI mice exhibited higher synaptosomal NR2A and NR2B levels in the hippocampus as compared to the GH mice. Whole-cell patch clamp recordings of CA1 neurons in hippocampal slices showed that the SI mice exhibited a higher input-output relationship of NMDAR-EPSCs as compared to the GH mice. Application of the NR2B -specific antagonist ifenprodil produced a greater attenuating effect on NMDAR-EPSCs in slices from the SI mice. NMDAR EPSCs recorded from the SI mice had a slower deactivation kinetic. MK-801, CPP and ifenprodil, the NMDA antagonists, reversed acute stress-induced exaggeration of aggressive and depressive behaviors. Furthermore, acute stress-induced exacerbation of attack behavior in the SI mice was abolished after the knockdown of NR2B expression. These results suggest that social isolation-induced increased expression of NMDA receptors in the hippocampus involves stress exacerbation of aggressive behaviors. Amelioration of aggressive behaviors by NMDA antagonists may open a new avenue for the treatment of psychopathologies that involve outbursts of emotional aggression in neglected children.

  5. NMDA receptor is involved in neuroinflammation in intracerebroventricular colchicine-injected rats.

    PubMed

    Sil, Susmita; Ghosh, Tusharkanti; Ghosh, Rupsa

    2016-07-01

    The neurodegeneration in intracerebroventricular (icv) colchicine injected (ICIR) rats is linked with neuroinflammation. Glutamate excitotoxicity through NMDA receptors is involved with the neuroinflammation in some animal models of Alzheimer Disease (AD), but it has not been explored in ICIR rats. The aim of this study was to investigate the role of NMDA receptors (by blocking it's activity with memantine) in colchicine-induced neuroinflammation and neurodegeneration and impacts on peripheral immune parameters in ICIR rats. Levels of inflammatory markers (IL-1β, TNFα, ROS, nitrite) in the hippocampus and serum, histopathology of the hippocampus and select peripheral immune parameters were measured 14 and 21-days after icv colchicine injection in rats. These parameters were also measured in rats that received daily per os administration of memantine (20 mg/kg) in both study durations. Neuroinflammation in the hippocampus of ICIR rats was associated with neurodegeneration (chromatolysis, plaque formation), along with changes in inflammatory markers in the serum and alterations in peripheral immune parameters (phagocytic activity of WBC and splenic PMN, cytotoxic activity/leukocyte adhesion inhibition by splenic MNC). Administration of memantine to ICIR rats resulted in mitigation of colchicine-induced inflammation in the hippocampus, inflammatory markers in the serum and neurodegeneration and also led to recovery of the measured immune endpoints; most of these effects were greater with the longer duration of study. Phagocytic activity of WBC and splenic PMN cells appeared to correlate with levels of the measured central inflammatory markers. It appears from the results that neuroinflammation might be linked with the NMDA receptor activity in ICIR rats and that this receptor is involved in the process of progressive neuroinflammation and neurodegeneration in the hippocampus of ICIR and potentially in immunomodulation in these same hosts.

  6. Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

    PubMed Central

    Nagy, József; Kolok, Sándor; Boros, András; Dezső, Péter

    2005-01-01

    Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol’s action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory “upregulation” of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal. Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms, but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence. PMID:18369402

  7. Effects of Memantine, an NMDA Antagonist, on Metabolic Syndromes in Female NMRI Mice

    PubMed Central

    Osanloo, Naser; Sarahian, Nahid; Zardooz, Homeira; Sahraei, Hedayat; Sahraei, Mohammad; Sadeghi, Bahareh

    2015-01-01

    Introduction: The brain glutamate neurotransmitter system and its NMDA (N-methyl-D-aspartate) receptors in the nucleus accumbens play an important role in the incidence of sensitivity and addiction. The present study examined the inhibitory effect of glutamate NMDA receptors in the nucleus accumbens in response to chronic stress. Methods: After the unilateral and bilateral placement of cannula(e) in the nucleus accumbens, one group of the animals received different doses of intra-accumbens memantine (0.1, 0.5 and 1 μg/mouse) 5 minutes before receiving the electric shock stress at their soles (using a Communication Box) and the other group received intraperitoneal memantine (doses of 0.1, 0.5 and 1mg/kg) 30 minutes before receiving the same shock. Chronic stress increased the animals’ weight, plasma corticosterone, food and water intake, but reduced their defecation rates and eating latency. Results: The intraperitoneal administration of memantine increased plasma corticosterone, water intake, fecal weight, and eating latency, but had no effect on food intake or weight. The dose and site-dependent intra-accumbens administration of memantine either exacerbated the effects of stress on plasma corticosterone levels, water and food intake, or had no effect on these parameters. Furthermore, the administration of memantine had no effect on animal’s weight and inhibited the effects of stress on fecal weight and eating latency. Discussion: The inhibition of glutamate NMDA receptors in the nucleus accumbens can inhibit and/or exacerbate the dose and site-dependent effects of chronic stress, and gender plays a significant role in producing this effect too. PMID:26649162

  8. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis mimicking a primary psychiatric disorder in an adolescent.

    PubMed

    Lebon, Sébastien; Mayor-Dubois, Claire; Popea, Irina; Poloni, Claudia; Selvadoray, Nalini; Gumy, Alain; Roulet-Perez, Eliane

    2012-12-01

    Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis likely has a wider clinical spectrum than previously recognized. This article reports a previously healthy 16-year-old girl who was diagnosed with anti-NMDA receptor encephalitis 3 months after onset of severe depression with psychotic features. She had no neurological manifestations, and cerebral magnetic resonance imaging (MRI) was normal. Slow background on electroencephalogram and an oligoclonal band in the cerebrospinal fluid prompted the search for anti-NMDA receptor antibodies. She markedly improved over time but remained with mild neuropsychological sequelae after a trial of late immunotherapy. Only a high index of suspicion enables recognition of the milder forms of the disease masquerading as primary psychiatric disorders.

  9. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: an unusual cause of autistic regression in a toddler.

    PubMed

    Scott, Ori; Richer, Lawrence; Forbes, Karen; Sonnenberg, Lyn; Currie, Angela; Eliyashevska, Myroslava; Goez, Helly R

    2014-05-01

    Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy's cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.

  10. The NMDA receptor ‘glycine modulatory site’ in schizophrenia: d-serine, glycine, and beyond

    PubMed Central

    Balu, Darrick T; Coyle, Joseph T

    2016-01-01

    Schizophrenia is a severe psychiatric illness that is characterized by reduced cortical connectivity, for which the underlying biological and genetic causes are not well understood. Although the currently approved antipsychotic drug treatments, which primarily modulate dopaminergic function, are effective at reducing positive symptoms (i.e. delusions and hallucinations), they do little to improve the disabling cognitive and negative (i.e. anhedonia) symptoms of patients with schizophrenia. This review details the recent genetic and neurobiological findings that link N-methyl-d-aspartate receptor (NMDAR) hypofunction to the etiology of schizophrenia. It also highlights potential treatment strategies that augment NMDA receptor function to treat the synaptic deficits and cognitive impairments. PMID:25540902

  11. Synthesis of benzopolycyclic cage amines: NMDA receptor antagonist, trypanocidal and antiviral activities

    PubMed Central

    Torres, Eva; Duque, María D.; López-Querol, Marta; Taylor, Martin C.; Naesens, Lieve; Ma, Chunlong; Pinto, Lawrence H.; Sureda, Francesc X.; Kelly, John M.; Vázquez, Santiago

    2012-01-01

    The synthesis of several 6,7,8,9,10,11-hexahydro-9-methyl-5,7:9,11-dimethano-5H-benzocyclononen-7-amines is reported. Several of them display low micromolar NMDA receptor antagonist and/or trypanocidal activities. Two compounds are endowed with micromolar anti vesicular stomatitis virus activity, while only one compound shows micromolar anti-influenza activity. The anti-influenza activity of this compound does not seem to be mediated by blocking of the M2 protein. PMID:22178660

  12. Optic Neuropathy As the Initial Presenting Sign of N-methyl-d-aspartate (NMDA) Encephalitis.

    PubMed

    Mugavin, Mark; Mueller, Brett H; Desai, Masoom; Golnik, Karl C

    2017-04-01

    A 52-year-old woman presented with painless vision loss for 3 months. She was in custody for allegedly robbing a bank and had recently been diagnosed with paranoid schizophrenia. She had 20/100 VA OD, a 2+RAPD, and optic atrophy. Extensive diagnostic workup including MRI, Fluorescein Angiography, Infectious Disease Panel, lumbar puncture, and leptomeningeal biopsy were unrevealing. Vision in her right eye declined to NLP and her left eye declined to 20/200 VA. Anti N-methyl-D-aspartate (NMDA) Autoimmune Encephalitis was diagnosed based on CSF serology and clinical suspicion. Her clinical course improved as she was treated with corticosteroids and rituximab.

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

    PubMed

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

    2015-08-01

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

  14. Retinal NMDA receptor function and expression are altered in a mouse lacking d-amino acid oxidase

    PubMed Central

    Morgans, Catherine W.; Tekmen, Merve; Sullivan, Steven J.; Esguerra, Manuel; Konno, Ryuichi; Miller, Robert F.

    2013-01-01

    d-serine is present in the vertebrate retina and serves as a coagonist for the N-methyl-d-aspartate (NMDA) receptors of ganglion cells. Although the enzyme d-amino acid oxidase (DAO) has been implicated as a pathway for d-serine degradation, its role in the retina has not been established. In this study, we investigated the role of DAO in regulating d-serine levels using a mutant mouse line deficient in DAO (ddY/DAO−) and compared these results with their wild-type counterparts (ddY/DAO+). Our results show that DAO is functionally present in the mouse retina and normally serves to reduce the background levels of d-serine. The enzymatic activity of DAO was restricted to the inner plexiform layer as determined by histochemical analysis. Using capillary electrophoresis, we showed that mutant mice had much higher levels of d-serine. Whole cell recordings from identified retinal ganglion cells demonstrated that DAO-deficient animals had light-evoked synaptic activity strongly biased toward a high NMDA-to-AMPA receptor ratio. In contrast, recordings from wild-type ganglion cells showed a more balanced ratio between the two receptor subclasses. Immunostaining for AMPA and NMDA receptors was carried out to compare the two receptor ratios by quantitative immunofluorescence. These studies revealed that the mutant mouse had a significantly higher representation of NMDA receptors compared with the wild-type controls. We conclude that 1) DAO is an important regulatory enzyme and normally functions to reduce d-serine levels in the retina, and 2) d-serine levels play a role in the expression of NMDA receptors and the NMDA-to-AMPA receptor ratio. PMID:24068757

  15. Differential modulation of GABAA and NMDA receptors by α7-nicotinic receptor desensitization in cultured rat hippocampal neurons

    PubMed Central

    Shen, Lei; Cui, Wen-yu; Chen, Ru-zhu; Wang, Hai

    2016-01-01

    Aim: To explore the modulatory effect of desensitized α7-containing nicotinic receptors (α7-nAChRs) on excitatory and inhibitory amino acid receptors in cultured hippocampal neurons and to identify the mechanism underlying this effect. Methods: Whole-cell patch-clamp recordings were performed on cultured rat hippocampal neurons to measure α7-nAChR currents and to determine the role of desensitized α7-nAChRs on brain amino acid receptor activity. Results: Pulse and perfusion applications of the α7-nAChR agonist choline were applied to induce different types of α7-nAChR desensitization in cultured hippocampal neurons. After a brief choline pulse, α7-nAChR was desensitized as a result of receptor activation, which reduced the response of the A type γ-aminobutyric acid (GABAA) receptor to its agonist, muscimol, and enhanced the response of the NMDA receptor to its agonist NMDA. By contrast, the responses of glycine or AMPA receptors to their agonists, glycine or AMPA, respectively, were not affected. Pretreatment with the α7-nAChR antagonist methyllycaconitine (MLA, 10 nmol/L) blocked the choline-induced negative modulation of the GABAA receptor and the positive modulation of the NMDA receptor. The regulation of the GABAA and NMDA receptors was confirmed using another type of α7-nAChR desensitization, which was produced by a low concentration of choline perfusion. The negative modulation of the GABAA receptor was characterized by choline-duration dependency and intracellular calcium dependency, but the positive modulation of the NMDA receptor was not associated with cytoplasmic calcium. Conclusion: Brain GABAA and NMDA receptors are modulated negatively and positively, respectively, by desensitized α7-nAChR as a result of choline pretreatment in cultured hippocampal neurons. PMID:26806304

  16. NMDA and PACAP Receptor Signaling Interact to Mediate Retinal-Induced SCN Cellular Rhythmicity in the Absence of Light

    PubMed Central

    Webb, Ian C.; Coolen, Lique M.; Lehman, Michael N.

    2013-01-01

    The “core” region of the suprachiasmatic nucleus (SCN), a central clock responsible for coordinating circadian rhythms, shows a daily rhythm in phosphorylation of extracellular regulated kinase (pERK). This cellular rhythm persists under constant darkness and, despite the absence of light, is dependent upon inputs from the eye. The neural signals driving this rhythmicity remain unknown and here the roles of glutamate and PACAP are examined. First, rhythmic phosphorylation of the NR1 NMDA receptor subunit (pNR1, a marker for receptor activation) was shown to coincide with SCN core pERK, with a peak at circadian time (CT) 16. Enucleation and intraocular TTX administration attenuated the peak in the pERK and pNR1 rhythms, demonstrating that activation of the NMDA receptor and ERK in the SCN core at CT16 are dependent on retinal inputs. In contrast, ERK and NR1 phosphorylation in the SCN shell region were unaffected by these treatments. Intraventricular administration of the NMDA receptor antagonist MK-801 also attenuated the peak in SCN core pERK, indicating that ERK phosphorylation in this region requires NMDA receptor activation. As PACAP is implicated in photic entrainment and is known to modulate glutamate signaling, the effects of a PAC1 receptor antagonist (PACAP 6-38) on SCN core pERK and pNR1 also were examined. PACAP 6-38 administration attenuated SCN core pERK and pNR1, suggesting that PACAP induces pERK directly, and indirectly via a modulation of NMDA receptor signaling. Together, these data indicate that, in the absence of light, retinal-mediated NMDA and PAC1 receptor activation interact to induce cellular rhythms in the SCN core. These results highlight a novel function for glutamate and PACAP release in the hamster SCN apart from their well-known roles in the induction of photic circadian clock resetting. PMID:24098484

  17. The role of NMDA and GABAA receptors in the inhibiting effect of 3 MPa nitrogen on striatal dopamine level.

    PubMed

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

    2007-10-24

    Nitrogen pressure exposure, in rats, resulted in a decreased dopamine (DA) level by the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, due to the narcotic potency of nitrogen. In the SNc, the nigrostriatal pathway is under glutamatergic and GABAergic control mediated by ion-channel NMDA and GABA(A) receptors, main targets of volatile anesthetics. The aim of this study was to investigate the role of these receptors in the regulation of striatal dopamine level under nitrogen narcosis. Under general anesthesia, male Sprague-Dawley rats were bilaterally implanted in the striatum with dopamine-sensitive electrodes and, in the SNc, with guide cannulae for drug injections. After recovery from surgery, the striatal dopamine level was quantified using differential pulse voltammetric measurements in freely moving rats. Focal injections of agonists (NMDA/muscimol) and antagonists (AP7/gabazine) of NMDA/GABA(A) receptors were made within SNc. Both normobaric condition and 3 MPa nitrogen pressure were studied. Control experiments confirmed a direct glutamatergic control on the striatal DA level through NMDA receptors. Both direct and indirect GABAergic control through two different types of GABA(A) receptors located on GABAergic interneurons and on DA cells were indicated. Under nitrogen pressure, the decrease in dopamine level (20%) was suppressed by both NMDA and GABA(A) agonist infusion. There was an unexpected increasing DA level, induced by AP7 (about 10%) and gabazine (about 30%). These results indicate that NMDA receptors remain functional and suggest a decreased glutamate release. The findings also describe an increase of GABA(A) receptor-mediated inhibition on DA cells under nitrogen pressure exposure.

  18. 4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: a novel, potent, and selective NR1/2B NMDA receptor antagonist.

    PubMed

    Zhou, Z L; Cai, S X; Whittemore, E R; Konkoy, C S; Espitia, S A; Tran, M; Rock, D M; Coughenour, L L; Hawkinson, J E; Boxer, P A; Bigge, C F; Wise, L D; Weber, E; Woodward, R M; Keana, J F

    1999-07-29

    A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K(+) channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a approximately 25-fold increase in NR1A/2B potency (IC(50) = 0.025 microM). p-Methyl substitution on the benzyl ring (10b) produced a approximately 3-fold increase in MES activity (ED(50) = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of K(+) channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperid ine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.

  19. NMDA receptor subunits in the adult rat hippocampus undergo similar changes after 5 minutes in an open field and after LTP induction.

    PubMed

    Baez, Maria Veronica; Oberholzer, Maria Victoria; Cercato, Magali Cecilia; Snitcofsky, Marina; Aguirre, Alejandra Ines; Jerusalinsky, Diana Alicia

    2013-01-01

    NMDA receptor subunits change during development and their synaptic expression is modified rapidly after synaptic plasticity induction in hippocampal slices. However, there is scarce information on subunits expression after synaptic plasticity induction or memory acquisition, particularly in adults. GluN1, GluN2A and GluN2B NMDA receptor subunits were assessed by western blot in 1) adult rats that had explored an open field (OF) for 5 minutes, a time sufficient to induce habituation, 2) mature rat hippocampal neuron cultures depolarized by KCl and 3) hippocampal slices from adult rats where long term potentiation (LTP) was induced by theta-burst stimulation (TBS). GluN1 and GluN2A, though not GluN2B, were significantly higher 70 minutes--but not 30 minutes--after a 5 minutes session in an OF. GluN1 and GluN2A total immunofluorescence and puncta in neurites increased in cultures, as evaluated 70 minutes after KCl stimulation. Similar changes were found in hippocampal slices 70 minutes after LTP induction. To start to explore underlying mechanisms, hippocampal slices were treated either with cycloheximide (a translation inhibitor) or actinomycin D (a transcription inhibitor) during electrophysiological assays. It was corroborated that translation was necessary for LTP induction and expression. The rise in GluN1 depends on transcription and translation, while the increase in GluN2A appears to mainly depend on translation, though a contribution of some remaining transcriptional activity during actinomycin D treatment could not be rouled out. LTP effective induction was required for the subunits to increase. Although in the three models same subunits suffered modifications in the same direction, within an apparently similar temporal course, further investigation is required to reveal if they are related processes and to find out whether they are causally related with synaptic plasticity, learning and memory.

  20. Morphine-Induced Analgesic Tolerance Effect on Gene Expression of the NMDA Receptor Subunit 1 in Rat Striatum and Prefrontal Cortex

    PubMed Central

    Ahmadi, Shamseddin; Rafieenia, Fatemeh; Rostamzadeh, Jalal

    2016-01-01

    Introduction: Morphine is a potent analgesic but its continual use results in analgesic tolerance. Mechanisms of this tolerance remain to be clarified. However, changes in the functions of μ-opioid and N-Methyl-D-aspartate (NMDA) receptors have been proposed in morphine tolerance. We examined changes in gene expression of the NMDA receptor subunit 1 (NR1) at mRNA levels in rat striatum and prefrontal cortex (PFC) after induction of morphine tolerance. Methods: Morphine (10 mg/kg, IP) was injected in male Wistar rats for 7 consecutive days (intervention group), but control rats received just normal saline (1 mL/kg, IP). We used a hotplate test of analgesia to assess induction of tolerance to analgesic effects of morphine on days 1 and 8 of injections. Later, two groups of rats were sacrificed one day after 7 days of injections, their whole brains removed, and the striatum and PFC immediately dissected. Then, the NR1 gene expression was examined with a semi-quantitative RT-PCR method. Results: The results showed that long-term morphine a administration induces tolerance to analgesic effect of the opioid, as revealed by a significant decrease in morphine-induced analgesia on day 8 compared to day 1 of the injections (P<0.001). The results also showed that the NR1 gene expression at mRNA level in rats tolerant to morphine was significantly increased in the striatum (P<0.01) but decreased in the PFC (P<0.001). Conclusion: Therefore, changes in the NR1 gene expression in rat striatum and PFC have a region-specific association with morphine-induced analgesic tolerance. PMID:27563417

  1. Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission.

    PubMed

    Marcus, Monica M; Wiker, Charlotte; Frånberg, Olivia; Konradsson-Geuken, Asa; Langlois, Xavier; Jardemark, Kent; Svensson, Torgny H

    2010-08-01

    Compared to both first- and second-generation antipsychotic drugs (APDs), clozapine shows superior efficacy in treatment-resistant schizophrenia. In contrast to most APDs clozapine possesses high affinity for alpha2-adrenoceptors, and clinical and preclinical studies provide evidence that the alpha2-adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for alpha2-adrenoceptors than clozapine but higher than most other APDs. Here we examined, in rats, the effects of adding idazoxan to risperidone on antipsychotic effect using the conditioned avoidance response (CAR) test, extrapyramidal side-effect (EPS) liability using the catalepsy test, brain dopamine efflux using in-vivo microdialysis in freely moving animals, cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo alpha2A- and alpha2C-adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was approximately 0.4 mg/kg, which produced 11% and 17% in-vivo receptor occupancy at alpha2A- and alpha2C-adrenoceptors, respectively. Addition of idazoxan (1.5 mg/kg) to a low dose of risperidone (0.25 mg/kg) enhanced the suppression of CAR, but did not enhance catalepsy. Both cortical dopamine release and NMDA receptor-mediated responses were enhanced. These data propose that the therapeutic effect of risperidone in schizophrenia can be enhanced and its EPS liability reduced by adjunctive treatment with an alpha2-adrenoceptor antagonist, and generally support the notion that the potent alpha2-adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.

  2. Antidepressant-Like Effect of the Leaves of Pseudospondias microcarpa in Mice: Evidence for the Involvement of the Serotoninergic System, NMDA Receptor Complex, and Nitric Oxide Pathway

    PubMed Central

    Adongo, Donatus Wewura; Kukuia, Kennedy Kwami Edem; Mante, Priscilla Kolibea; Ameyaw, Elvis Ofori; Woode, Eric

    2015-01-01

    Depression continues to be a major global health problem. Although antidepressants are used for its treatment, efficacy is often inconsistent. Thus, the search for alternative therapeutic medicines for its treatment is still important. In this study, the antidepressant-like effect of Pseudospondias microcarpa extract (30–300 mg kg−1, p.o.) was investigated in two predictive models of depression—forced swimming test and tail suspension test in mice. Additionally, the mechanism(s) of action involved were assessed. Acute treatment with the extract dose dependently reduced immobility of mice in both models. The antidepressant-like effect of the extract (100 mg kg−1, p.o.) was blocked by p-chlorophenylalanine and cyproheptadine but not prazosin, propranolol, or yohimbine. Concomitant administration of d-cycloserine and the extract potentiated the anti-immobility effect. In contrast, d-serine, a full agonist of glycine/NMDA receptors, abolished the effects. Anti-immobility effects of PME were prevented by pretreatment of mice with L-arginine (750 mg kg−1, i.p.) and sildenafil (5 mg kg−1, i.p.). On the contrary, pretreatment of mice with L-NAME (30 mg kg−1, i.p.) or methylene blue (10 mg kg−1, i.p.) potentiated its effects. The extract produces an antidepressant-like effect in the FST and TST that is dependent on the serotoninergic system, NMDA receptor complex, and the nitric oxide pathway. PMID:26539489

  3. 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.

  4. Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology.

    PubMed

    Yang, Jianming; Hu, Dehui; Xia, Jianxun; Liu, Jianuo; Zhang, Gang; Gendelman, Howard E; Boukli, Nawal M; Xiong, Huangui

    2013-09-01

    A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSC(NMDAR). In contrast, control (untreated) MCM had limited effects on EPSC(NMDAR). Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC(NR2AR)) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC(NR2BR)) for MCM showed significant increased EPSC(NR2BR) when compared to EPSC(NR2AR) enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC(NMDAR) evoked by stronger stimulations. This suggested that increase in EPSC(NMDAR) was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (<3 kD) to medium (3-10 kD) molecular weight mediated the observed increases in EPSC(NMDAR). The link between activation of NR2BRs and HIV-1gp120 MCM for neuronal injury was demonstrated by NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.

  5. Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: Implications for HIV-1-associated neuropathology

    PubMed Central

    Yang, Jianming; Hu, Dehui; Xia, Jianxun; Liu, Jianuo; Zhang, Gang; Gendelman, Howard E.; Boukli, Nawal M.; Xiong, Huangui

    2013-01-01

    A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its ability to affact NMDAR-mediated excitatory postsynaptic currents (EPSCNMDAR) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSCNMDAR. In contrast, control (untreated) MCM had limited effects on EPSCNMDAR. Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSCNR2AR) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSCNR2BR) for MCM showed significant increased EPSCNR2BR when compared to EPSCNR2AR enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSCNMDAR evoked by stronger stimulations. This suggested that increase in EPSCNMDAR was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (<3kD) to medium (3-10kD) molecular weight mediated the observed increases in EPSCNMDAR. The link between activation of NR2BRs and HIV-1gp120 MCM for neuronal injury was demonstrated by NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs. PMID:23660833

  6. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.

    PubMed

    Carlén, M; Meletis, K; Siegle, J H; Cardin, J A; Futai, K; Vierling-Claassen, D; Rühlmann, C; Jones, S R; Deisseroth, K; Sheng, M; Moore, C I; Tsai, L-H

    2012-05-01

    Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.

  7. Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury.

    PubMed

    Shan, Yuexin; Liu, Baosong; Li, Lijun; Chang, Ning; Li, Lei; Wang, Hanbin; Wang, Dianshi; Feng, Hua; Cheung, Carol; Liao, Mingxia; Cui, Tianyuan; Sugita, Shuzo; Wan, Qi

    2009-12-01

    Dysfunction of PTEN-induced kinase-1 (PINK1) is implicated in neurodegeneration. We report here that oxygen-glucose deprivation (OGD), an in vitro insult mimicking ischemic neuron injury, resulted in a significant reduction of PINK1 protein expression in cultured cortical neurons. The decrease of PINK1 expression was blocked by the antagonists of NMDA receptors. We revealed that the overactivation of NR2B-containing NMDA receptors (NR2BRs) was responsible for the OGD-induced PINK1 reduction. The overactivated NR2BRs also inhibited the phosphorylation, but not the protein expression, of the cell survival-promoting kinase Akt after OGD insult, indicating that OGD-induced reduction of PINK1 protein is specific in the injury paradigm. We further showed that enhancing the protein expression of PINK1 antagonized OGD-induced reduction of Akt phosphorylation, suggesting that Akt may be a downstream target of PINK1 in ischemic neuron injury. Importantly, we provided evidence that both NR2BR antagonist and PINK1 over-expression protected against OGD-induced neuronal death. These results suggest that the overactivation of NR2BRs may contribute to ischemic neuron death through suppressing PINK1-dependent survival signaling. Thus, selectively antagonizing NR2BR signal pathway-induced neurotoxicity may be a potential neuroprotection strategy.

  8. 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

  9. NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production.

    PubMed

    Lesné, Sylvain; Ali, Carine; Gabriel, Cecília; Croci, Nicole; MacKenzie, Eric T; Glabe, Charles G; Plotkine, Michel; Marchand-Verrecchia, Catherine; Vivien, Denis; Buisson, Alain

    2005-10-12

    Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-beta (Abeta) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of Abeta. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-beta precursor protein (KPI-APP) followed by a shift from alpha-secretase to beta-secretase-mediated APP processing. This shift is a result of the inhibition of the alpha-secretase candidate tumor necrosis factor-alpha converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal Abeta secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase Abeta production and represent a causal risk factor for developing AD.

  10. Hypersensitivity of dopamine transmission in the rat striatum after treatment with the NMDA receptor antagonist amantadine.

    PubMed

    Peeters, Magali; Page, Guylène; Maloteaux, Jean-Marie; Hermans, Emmanuel

    2002-09-13

    Amantadine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to increase dopamine synthesis and release in the striatum, is frequently associated with L-DOPA in the treatment of Parkinson's disease. However, the biochemical mechanisms involved in the effect of amantadine and the consequences of its repetitive administration on the modulation of striatal dopamine transmission still need to be clarified. We have investigated the effects of short-term amantadine treatments on the expression of dopamine receptors and the functional coupling to G proteins in rat striatal membranes. Dopamine-induced stimulation of guanosine 5'-[gamma-35S]triphosphate ([35S]GTPgammaS) binding was significantly enhanced (40%) in striatum homogenates from rats treated for 4 days with amantadine (40 mg/kg, i.p.) compared to vehicle-treated animals. This effect was specific for dopamine receptors and was transient as no significant modifications were observed when animals were treated for either 2 or 7 days. Administration of amantadine did not directly affect the animal behaviour. However, treated animals exhibited hypersensitive dopamine transmission since rats treated for 4 days showed exacerbated responses to a single apomorphine administration (enhanced locomotor activity and reduced stereotypy). Since the effects of amantadine administration differ from those usually observed with direct dopamine receptor agonists or other NMDA receptor antagonists, we suggest that multiple biochemical mechanisms contribute to the modulation of dopamine transmission by amantadine.

  11. Molecular lock regulates binding of glycine to a primitive NMDA receptor

    PubMed Central

    Yu, Alvin; Alberstein, Robert; Thomas, Alecia; Zimmet, Austin; Grey, Richard; Mayer, Mark L.; Lau, Albert Y.

    2016-01-01

    The earliest metazoan ancestors of humans include the ctenophore Mnemiopsis leidyi. The genome of this comb jelly encodes homologs of vertebrate ionotropic glutamate receptors (iGluRs) that are distantly related to glycine-activated NMDA receptors and that bind glycine with unusually high affinity. Using ligand-binding domain (LBD) mutants for electrophysiological analysis, we demonstrate that perturbing a ctenophore-specific interdomain Arg-Glu salt bridge that is notably absent from vertebrate AMPA, kainate, and NMDA iGluRs greatly increases the rate of recovery from desensitization, while biochemical analysis reveals a large decrease in affinity for glycine. X-ray crystallographic analysis details rearrangements in the binding pocket stemming from the mutations, and molecular dynamics simulations suggest that the interdomain salt bridge acts as a steric barrier regulating ligand binding and that the free energy required to access open conformations in the glycine-bound LBD is largely responsible for differences in ligand affinity among the LBD variants. PMID:27791085

  12. 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

  13. Synthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists.

    PubMed

    Katayama, S; Ae, N; Nagata, R

    2001-05-18

    The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.

  14. NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus.

    PubMed

    Wu, Qi; Zheng, Ruimao; Srisai, Dollada; McKnight, G Stanley; Palmiter, Richard D

    2013-09-03

    Diphtheria toxin-mediated, acute ablation of hypothalamic neurons expressing agouti-related protein (AgRP) in adult mice leads to anorexia and starvation within 7 d that is caused by hyperactivity of neurons within the parabrachial nucleus (PBN). Because NMDA glutamate receptors are involved in various synaptic plasticity-based behavioral modifications, we hypothesized that modulation of the NR2A and NR2B subunits of the NMDA receptor in PBN neurons could contribute to the anorexia phenotype. We observed by Western blot analyses that ablation of AgRP neurons results in enhanced expression of NR2B along with a modest suppression of NR2A. Interestingly, systemic administration of LiCl in a critical time window before AgRP neuron ablation abolished the anorectic response. LiCl treatment suppressed NR2B levels in the PBN and ameliorated the local Fos induction that is associated with anorexia. This protective role of LiCl on feeding was blunted in vagotomized mice. Chronic infusion of RO25-6981, a selective NR2B inhibitor, into the PBN recapitulated the role of LiCl in maintaining feeding after AgRP neuron ablation. We suggest that the accumulation of NR2B subunits in the PBN contributes to aphagia in response to AgRP neuron ablation and may be involved in other forms of anorexia.

  15. PACAP modulates the consolidation and extinction of the contextual fear conditioning through NMDA receptors.

    PubMed

    Schmidt, S D; Myskiw, J C; Furini, C R G; Schmidt, B E; Cavalcante, L E; Izquierdo, I

    2015-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has a broad spectrum of biological functions including neurotransmitter, neurotrophic and neuroprotective. Moreover, it has been suggested that PACAP plays a role in the modulation of learning and memory as well as on the modulation of glutamate signaling. Thus, in the current study we investigated in the CA1 region of hippocampus and in the basolateral amygdala (BLA) the role of PACAP in the consolidation and extinction of contextual fear conditioning (CFC) and the interaction between PACAP and NMDA receptors. Male rats with cannulae implanted in the CA1 region of the hippocampus or in the BLA received immediately after the training or extinction training of the CFC infusions of the Vehicle, PACAP-38 (40 pg/side), PACAP 6-38 (40 pg/side) or PACAP 6-38 plus D-serine (50 μg/side). After 24h, the animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of hippocampus, PACAP participates in the consolidation and extinction of the CFC, and in the BLA, PACAP participates only in the consolidation of the CFC. Additionally, the results suggest that the action of PACAP on the consolidation and extinction of the CFC is mediated by the glutamate NMDA receptors.

  16. Preclinical anxiolytic profiles of 7189 and 8319, novel non-competitive NMDA antagonists

    SciTech Connect

    Dunn, R.W.; Corbett, R.; Martin, L.L.; Payack, J.F.; Laws-Ricker, L.; Wilmot, C.A.; Rush, D.K.; Cornfeldt, M.L.; Fielding, S. )

    1990-01-01

    Antagonists at excitatory amino acid receptors, especially the N-methyl-d-aspartate (NMDA) subtype, have been shown to possess anticonvulsant and anxiolytic properties. Two closely related benzeneethanamines, are potential novel anxiolytic agents which bind with high affinity to the NMDA receptor at the non-competitive site and are relatively non-toxic (LD50's-160 mg/kg, ip). 7189 and 8319 showed anxiolytic effects in schedule controlled conflict assays as well as in the social interaction (SI) and elevated plus maze (EPM) procedures in rats. Following intraperitoneal administration of 7189 at 20 to 60 mg/kg, conflict responding was increased from 2- to 7-fold in the modified Cook and Davidson and Geller conflict paradigms. 8319, at 2.5 to 5 mg/kg, produced a two fold increase in conflict responding. In the non-schedule controlled procedures, 7189 at 20 mg/kg increased SI time by 23% while in the EPM at 10 to 20 mg/kg, open arm exploration time increased by 41 to 77%. Likewise, 8319 at 2.5 and 5 mg/kg increased open arm exploration and SI time by 50 and 37%, respectively. In summary, 7189 and 8319 were efficacious in four behavioral procedures predictive of potential anxiolytic agents. Although these compounds have not been submitted for clinical evaluation, they may represent a new class of beneficial compounds for the treatment of anxiety.

  17. Hippocampal NMDA receptors are involved in rats' spontaneous object recognition only under high memory load condition.

    PubMed

    Sugita, Manami; Yamada, Kazuo; Iguchi, Natsumi; Ichitani, Yukio

    2015-10-22

    The possible involvement of hippocampal N-methyl-D-aspartate (NMDA) receptors in spontaneous object recognition was investigated in rats under different memory load conditions. We first estimated rats' object memory span using 3-5 objects in "Different Objects Task (DOT)" in order to confirm the highest memory load condition in object recognition memory. Rats were allowed to explore a field in which 3 (3-DOT), 4 (4-DOT), or 5 (5-DOT) different objects were presented. After a delay period, they were placed again in the same field in which one of the sample objects was replaced by another object, and their object exploration behavior was analyzed. Rats could differentiate the novel object from the familiar ones in 3-DOT and 4-DOT but not in 5-DOT, suggesting that rats' object memory span was about 4. Then, we examined the effects of hippocampal AP5 infusion on performance in both 2-DOT (2 different objects were used) and 4-DOT. The drug treatment before the sample phase impaired performance only in 4-DOT. These results suggest that hippocampal NMDA receptors play a critical role in spontaneous object recognition only when the memory load is high.

  18. S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke

    PubMed Central

    Shi, Zhong-Qing; Sunico, Carmen R.; McKercher, Scott R.; Cui, Jiankun; Feng, Gen-Sheng; Nakamura, Tomohiro; Lipton, Stuart A.

    2013-01-01

    Overproduction of nitric oxide (NO) can cause neuronal damage, contributing to the pathogenesis of several neurodegenerative diseases and stroke (i.e., focal cerebral ischemia). NO can mediate neurotoxic effects at least in part via protein S-nitrosylation, a reaction that covalently attaches NO to a cysteine thiol (or thiolate anion) to form an S-nitrosothiol. Recently, the tyrosine phosphatase Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) and its downstream pathways have emerged as important mediators of cell survival. Here we report that in neurons and brain tissue NO can S-nitrosylate SHP-2 at its active site cysteine, forming S-nitrosylated SHP-2 (SNO–SHP-2). We found that NMDA exposure in vitro and transient focal cerebral ischemia in vivo resulted in increased levels of SNO–SHP-2. S-Nitrosylation of SHP-2 inhibited its phosphatase activity, blocking downstream activation of the neuroprotective physiological ERK1/2 pathway, thus increasing susceptibility to NMDA receptor-mediated excitotoxicity. These findings suggest that formation of SNO–SHP-2 represents a key chemical reaction contributing to excitotoxic damage in stroke and potentially other neurological disorders. PMID:23382182

  19. NMDA-antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia.

    PubMed

    Kasischke, K; Ludolph, A C; Riepe, M W

    1996-08-23

    Glutamate antagonists mitigate hypoxic damage upon acute inhibition of energy metabolism. The goal of this study was to investigate their effect on increased hypoxic tolerance induced by preceding chemical inhibition of energy metabolism. While recovery of population spike amplitude (psap) is 30% of onset in slices prepared from control animals (15 min hypoxia, 45 min recovery), recovery exceeds 90% in slices prepared from animals that underwent mild chemical hypoxia in vivo by treatment with 20 mg/kg 3-nitropropionic acid 1 h prior to slice preparation (p-slices). In p-slices perfused for 5 min with D(-)-2-amino-5-phosphonopentanoic acid (APV) (100 microM) 45 min prior to hypoxia, recovery declines to 42 +/- 13% (mean +/- SEM). In contrast, posthypoxic recovery after similar perfusion with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) is 72 +/- 15% (P < 0.05). We conclude that increased hypoxic tolerance is abolished by N-methyl-D-aspartate (NMDA)-antagonists but not non-NMDA-antagonists.

  20. 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.

  1. Influence of vestibular input on spatial and nonspatial memory and on hippocampal NMDA receptors.

    PubMed

    Besnard, S; Machado, M L; Vignaux, G; Boulouard, M; Coquerel, A; Bouet, V; Freret, T; Denise, P; Lelong-Boulouard, V

    2012-04-01

    It has recently been shown that a lack of vestibular sensory information decreases spatial memory performance and induces biochemical changes in the hippocampus in rodents. After vestibular neurectomy, patients display spatial memory deficit and hippocampal atrophy. Our objectives were to explore: (a) spatial (Y maze, radial-arm maze), and non-spatial (object recognition) memory performance, (b) modulation of NMDA receptors within the hippocampus using radioligand binding, and (c) hippocampal atrophy, using MRI, in a rat model of bilateral labyrinthectomy realized in two operations. Chemical vestibular lesions (VLs) were induced in 24 animals by transtympanic injections of sodium arsanilate (30 mg/0.1 ml/ear), one side being lesioned 3 weeks after the other. The control group received transtympanic saline solution (0.1 ml/ear) (n = 24). Spatial memory performance (Y maze and radial maze) decreased after VL. Conversely, non-spatial memory performance (object recognition) was not affected by VL. No hippocampal atrophy was observed with MRI, but density of NMDA receptors were increased in the hippocampus after VL. These findings show that the lack of vestibular information induced specific deficits in spatial memory. Additionally, quantitative autoradiographic data suggest the involvement of the glutamatergic system in spatial memory processes related to vestibular information. When studying spatial memory performances in the presence of vestibular syndrome, two-step labyrinthectomy is a suitable procedure for distinguishing between the roles of the specific components of vestibular input loss and those of impaired locomotor activity.

  2. 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

  3. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior

    PubMed Central

    Carlén, M; Meletis, K; Siegle, J H; Cardin, J A; Futai, K; Vierling-Claassen, D; Rühlmann, C; Jones, S R; Deisseroth, K; Sheng, M; Moore, C I; Tsai, L-H

    2012-01-01

    Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors. PMID:21468034

  4. NMDA antagonist MK-801 impairs acquisition of place strategies, but not their use.

    PubMed

    Mackes, Jennifer L; Willner, Jeffrey

    2006-11-25

    Evidence that NMDA receptors contribute to synaptic plasticity in the hippocampus has stimulated research on their role in behavioral learning and memory. Recent studies indicate that NMDA antagonists decrease use of place strategies by rats in a T-maze task that can be solved using either a "place" or "response" strategy. In the present study, rats were given MK-801 before maze exposure and/or training on this redundant strategy T-maze task. MK-801 did not impair rats' ability to learn the task, but did change the strategies they used on a probe trial administered after learning. MK-801 decreased use of place strategies only when administered before both maze exposure and training; rats given MK-801 only before maze exposure or only before training tended to use place strategies on the probe trial. These results show that MK-801 does not prevent rats from utilizing previously acquired spatial information, but does appear to impair the acquisition of spatial information needed for place strategies.

  5. Role of calcium, glutamate and NMDA in major depression and therapeutic application.

    PubMed

    Deutschenbaur, Lorenz; Beck, Johannes; Kiyhankhadiv, Anna; Mühlhauser, Markus; Borgwardt, Stefan; Walter, Marc; Hasler, Gregor; Sollberger, Daniel; Lang, Undine E

    2016-01-04

    Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.

  6. Indantadol, a novel NMDA antagonist and nonselective MAO inhibitor for the potential treatment of neuropathic pain.

    PubMed

    Mattia, Consalvo; Coluzzi, Flaminia

    2007-09-01

    Indantadol is an oral and nonselective monoamine oxidase inhibitor and NMDA antagonist that is being developed by Vernalis plc, under license from Chiesi Farmaceutici SpA, for the potential treatment of neuropathic pain. In preclinical studies, indantadol exhibited neuroprotective effects after kainite-induced seizures, and displayed anticonvulsant and antihyperalgesic activity. Indantadol also caused a dose-dependent decrease in exploratory motility. In a human heat-capsaicin-induced pain model, indantadol at a dose of 500 mg effectively reduced the area of secondary hyperalgesia to 67%. Indantadol undergoes extensive liver metabolism, withthe formation of two major metabolites - CHF-3567 and 2-aminoindane. The drug is excreted in urine partially as the parent compound, but mostly as CHF-3567. The tolerability profile of indantadol at single doses up to 600 mg and twice-daily doses up to 400 mg in clinical trials was significantly more favorable than for other NMDA antagonists. Most side effects have been observed to be mild, and include dizziness and asthenia. Indantadol is currently in phase II clinical trials in patients with diabetic peripheral neuropathic pain. Given the results available to date, indantadol may have a role in the treatment of neuropathic pain if the favorable pharmacokinetic profile and efficacy of the drug are maintained in more extensive clinical trials.

  7. Molecular lock regulates binding of glycine to a primitive NMDA receptor.

    PubMed

    Yu, Alvin; Alberstein, Robert; Thomas, Alecia; Zimmet, Austin; Grey, Richard; Mayer, Mark L; Lau, Albert Y

    2016-11-01

    The earliest metazoan ancestors of humans include the ctenophore Mnemiopsis leidyi The genome of this comb jelly encodes homologs of vertebrate ionotropic glutamate receptors (iGluRs) that are distantly related to glycine-activated NMDA receptors and that bind glycine with unusually high affinity. Using ligand-binding domain (LBD) mutants for electrophysiological analysis, we demonstrate that perturbing a ctenophore-specific interdomain Arg-Glu salt bridge that is notably absent from vertebrate AMPA, kainate, and NMDA iGluRs greatly increases the rate of recovery from desensitization, while biochemical analysis reveals a large decrease in affinity for glycine. X-ray crystallographic analysis details rearrangements in the binding pocket stemming from the mutations, and molecular dynamics simulations suggest that the interdomain salt bridge acts as a steric barrier regulating ligand binding and that the free energy required to access open conformations in the glycine-bound LBD is largely responsible for differences in ligand affinity among the LBD variants.

  8. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

    PubMed

    Hammer, C; Stepniak, B; Schneider, A; Papiol, S; Tantra, M; Begemann, M; Sirén, A-L; Pardo, L A; Sperling, S; Mohd Jofrry, S; Gurvich, A; Jensen, N; Ostmeier, K; Lühder, F; Probst, C; Martens, H; Gillis, M; Saher, G; Assogna, F; Spalletta, G; Stöcker, W; Schulz, T F; Nave, K-A; Ehrenreich, H

    2014-10-01

    In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.

  9. NMDA-induced burst discharge in guinea pig trigeminal motoneurons in vitro.

    PubMed

    Kim, Y I; Chandler, S H

    1995-07-01

    1. The responses of guinea pig trigeminal motoneurons (TMNs) to N-methyl-D,L-aspartate (NMA) were studied using brain stem slice preparations and whole cell patch-clamp (n = 89) or conventional microelectrode (n = 22) recording techniques. The primary goals of this study were to determine whether N-methyl-D-aspartate (NMDA) receptor activation would produce spontaneous bursting activity in TMNs and, if so, the underlying mechanisms responsible for the generation of these bursts. 2. Bath-applied NMA (100-300 microM, n = 80) in standard perfusion medium elicited depolarization, increase in apparent input resistance (Rinp), and rhythmic burst discharges (1-90 s in duration) from TMNs. These effects were blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5, 30 microM, n = 6), but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5-10 microM, n = 10). Furthermore, the burst-inducing effect of NMA was not mimicked by the non-NMDA receptor agonists kainate (KA, 5-10 microM, n = 6) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 5-10 microM, n = 5). 3. In tetrodotoxin (TTX) treatment conditions (n = 13), NMA elicited depolarization, an increase in apparent Rinp, and rhythmic membrane potential oscillations without action potential bursts (i.e., plateau potentials), suggesting that the effects of NMA observed in the TTX-free condition resulted from activation of postsynaptic NMDA receptors. 4. Graded depolarization of neurons (n = 20) by intracellular direct current injection generally led to a graded increase in frequency and duration of the NMA-induced bursts and plateau potentials until these rhythmic events eventually became transformed into continuous spike discharge and maintained depolarization, respectively. Removal of Mg2+ from the perfusion medium (n = 11) also turned the bursts and plateau potentials into continuous spike discharge and maintained depolarization, respectively

  10. Inhibition of NMDA-gated ion channels by the P2 purinoceptor antagonists suramin and reactive blue 2 in mouse hippocampal neurones

    PubMed Central

    Peoples, Robert W; Li, Chaoying

    1998-01-01

    The action of suramin and reactive blue 2 on N-methyl-D-aspartate (NMDA)-activated ion current was studied in mouse hippocampal neurones in culture by use of whole-cell patch-clamp recording.Suramin and reactive blue 2 inhibited steady-state current activated by 25 μM NMDA with IC50 values of 68 and 11 μM, respectively.Reactive blue 2 produced a gradual decline of NMDA-activated current to a steady-state, but this slow onset was not an indication of use-dependence, as it could be eliminated by exposure to reactive blue 2 before NMDA application. In addition, NMDA-activated current recovered completely from inhibition by reactive blue 2 in the absence of agonist.The slow onset of inhibition by reactive blue 2 was not apparently due to an action at an intracellular site, as inclusion of 250 μM reactive blue 2 in the recording pipette did not alter inhibition by 25 μM reactive blue 2 applied externally.Reactive blue 2 and suramin inhibited NMDA-gated channels in a voltage-independent manner.Reactive blue 2, 25 μM, decreased the maximal response to NMDA from 1441 to 598 pA without changing its EC50. In contrast, 75 μM suramin increased the EC50 for NMDA from 13 to 35 μM, and decreased the maximal response to NMDA from 1822 to 1498 pA. Schild analysis of suramin inhibition of NMDA-activated current yielded a nonlinear plot.Both agents decreased the maximal response to glycine without altering its EC50.Suramin and reactive blue 2 appear to inhibit NMDA receptor-channels in a manner that is noncompetitive with respect to both NMDA and glycine. However, inhibition by suramin differed from that by reactive blue 2, in that suramin significantly increased the EC50 of NMDA. PMID:9641559

  11. Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism.

    PubMed

    Kiani, Reza; Lawden, Mark; Eames, Penelope; Critchley, Peter; Bhaumik, Sabyasachi; Odedra, Sunita; Gumber, Rohit

    2015-02-01

    We report anti-N-methyl-d-aspartate (NMDA) receptor encephalitis in two patients with autism and intellectual disability presenting with neuropsychiatric symptoms of catatonia and neuroleptic malignant syndrome. Case reports such as these help raise awareness of this clinical issue. By paving the way for earlier diagnoses they ultimately maximise the potential for curative treatments and prevention of long-term complications.

  12. 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

  13. GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome.

    PubMed

    Ferreira, Joana S; Schmidt, Jeannette; Rio, Pedro; Águas, Rodolfo; Rooyakkers, Amanda; Li, Ka Wan; Smit, August B; Craig, Ann Marie; Carvalho, Ana Luisa

    2015-06-03

    NMDA receptors play a central role in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the CNS. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial. We report a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic levels of AMPA receptors are increased and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor. We used quantitative proteomic analysis to identify changes in the composition of postsynaptic densities from GluN2B(-/-) mouse primary neuronal cultures and found altered levels of several ubiquitin proteasome system components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator restored the synaptic levels of AMPA receptors in GluN2B(-/-) neurons and their endocytosis, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions.

  14. Blockade of NR2B-Containing NMDA Receptors Prevents BDNF Enhancement of Glutamatergic Transmission in Hippocampal Neurons

    PubMed Central

    Crozier, Robert A.; Black, Ira B.; Plummer, Mark R.

    1999-01-01

    Application of brain-derived neurotrophic factor (BDNF) to hippocampal neurons has profound effects on glutamatergic synaptic transmission. Both pre- and postsynaptic actions have been identified that depend on the age and type of preparation. To understand the nature of this diversity, we have begun to examine the mechanisms of BDNF action in cultured dissociated embryonic hippocampal neurons. Whole-cell patch-clamp recording during iontophoretic application of glutamate revealed that BDNF doubled the amplitude of induced inward current. Coexposure to BDNF and the NMDA receptor antagonist AP-5 markedly reduced, but did not entirely prevent, the increase in current. Coexposure to BDNF and ifenprodil, an NR2B subunit antagonist, reproduced the response observed with AP-5, suggesting BDNF primarily enhanced activity of NR2B-containing NMDA receptors with a lesser effect on non-NMDA receptors. Protein kinase involvement was confirmed with the broad spectrum inhibitor staurosporine, which prevented the response to BDNF. PKCI19-31 and H-89, selective antagonists of PKC and PKA, had no effect on the response to BDNF, whereas autocamtide-2-related inhibitory peptide, an antagonist of CaM kinase II, reduced response magnitude by 60%. These results demonstrate the predominant role of a specific NMDA receptor subtype in BDNF modulation of hippocampal synaptic transmission. PMID:10492007

  15. Olfactory Bulb Glomerular NMDA Receptors Mediate Olfactory Nerve Potentiation and Odor Preference Learning in the Neonate Rat

    PubMed Central

    Harley, Carolyn W.; Yuan, Qi

    2012-01-01

    Rat pup odor preference learning follows pairing of bulbar beta-adrenoceptor activation with olfactory input. We hypothesize that NMDA receptor (NMDAR)-mediated olfactory input to mitral cells is enhanced during training, such that increased calcium facilitates and shapes the critical cAMP pattern. Here, we demonstrate, in vitro, that olfactory nerve stimulation, at sniffing frequencies, paired with beta-adrenoceptor activation, potentiates olfactory nerve-evoked mitral cell firing. This potentiation is blocked by a NMDAR antagonist and by increased inhibition. Glomerular dishinhibtion also induces NMDAR-sensitive potentiation. In vivo, in parallel, behavioral learning is prevented by glomerular infusion of an NMDAR antagonist or a GABAA receptor agonist. A glomerular GABAA receptor antagonist paired with odor can induce NMDAR-dependent learning. The NMDA GluN1 subunit is phosphorylated in odor-specific glomeruli within 5 min of training suggesting early activation, and enhanced calcium entry, during acquisition. The GluN1 subunit is down-regulated 3 h after learning; and at 24 h post-training the GluN2B subunit is down-regulated. These events may assist memory stability. Ex vivo experiments using bulbs from trained rat pups reveal an increase in the AMPA/NMDA EPSC ratio post-training, consistent with an increase in AMPA receptor insertion and/or the decrease in NMDAR subunits. These results support a model of a cAMP/NMDA interaction in generating rat pup odor preference learning. PMID:22496886

  16. Early chronic blockade of NR2B subunits and transient activation of NMDA receptors modulate LTP in mouse auditory cortex.

    PubMed

    Mao, Yuting; Zang, Shaoyun; Zhang, Jiping; Sun, Xinde

    2006-02-16

    In the auditory cortex, the properties of NMDA receptors depend primarily on the ratio of NR2A and NR2B subunits. NR2B subunit expression is high at the beginning of critical period and lower in adulthood. Because NMDA receptors are crucial in triggering long-term potentiation (LTP) and long-term depression, developmental or experience-dependent modification of NMDAR subunit composition is likely to influence synaptic plasticity. To examine how NMDA subunit change during postnatal development affect the adult synaptic plasticity, we employed chronic ifenprodil blockade of NR2B subunits and analyzed evoked field potentials in adult C57BL/6 mice auditory cortex (AC). We found that chronic loss of NR2B activity led to a decline in LTP magnitude in the AC of adult mice. Adding NMDA to the artificial cerebrospinal fluid (ACSF) in blocked mice had the opposite effect, producing LTP magnitudes at or exceeding those found in treated or untreated animals. These results suggest that, even in adulthood when NR2B expression is downregulated, these receptor subunits play an important role in experience-dependent plasticity of mouse auditory cortex. Blockade from P60 did not result in any decrease of LTP amplitude, suggesting that chronic block in postnatal period may permanently affect cortical circuits so that they cannot produce significant LTP in adulthood.

  17. [Effects of agonists and antagonists of benzodiazepine, GABA and NMDA receptors, on caffeine-induced seizures in mice].

    PubMed

    Inano, S

    1992-08-01

    In mice, tonic convulsive seizure induced by intravenous administration of caffeine (adenosine A1, A2 receptors antagonist) was significantly potentiated by any one of L-PIA (adenosine A1 receptor agonist), NECA (adenosine A2 receptor agonist) and 2-ClAd (adenosine A1, A2 receptors agonist). The caffeine-induced seizure was unaffected by diazepam (benzodiazepine receptor agonist), but was inhibited by Ro 15-1788 (antagonist or partial agonist). beta-DMCM (antagonist or inverse agonist) increased the seizure. Muscimol (GABA-a receptor agonist), baclofen (GABA-b receptor agonist) and AOAA (GABA transaminase inhibitor) did not show significant effect on caffeine-induced convulsion. Bicuculline (GABA-a receptor antagonist) and picrotoxin (chloride channel blocker) significantly potentiated the convulsion at the doses which did not induce it. Caffeine-induced convulsion was potentiated by NMDA with its non-convulsive dose. CPP (competitive NMDA receptor antagonist) and MK-801 (non-competitive NMDA receptor antagonist) significantly inhibited the seizures. These results suggest that caffeine-induced seizure is not caused by blockade of adenosine receptors. Caffeine may act to beta-carboline sensitive benzodiazepine receptor (Type 1) which has no linkage with GABA-a receptor. Furthermore, it is implied that caffeine plays some role at NMDA receptor calcium ion channel complex.

  18. Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains.

    PubMed

    Weed, Michael R; Bookbinder, Mark; Polino, Joseph; Keavy, Deborah; Cardinal, Rudolf N; Simmermacher-Mayer, Jean; Cometa, Fu-ni L; King, Dalton; Thangathirupathy, Srinivasan; Macor, John E; Bristow, Linda J

    2016-01-01

    Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

  19. NMDA Receptor- and ERK-Dependent Histone Methylation Changes in the Lateral Amygdala Bidirectionally Regulate Fear Memory Formation

    ERIC Educational Resources Information Center

    Gupta-Agarwal, Swati; Jarome, Timothy J.; Fernandez, Jordan; Lubin, Farah D.

    2014-01-01

    It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory…

  20. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex

    PubMed Central

    Lalo, U.; Palygin, O.; Verkhratsky, A.; Grant, S. G. N.; Pankratov, Y.

    2016-01-01

    Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca2+-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca2+-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity. PMID:27640997

  1. Olfactory bulb glomerular NMDA receptors mediate olfactory nerve potentiation and odor preference learning in the neonate rat.

    PubMed

    Lethbridge, Rebecca; Hou, Qinlong; Harley, Carolyn W; Yuan, Qi

    2012-01-01

    Rat pup odor preference learning follows pairing of bulbar beta-adrenoceptor activation with olfactory input. We hypothesize that NMDA receptor (NMDAR)-mediated olfactory input to mitral cells is enhanced during training, such that increased calcium facilitates and shapes the critical cAMP pattern. Here, we demonstrate, in vitro, that olfactory nerve stimulation, at sniffing frequencies, paired with beta-adrenoceptor activation, potentiates olfactory nerve-evoked mitral cell firing. This potentiation is blocked by a NMDAR antagonist and by increased inhibition. Glomerular disinhibition also induces NMDAR-sensitive potentiation. In vivo, in parallel, behavioral learning is prevented by glomerular infusion of an NMDAR antagonist or a GABA(A) receptor agonist. A glomerular GABA(A) receptor antagonist paired with odor can induce NMDAR-dependent learning. The NMDA GluN1 subunit is phosphorylated in odor-specific glomeruli within 5 min of training suggesting early activation, and enhanced calcium entry, during acquisition. The GluN1 subunit is down-regulated 3 h after learning; and at 24 h post-training the GluN2B subunit is down-regulated. These events may assist memory stability. Ex vivo experiments using bulbs from trained rat pups reveal an increase in the AMPA/NMDA EPSC ratio post-training, consistent with an increase in AMPA receptor insertion and/or the decrease in NMDAR subunits. These results support a model of a cAMP/NMDA interaction in generating rat pup odor preference learning.

  2. Role for the NR2B Subunit of the NMDA Receptor in Mediating Light Input to the Circadian System

    PubMed Central

    Wang, LM; Schroeder, A; Loh, D; Smith, D; Lin, K; Han, JH; Michel, S; Hummer, DL; Ehlen, JC; Albers, HE; Colwell, CS

    2008-01-01

    Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells that utilize glutamate as a neurotransmitter. A variety of evidence suggests that the release of glutamate then activates N-methyl-Daspartate (NMDA) receptors within the SCN and triggers a signaling cascade that ultimately leads to phase shifts in the circadian system. In this study, we first sought to explore the role of the NR2B subunit in mediating the effects of light on the circadian system. We found that localized microinjection of the NR2B subunit antagonist ifenprodil into the SCN region inhibits the magnitude of light-induced phase shifts of the circadian rhythm in wheel-running activity. Next, we found that the NR2B message and levels of phospho-NR2B levels vary with time of day in SCN tissue using semi-quantitative real-time PCR and Western blot analysis, respectively. Functionally, we found that blocking the NR2B subunit with ifenprodil significantly reduced the magnitude of NMDA currents recorded in SCN neurons. Ifenprodil also significantly reduced the magnitude of NMDA-induced calcium changes in SCN cells. Together, these results demonstrate that the NR2B subunit is an important component of NMDA receptor mediated responses within SCN neurons and that this subunit contributes to light-induced phase shifts of the mammalian circadian system. PMID:18380671

  3. Anti-NMDA Receptor Encephalitis in a Patient with Previous Psychosis and Neurological Abnormalities: A Diagnostic Challenge

    PubMed Central

    Heekin, R. David; Catalano, Maria C.; Frontera, Alfred T.; Catalano, Glenn

    2015-01-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder characterized by IgG autoantibodies directed against the NR1 subunit of the NMDA glutamate receptor. Psychiatric symptoms are common and include psychosis, mania, depressed mood, aggression, and speech abnormalities. Neurological symptoms such as seizures, decreased responsiveness, dyskinesias, and other movement abnormalities and/or autonomic instability are frequently seen as well. We present the case of a woman who was followed up at our facility for over 14 years for the treatment of multiple neuropsychiatric symptoms. Initially, she presented with paresthesias, memory loss, and manic symptoms. Nine years later, she presented to our facility again, this time with left sided numbness, left eyelid droop, and word finding difficulties. Finally, five years later, she presented with manic symptoms, hallucinations, and memory impairment. During her hospitalization, she subsequently developed catatonic symptoms and seizures. During her stay, it was discovered that she was positive for anti-NMDA receptor antibodies and her symptoms responded well to appropriate therapy. This case demonstrates that it may be useful for clinicians to consider screening for anti-NMDA receptor antibodies in long-term patients with neuropsychiatric symptoms that have not adequately responded to therapy. PMID:26199781

  4. Prenatal methamphetamine exposure induces long-lasting alterations in memory and development of NMDA receptors in the hippocampus.

    PubMed

    Šlamberová, R; Vrajová, M; Schutová, B; Mertlová, M; Macúchová, E; Nohejlová, K; Hrubá, L; Puskarčíková, J; Bubeníková-Valešová, V; Yamamotová, A

    2014-01-01

    Since close relationship was shown between drug addiction and memory formation, the aim of the present study was to investigate the effects of interaction between prenatal methamphetamine (MA) exposure and MA treatment in adulthood on spatial and non-spatial memory and on the structure of the N-methyl-D-aspartate (NMDA) receptors in the hippocampus. Adult male rats prenatally exposed to MA (5 mg/kg) or saline were tested in adulthood. Non-spatial memory was examined in the Object Recognition Test (ORT) and spatial memory in the Object Location Test (OLT) and in the Memory Retention Test (MRT) conducted in the Morris Water Maze (MWM), respectively. Based on the type of the memory test animals were injected either acutely (ORT, OLT) or long-term (MWM) with MA (1 mg/kg). After each testing, animals were sacrificed and brains were removed. The hippocampus was then examined in Western Blot analysis for occurrence of different NMDA receptors' subtypes. Our results demonstrated that prenatal MA exposure affects the development of the NMDA receptors in the hippocampus that might correspond with improvement of spatial memory tested in adulthood in the MWM. On the other hand, the effect of prenatal MA exposure on non-spatial memory examined in the ORT was the opposite. In addition, we showed that the effect of MA administration in adulthood on NMDA receptors is influenced by prenatal MA exposure, which seems to correlate with the spatial memory examined in the OLT.

  5. Understanding Neuropsychiatric Diseases, Analyzing the Peptide Sharing between Infectious Agents and the Language-Associated NMDA 2A Protein

    PubMed Central

    Lucchese, Guglielmo

    2016-01-01

    Language disorders and infections may occur together and often concur, to a different extent and via different modalities, in characterizing brain pathologies, such as schizophrenia, autism, epilepsies, bipolar disorders, frontotemporal neurodegeneration, and encephalitis, inter alia. The biological mechanism(s) that might channel language dysfunctions and infections into etiological pathways connected to neuropathologic sequelae are unclear. Searching for molecular link(s) between language disorders and infections, the present study explores the language-associated NMDA 2A subunit for peptide sharing with pathogens that have been described in concomitance with neuropsychiatric diseases. It was found that a vast peptide commonality links the human glutamate ionotropic receptor NMDA 2A subunit to infectious agents. Such a link expands to and interfaces with neuropsychiatric disorders in light of the specific allocation of NMDA 2A gene expression in brain areas related to language functions. The data hint at a possible pathologic scenario based on anti-pathogen immune responses cross-reacting with NMDA 2A in the brain. PMID:27148089

  6. Spatial Discrimination Reversal Learning in Weanling Rats Is Impaired by Striatal Administration of an NMDA-Receptor Antagonist

    ERIC Educational Resources Information Center

    Watson, Deborah J.; Stanton, Mark E.

    2009-01-01

    The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801…

  7. Homocysteine-NMDA receptor mediated activation of extracellular-signal regulated kinase leads to neuronal cell death

    PubMed Central

    Poddar, Ranjana; Paul, Surojit

    2009-01-01

    Hyper-homocysteinemia is an independent risk factor for stroke and neurological abnormalities. However the underlying cellular mechanisms by which elevated homocysteine can promote neuronal death is not clear. In the present study we have examined the role of NMDA receptor mediated activation of the extracellular-signal regulated mitogen activated protein (ERK MAP) kinase pathway in homocysteine-dependent neurotoxicity. The study demonstrates that in neurons L-homocysteine-induced cell death is mediated through activation of NMDA receptors. The study also shows that homocysteine-dependent NMDA receptor stimulation and resultant Ca2+ influx leads to rapid and sustained phosphorylation of ERK MAP kinase. Inhibition of ERK phosphorylation attenuates homocysteine mediated neuronal cell death thereby demonstrating that activation of ERK MAP kinase signaling pathway is an intermediate step that couples homocysteine mediated NMDA receptor stimulation to neuronal death. The findings also show that cAMP response-element binding protein (CREB), a pro-survival transcription factor and a downstream target of ERK, is only transiently activated following homocysteine exposure. The sustained activation of ERK but a transient activation of CREB together suggest that exposure to homocysteine initiates a feedback loop that shuts off CREB signaling without affecting ERK phosphorylation and thereby facilitates homocysteine mediated neurotoxicity. PMID:19508427

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

    PubMed

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

    2013-04-01

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

  9. Effects of NMDA administration in the substantia nigra pars compacta on the striatal dopamine release before and after repetitive exposures to nitrogen narcosis in rats.

    PubMed

    Lavoute, C; Weiss, M; Rostain, J C

    2006-01-01

    Hyperbaric nitrogen-oxygen exposure developed in rats a decrement of the striatal dopamine release, which was reversed by repetitive exposures. This dopamine decrease could be the result of the antagonistic effect of nitrogen on NMDA receptors. The increment of the dopamine release, following repetitive exposures to nitrogen, could be attributed to a desensitisation of NMDA receptors to the effects of nitrogen. To test these hypotheses, male Sprague-Dawley rats were implanted with electrodes in the striatum to measure dopamine release by voltammetry and cannula in the substantia nigra pars compacta for NMDA injection. Free-moving rats were exposed up to 3MPa of nitrogen-oxygen mixture before and after 5 exposures to 1MPa. At the first exposure to 3MPa, the dopamine level decreased (-15%) but is counteracted by NMDA administration. In contrast, after repetitive exposure, the second exposure to 3MPa, induces a 10% dopamine increase. NMDA administration significantly potentiated this increase. Our results neither support the hypothesis of an antagonist effect of nitrogen on NMDA receptors at the first exposure, nor that of a NMDA receptor desensitization following repetitive exposures to hyperbaric nitrogen.

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

    PubMed

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L; Anggono, Victor; Gether, Ulrik; Huganir, Richard L; Madsen, Kenneth L

    2013-08-27

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling. Here, we demonstrate that in somatic and dendritic regions of hippocampal neurons a large fraction of the fluorescent signal originates from intracellular pH-GluA2, and that the decline in fluorescence in response to NMDA and AMPA primarily describes an intracellular acidification, which quenches the pHluorin signal from intracellular receptor pools. Neurons expressing an endoplasmic reticulum-retained mutant of GluA2 (pH-GluA2 ΔC49) displayed a larger response to NMDA than neurons expressing wild-type pH-GluA2. A similar NMDA-elicited decline in pHluorin signal was observed by expressing cytosolic pHluorin alone without fusion to GluA2 (cyto-pHluorin). Intracellular acidification in response to NMDA was further confirmed by using the ratiometric pH indicator carboxy-SNARF-1. The NMDA-induced decline was followed by rapid recovery of the fluorescent signal from both cyto-pHluorin and pH-GluA2. The recovery was sodium-dependent and sensitive to Na(+)/H(+)-exchanger (NHE) inhibitors. Moreover, recovery was more rapid after shRNA-mediated knockdown of the GluA2 binding PDZ domain-containing protein interacting with C kinase 1 (PICK1). Interestingly, the accelerating effect of PICK1 knockdown on the fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity.

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

    PubMed

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

    2010-01-01

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

  12. N-methyl-D-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors.

    PubMed

    Fink, K; Schlicker, E; Göthert, M

    1994-02-01

    In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mumol/l or 0.032 mumol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine and the selective H2 receptor agonist dimaprit (each up to 10 mumol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.

  13. HIV-1 envelope protein gp120 potentiates NMDA-evoked noradrenaline release by a direct action at rat hippocampal and cortical noradrenergic nerve endings.

    PubMed

    Pittaluga, A; Raiteri, M

    1994-11-01

    Exposure of rat or human neocortical or hippocampal tissue to glutamate receptor agonists elicits as Ca(2+)-dependent, exocytotic-like release of previously accumulated [3H]noradrenaline through activation of both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors colocalized on the noradrenergic axon terminals. Here we show that the NMDA (100 microM)-evoked release of [3H]noradrenaline from superfused thin layers of isolated rat hippocampal or cortical nerve endings was potentiated when the human immunodeficiency virus type 1 coat protein gp120 was added to the superfusion medium concomitantly with NMDA. The effect of gp120 (10 pM to 3 nM) on the 100 microM NMDA-evoked release of [3H]noradrenaline was concentration-dependent; the maximal effect (approximately 140% potentiation) was reached at 100 pM of gp120. The protein was inactive on its own. The [3H]noradrenaline release evoked by NMDA (100 microM)+gp120 (100 pM) was prevented by classical NMDA receptor antagonists, as well as by 10 microM memantine. Neither the release evoked by NMDA nor that elicited by NMDA+gp120 was sensitive to the nitric oxide synthase inhibitor NG-nitro-L-arginine, suggesting no involvement of nitric oxide. The [3H]noradrenaline release elicited by 100 microM AMPA was unaffected by gp120. The protein potentiated the release evoked by 100 microM glutamate; the effect of 100 pM gp120 was quantitatively identical to that of 1 microM glycine, with no apparent additivity between gp120 and glycine. The antagonism by 1 microM 7-chloro-kynurenic acid of the NMDA-induced [3H]noradrenaline release was reversed by glycine or gp120.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Cannabinoid Receptor Activation Modifies NMDA Receptor Mediated Release of Intracellular Calcium: Implications for Endocannabinoid Control of Hippocampal Neural Plasticity

    PubMed Central

    Hampson, Robert E.; Miller, Frances; Palchik, Guillermo; Deadwyler, Sam A.

    2011-01-01

    Chronic activation or inhibition of cannabinoid receptors (CB1) leads to continuous suppression of neuronal plasticity in hippocampus and other brain regions, suggesting that endocannabinoids may have a functional role in synaptic processes that produce state-dependent transient modulation of hippocampal cell activity. In support of this, it has previously been shown in vitro that cannabinoid CB1 receptors modulate second messenger systems in hippocampal neurons that can modulate intracellular ion channels, including channels which release calcium from intracellular stores. Here we demonstrate in hippocampal slices a similar endocannabinoid action on excitatory glutamatergic synapses via modulation of NMDA-receptor mediated intracellular calcium levels in confocal imaged neurons. Calcium entry through glutamatergic NMDA-mediated ion channels increases intracellular calcium concentrations via modulation of release from ryanodine-sensitive channels in endoplasmic reticulum. The studies reported here show that NMDA-elicited increases in Calcium Green fluorescence are enhanced by CB1 receptor antagonists (i.e. rimonabant), and inhibited by CB1 agonists (i.e. WIN 55,212-2). Suppression of endocannabinoid breakdown by either reuptake inhibition (AM404) or fatty-acid amide hydrolase inhibition (URB597) produced suppression of NMDA elicited calcium increases comparable to WIN 55,212-2, while enhancement of calcium release provoked by endocannabinoid receptor antagonists (Rimonabant) was shown to depend on the blockade of CB1 receptor mediated de-phosphorylation of Ryanodine receptors. Such CB1 receptor modulation of NMDA elicited increases in intracellular calcium may account for the respective disruption and enhancement by CB1 agents of trial-specific hippocampal neuron ensemble firing patterns during performance of a short-term memory task, reported previously from this laboratory. PMID:21288475

  15. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD.

    PubMed

    He, Qionger; Titley, Heather; Grasselli, Giorgio; Piochon, Claire; Hansel, Christian

    2013-03-01

    Ethanol profoundly influences cerebellar circuit function and motor control. It has recently been demonstrated that functional N-methyl-(D)-aspartate (NMDA) receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in the adult cerebellum. Using whole cell patch-clamp recordings from mouse cerebellar slices, we examined whether ethanol can affect NMDA receptor signaling in mature Purkinje cells. NMDA receptor-mediated currents were isolated by bath application of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol[f]quinoxaline (NBQX). The remaining (D)-2-amino-5-phosphonovaleric acid ((D)-APV)-sensitive current was reduced by ethanol at concentrations as low as 10 mM. At a concentration of 50 mM ethanol, the blockade of (D)-APV-sensitive CF-excitatory postsynaptic currents was significantly stronger. Ethanol also altered the waveform of CF-evoked complex spikes by reducing the afterdepolarization. This effect was not seen when NMDA receptors were blocked by (D)-APV before ethanol wash-in. In contrast to CF synaptic transmission, parallel fiber (PF) synaptic inputs were not affected by ethanol. Finally, ethanol (10 mM) impaired long-term depression (LTD) at PF to Purkinje cell synapses as induced under control conditions by paired PF and CF activity. However, LTD induced by pairing PF stimulation with depolarizing voltage steps (substituting for CF activation) was not blocked by ethanol. These observations suggest that the sensitivity of cerebellar circuit function and plasticity to low concentrations of ethanol may be caused by an ethanol-mediated impairment of NMDA receptor signaling at CF synapses onto cerebellar Purkinje cells.

  16. 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.

  17. 5-HT(1A) and NMDA receptors interact in the rat medial septum and modulate hippocampal-dependent spatial learning.

    PubMed

    Elvander-Tottie, Elin; Eriksson, Therese M; Sandin, Johan; Ogren, Sven Ove

    2009-12-01

    Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT(1A) receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT(1A) receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT(1A) receptor agonist (R)-8-OH-DPAT (1 or 4 microg/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 microg/rat). While intraseptal administration of (R)-8-OH-DPAT (4 microg) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 microg) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT(1A) receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT(1A) and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT(1A) receptor activation on memory, which may be clinically relevant.

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

    PubMed

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

    2017-03-01

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

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

    PubMed

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

    2013-01-10

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

  20. Assessment.

    ERIC Educational Resources Information Center

    Reising, Bob

    1998-01-01

    Argues (guided by "The Challenge of Change: Assessment in the 21st Century") that in the decades ahead, assessment will play an unprecedented role as the vehicle that will influence and guide scheduling, curriculum, and instruction. (SR)

  1. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory.

    PubMed

    Korotkova, Tatiana; Fuchs, Elke C; Ponomarenko, Alexey; von Engelhardt, Jakob; Monyer, Hannah

    2010-11-04

    Activity of parvalbumin-positive hippocampal interneurons is critical for network synchronization but the receptors involved therein have remained largely unknown. Here we report network and behavioral deficits in mice with selective ablation of NMDA receptors in parvalbumin-positive interneurons (NR1(PVCre-/-)). Recordings of local field potentials and unitary neuronal activity in the hippocampal CA1 area revealed altered theta oscillations (5-10 Hz) in freely behaving NR1(PVCre-/-) mice. Moreover, in contrast to controls, in NR1(PVCre-/-) mice the remaining theta rhythm was abolished by the administration of atropine. Gamma oscillations (35-85 Hz) were increased and less modulated by the concurrent theta rhythm in the mutant. Positional firing of pyramidal cells in NR1(PVCre-/-) mice was less spatially and temporally precise. Finally, NR1(PVCre-/-) mice exhibited impaired spatial working as well as spatial short- and long-term recognition memory but showed no deficits in open field exploratory activity and spatial reference learning.

  2. Postsynaptic, not presynaptic NMDA receptors are required for spike timing dependent LTD induction

    PubMed Central

    Carter, Brett C.; Jahr, Craig E.

    2016-01-01

    Long-term depression (LTD) between cortical layer 4 spiny stellate cells and layer 2/3 pyramidal cells requires the activation of NMDA receptors (NMDARs). In young rodents, this form of LTD has been repeatedly reported to require presynaptic NMDARs for its induction. Here we show that at this synapse in the somatosensory cortex of 2 to 3 week old rats and mice, postsynaptic, not presynaptic NMDARs are required for LTD induction. First, we find no evidence for functional NMDARs in L4 neuron axons using 2 photon laser scanning microscopy and 2 photon glutamate uncaging. Second, we find that genetic deletion of postsynaptic, but not presynaptic NMDARs prevents LTD induction. Finally, the pharmacology of the NMDAR requirement is consistent with a non-ionic signaling mechanism. PMID:27399842

  3. Distinct NMDA receptors provide differential modes of transmission at mossy fiber-interneuron synapses.

    PubMed

    Lei, Saobo; McBain, Chris J

    2002-03-14

    Dentate gyrus granule cells innervate inhibitory interneurons via a continuum of synapses comprised of either Ca(2+)-impermeable (CI) or Ca(2+)-permeable (CP) AMPA receptors. Synapses at the extreme ends of this continuum engage distinct postsynaptic responses, with activity at CI synapses being strongly influenced by NMDA receptor activation. NMDARs at CI synapses have a lower NR2B subunit composition and a higher open probability, which generate larger amplitude and more rapid EPSCs than their CP counterparts. A novel form of NMDAR-dependent long-term depression (iLTD) is associated with CI-mossy fiber synapses, whereas iLTD at CP synapses is dependent on Ca(2+)-permeable AMPA receptor activation. Induction of both forms of iLTD required elevation of postsynaptic calcium. Thus mossy fibers engage CA3 interneurons via multiple synapse types that will act to expand the computational repertoire of the mossy fiber-CA3 network.

  4. Stereotyped initiation of retinal waves by bipolar cells via presynaptic NMDA autoreceptors

    PubMed Central

    Zhang, Rong-wei; Li, Xiao-quan; Kawakami, Koichi; Du, Jiu-lin

    2016-01-01

    Glutamatergic retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. However, its initiation and underlying mechanism remain largely elusive. Here using larval zebrafish and multiple in vivo approaches, we discover that bipolar cells (BCs) are responsible for the generation of glutamatergic retinal waves. The wave originates from BC axon terminals (ATs) and propagates laterally to nearby BCs and vertically to downstream RGCs and the optic tectum. Its initiation is triggered by the activation of and consequent glutamate release from BC ATs, and is mediated by the N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) expressed at these ATs. Intercellular asymmetry of NMDAR expression at BC ATs enables the preferential initiation of waves at the temporal retina, where BC ATs express more NMDARs. Thus, our findings indicate that glutamatergic retinal waves are initiated by BCs through a presynaptic NMDA autoreceptor-dependent process. PMID:27586999

  5. Role of NMDA Receptors in Dopamine Neurons for Plasticity and Addictive Behaviors

    PubMed Central

    Zweifel, Larry S.; Argilli, Emanuela; Bonci, Antonello; Palmiter, Richard D.

    2008-01-01

    Summary A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors. PMID:18701073

  6. The impact of NMDA Receptor hypofunction on GABAergic interneurons in the pathophysiology of schizophrenia

    PubMed Central

    Cohen, Samuel M.; Tsien, Richard W.; Goff, Donald C.; Halassa, Michael M.

    2016-01-01

    While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-D-aspartate receptor (NMDAR) function. By highlighting post mortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics. PMID:25583246

  7. Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System.

    PubMed

    Mapelli, Lisa; Gagliano, Giuseppe; Soda, Teresa; Laforenza, Umberto; Moccia, Francesco; D'Angelo, Egidio U

    2017-02-01

    Neurovascular coupling (NVC) is the process whereby neuronal activity controls blood vessel diameter. In the cerebellum, the molecular layer is regarded as the main NVC determinant. However, the granular layer is a region with variable metabolic demand caused by large activity fluctuations that shows a prominent expression of NMDA receptors (NMDARs) and nitric oxide synthase (NOS) and is therefore much more suitable for effective NVC. Here, we show, in the granular layer of acute rat cerebellar slices, that capillary diameter changes rapidly after mossy fiber stimulation. Vasodilation required neuronal NMDARs and NOS stimulation and subsequent guanylyl cyclase activation that probably occurred in pericytes. Vasoconstriction required metabotropic glutamate receptors and CYP ω-hydroxylase, the enzyme regulating 20-hydroxyeicosatetraenoic acid production. Therefore, granular layer capillaries are controlled by the balance between vasodilating and vasoconstricting systems that could finely tune local blood flow depending on neuronal activity changes at the cerebellar input stage.

  8. Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus

    PubMed Central

    Dinamarca, Margarita C; Guzzetti, Francesca; Karpova, Anna; Lim, Dmitry; Mitro, Nico; Musardo, Stefano; Mellone, Manuela; Marcello, Elena; Stanic, Jennifer; Samaddar, Tanmoy; Burguière, Adeline; Caldarelli, Antonio; Genazzani, Armando A; Perroy, Julie; Fagni, Laurent; Canonico, Pier Luigi; Kreutz, Michael R; Gardoni, Fabrizio; Luca, Monica Di

    2016-01-01

    Synapses and nuclei are connected by bidirectional communication mechanisms that enable information transfer encoded by macromolecules. Here, we identified RNF10 as a novel synaptonuclear protein messenger. RNF10 is activated by calcium signals at the postsynaptic compartment and elicits discrete changes at the transcriptional level. RNF10 is enriched at the excitatory synapse where it associates with the GluN2A subunit of NMDA receptors (NMDARs). Activation of synaptic GluN2A-containing NMDARs and induction of long term potentiation (LTP) lead to the translocation of RNF10 from dendritic segments and dendritic spines to the nucleus. In particular, we provide evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. Notably, RNF10 silencing prevents the maintenance of LTP as well as LTP-dependent structural modifications of dendritic spines. DOI: http://dx.doi.org/10.7554/eLife.12430.001 PMID:26977767

  9. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience.

    PubMed

    Nakazawa, Kazu; Sun, Linus D; Quirk, Michael C; Rondi-Reig, Laure; Wilson, Matthew A; Tonegawa, Susumu

    2003-04-24

    Lesion and pharmacological intervention studies have suggested that in both human patients and animals the hippocampus plays a