Journal articles on the topic 'NMDA'
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Reyes Monreal, Marleni, María Eugenia Pérez Bonilla, Jessica Quintero Pérez, Arturo Reyes Lazalde, and Jorge Flores Hernández. "Lab-NMDAR: simuladores de la electrofisiología básica del receptor NMDA." Acta Universitaria 32 (November 23, 2022): 1–23. http://dx.doi.org/10.15174/au.2022.3597.
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Es necesario el desarrollo de software educativo que permita la implementación de prácticas de laboratorio. En este trabajo se presenta el diseño y desarrollo del programa Lab-NMDAR, constituido por tres simuladores para la enseñanza-aprendizaje de la electrofisiología del receptor NMDA: (1) simulador NMDAR-Bloqueo Mg2+, (2) simulador NMDAR-Glicina y (3) simulador canal único NMDA-Bloqueo Mg2+. El programa se implementó en Visual Basic® para ambiente Windows®. Con estos simuladores el alumno conoce la corriente NMDA, reproduce su dependencia del voltaje, simula su bloqueo por magnesio en registros de corriente macroscópica y en canal único, determina la participación de NMDA y glicina en la activación del receptor NMDA y produce experimentos virtuales dosis-respuesta. El programa es de fácil manejo, se ejecuta en una computadora personal con el mínimo de recursos.
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Wang, Ning, Linlin Chen, Nan Cheng, Jingyun Zhang, Tian Tian, and Wei Lu. "Active Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Regulates NMDA Receptor Mediated Postischemic Long-Term Potentiation (i-LTP) by Promoting the Interaction between CaMKII and NMDA Receptors in Ischemia." Neural Plasticity 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/827161.
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Active calcium/calmodulin-dependent protein kinase II (CaMKII) has been reported to take a critical role in the induction of long-term potentiation (LTP). Changes in CaMKII activity were detected in various ischemia models. It is tempting to know whether and how CaMKII takes a role in NMDA receptor (NMDAR)-mediated postischemic long-term potentiation (NMDA i-LTP). Here, we monitored changes in NMDAR-mediated field excitatory postsynaptic potentials (NMDA fEPSPs) at different time points following ischemia onsetin vitrooxygen and glucose deprivation (OGD) ischemia model. We found that 10 min OGD treatment induced significant i-LTP in NMDA fEPSPs, whereas shorter (3 min) or longer (25 min) OGD treatment failed to induce prominent NMDA i-LTP. CaMKII activity or CaMKII autophosphorylation displays a similar bifurcated trend at different time points following onset of ischemia bothin vitroOGD orin vivophotothrombotic lesion (PT) models, suggesting a correlation of increased CaMKII activity or CaMKII autophosphorylation with NMDA i-LTP. Disturbing the association between CaMKII and GluN2B subunit of NMDARs with short cell-permeable peptides Tat-GluN2B reversed NMDA i-LTP induced by OGD treatment. The results provide support to a notion that increased interaction between NMDAR and CaMKII following ischemia-induced increased CaMKII activity and autophosphorylation is essential for induction of NMDA i-LTP.
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Chisari, Mariangela, Charles F. Zorumski, and Steven Mennerick. "Cross talk between synaptic receptors mediates NMDA-induced suppression of inhibition." Journal of Neurophysiology 107, no. 9 (May 1, 2012): 2532–40. http://dx.doi.org/10.1152/jn.01145.2011.
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Past research has shown that calcium influx through NMDA receptors (NMDARs) depresses GABAA currents. We examined upstream triggers of this suppression, including involvement of target synaptic GABAA receptors and the NMDARs triggering suppression. In hippocampal neurons, conditioning with 20 μM NMDA for 20 s caused 50% suppression of GABA responses. The suppression was delayed by ∼60 s following NMDA application and persisted for at least 5 min following conditioning. Pharmacology experiments suggested a shift in both the sensitivity to GABA and a loss of functional receptors. NMDA conditioning strongly suppressed inhibitory postsynaptic currents and speeded decay kinetics. Synaptic NMDAR conditioning was necessary to suppress GABA current in pyramidal neurons; extrasynaptic NMDAR activation did not suppress, even when matched to synaptic activation. We found no evidence that specific synaptic NMDAR subunits mediate depression of GABA responses. Although physical colocalization of glutamate and GABAA receptors is mostly likely in extrasynaptic regions, our evidence suggests that NMDAR-induced suppression of GABA responsiveness prominently affects precise, moment-to-moment signaling from synaptic receptors to synaptic receptors.
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Fiorentini, C., and C. Missale. "Oligomeric assembly of dopamine D1 and glutamate NMDA receptors: molecular mechanisms and functional implications." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 1025–28. http://dx.doi.org/10.1042/bst0321025.
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In the striatum, dopamine D1R (D1 receptor) activation potentiates NMDA (N-methyl-D-aspartate) transmission and is required for NMDA-mediated long-term potentiation at corticostriatal synapses. By using a combination of co-immunoprecipitation, pull-out with glutathione S-transferase-fusion proteins and bioluminescence resonance energy transfer, we have reported that the D1R forms a heteromeric complex with the NMDAR (NMDA receptor) and that this mechanism is crucial to recruit the D1R to the postsynaptic density. By using confocal and radioligand-binding assay, we also demonstrated that the interaction with NMDAR abolishes agonist-mediated D1R sequestration, indicating that oligomerization with NMDAR could represent a novel regulatory mechanism modulating D1R cellular trafficking and desensitization.
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Arvanian, Victor L., and Lorne M. Mendell. "Removal of NMDA Receptor Mg2+ Block Extends the Action of NT-3 on Synaptic Transmission in Neonatal Rat Motoneurons." Journal of Neurophysiology 86, no. 1 (July 1, 2001): 123–29. http://dx.doi.org/10.1152/jn.2001.86.1.123.
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NT-3 has previously been reported to enhance AMPA/kainate receptor-mediated synaptic responses in motoneurons via an effect on the N-methyl-d-aspartate (NMDA) receptor. To investigate neurotrophin-3 (NT-3) action further, we measured the NMDA receptor (NMDAR)-mediated synaptic response directly by intracellular recording in motoneurons after blocking AMPA/kainate, GABAA, GABAB and glycine receptor-mediated responses pharmacologically. Two pathways were stimulated, the segmental dorsal root (DR) and the descending ventrolateral fasciculus (VLF). The DR-evoked NMDAR-mediated response in motoneurons of rats younger than 1 wk has two components, the initial one of which is generated monosynaptically. NT-3 strongly potentiated both NMDA components in a rapidly reversible manner. No NMDAR-mediated responses were present at VLF connections and at DR connections in older (1- to 2-wk-old) neonates. Bath-applied NT-3–induced potentiation of the AMPA/kainate receptor-mediated response occurred only at connections that exhibit a synaptic NMDA receptor-mediated response. Reducing Mg2+concentration in the bathing solution restored the NMDAR-mediated response elicited by DR stimulation in older neonates and by VLF throughout the neonatal period (0–2 wk). In low-Mg2+, NT-3 enhanced AMPA/kainate receptor-mediated responses elicited by inputs normally not influenced by NT-3. Thus a major reason for the loss of NT-3 action on AMPA/kainate synaptic responses is the reduced activity of the NMDA receptor due to developing Mg2+ block of NMDA receptor-channel complex as the animal matures, and both can be re-established by reducing Mg2+ concentration in fluid bathing the spinal cord.
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Rivas-Santisteban, Rafael, Iu Raïch, David Aguinaga, Carlos A. Saura, Rafael Franco, and Gemma Navarro. "The Expression of Cellular Prion Protein, PrPC, Favors pTau Propagation and Blocks NMDAR Signaling in Primary Cortical Neurons." Cells 12, no. 2 (January 11, 2023): 283. http://dx.doi.org/10.3390/cells12020283.
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Background: The N-methyl-D-aspartate receptor (NMDAR) is a target in current treatments for Alzheimer’s disease (AD). The human prion protein (PrPC) has an important role in the pathophysiology of AD. We hypothesized that PrPC modulates NMDA signaling, thus being a process associated with Alzheimer’s disease. Methods: NMDAR signaling was characterized in the absence or presence of PrPC in cAMP level determination, mitogen-activated protein kinase (MAPK) pathway and label-free assays in homologous and heterologous systems. Bioluminescence resonance energy transfer was used to detect the formation of NMDAR-PrPC complexes. AXIS™ Axon Isolation Devices were used to determine axonal transport of Tau and pTau proteins in cortical primary neurons in the absence or presence of PrPC. Finally, proximity ligation assays were used to quantify NMDA-PrPC complex formation in neuronal primary cultures isolated from APPSw/Ind transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). Results: We discovered a direct interaction between the PrPC and the NMDAR and we found a negative modulation of NMDAR-mediated signaling due to the NMDAR-PrPC interaction. In mice primary neurons, we identified NMDA-PrPC complexes where PrPC was capable of blocking NMDAR-mediated effects. In addition, we observed how the presence of PrPC results in increased neurotoxicity and neuronal death. Similarly, in microglial primary cultures, we observed that PrPC caused a blockade of the NMDA receptor link to the MAPK signaling cascade. Interestingly, a significant increase in NMDA-PrPC macromolecular complexes was observed in cortical neurons isolated from the APPSw,Ind transgenic model of AD. Conclusions: PrPC can interact with the NMDAR, and the interaction results in the alteration of the receptor functionality. NMDAR-PrPC complexes are overexpressed in neurons of APPSw/Ind mouse brain. In addition, PrPC exacerbates axonal transport of Tau and pTau proteins.
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Xue, Jiu-Gang, Takayoshi Masuoka, Xian-Di Gong, Ken-Shiung Chen, Yuchio Yanagawa, S. K. Alex Law, and Shiro Konishi. "NMDA receptor activation enhances inhibitory GABAergic transmission onto hippocampal pyramidal neurons via presynaptic and postsynaptic mechanisms." Journal of Neurophysiology 105, no. 6 (June 2011): 2897–906. http://dx.doi.org/10.1152/jn.00287.2010.
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N-methyl-d-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABAA receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.
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Hada, Binika, Mrigendra Bir Karmacharya, So R. Park, and Byung H. Choi. "Low-Intensity Ultrasound Decreases Ischemia-Induced Edema by Inhibiting N-Methyl-d-Aspartic Acid Receptors." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, no. 6 (November 2018): 675–81. http://dx.doi.org/10.1017/cjn.2018.331.
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AbstractBackground: We have previously shown that low-intensity ultrasound (LIUS), a noninvasive mechanical stimulus, inhibits brain edema formation induced by oxygen and glucose deprivation (OGD) or treatment with glutamate, a mediator of OGD-induced edema, in acute rat hippocampal slice model in vitro. Methods: In this study, we treated the rat hippocampal slices with N-methyl-d-aspartic acid (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) to determine whether these different glutamate receptor agonists induce edema. The hippocampal slices were then either sonicated with LIUS or treated with N-methyl-d-aspartic acid receptor (NMDAR) antagonists, namely, MK-801 and ketamine, and observed their effects on edema formation. Results: We observed that treatment with NMDA, an agonist of ionotropic glutamate receptors, induced brain edema at similar degrees compared with that induced by OGD. However, treatment with DHPG, an agonist of metabotropic glutamate receptors, did not significantly induce brain edema. Treatment with the NMDAR antagonists MK-801 or ketamine efficiently prevented brain edema formation by both OGD and NMDA in a concentration-dependent manner. N-Methyl-d-aspartic acid-induced brain edema was alleviated by LIUS in an intensity-dependent manner when ultrasound was administered at 30, 50, or 100 mW/cm2 for 20 minutes before the induction of the edema. Furthermore, LIUS reduced OGD- and NMDA-induced phosphorylation of NMDARs at Y1325. Conclusion: These results suggest that LIUS can inhibit OGD- or NMDA-induced NMDAR activation by preventing NMDAR phosphorylation, thereby reducing a subsequent brain edema formation. The mechanisms by which LIUS inhibits NMDAR phosphorylation need further investigation.
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Myme, Chaelon I. O., Ken Sugino, Gina G. Turrigiano, and Sacha B. Nelson. "The NMDA-to-AMPA Ratio at Synapses Onto Layer 2/3 Pyramidal Neurons Is Conserved Across Prefrontal and Visual Cortices." Journal of Neurophysiology 90, no. 2 (August 2003): 771–79. http://dx.doi.org/10.1152/jn.00070.2003.
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To better understand regulation of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complements across the cortex, and to investigate NMDA receptor (NMDAR)-based models of persistent activity, we compared NMDA/AMPA ratios in prefrontal (PFC) and visual cortex (VC) in rat. Whole cell voltage-clamp responses were recorded in brain slices from layer 2/3 pyramidal cells of the medial PFC and VC of rats aged p16–p21. Mixed miniature excitatory postsynaptic currents (mEPSCs) having AMPA receptor (AMPAR)- and NMDAR-mediated components were isolated in nominally 0 Mg2+ ACSF. Averaged mEPSCs were well-fit by double exponentials. No significant differences in the NMDA/AMPA ratio (PFC: 27 ± 1%; VC: 28 ± 3%), peak mEPSC amplitude (PFC: 19.1 ± 1 pA; VC: 17.5 ± 0.7 pA), NMDAR decay kinetics (PFC: 69 ± 8 ms; VC: 67 ± 6 ms), or degree of correlation between NMDAR- and AMPAR-mediated mEPSC components were found between the areas (PFC: n = 27; VC: n = 28). Recordings from older rats (p26–29) also showed no differences. EPSCs were evoked extracellularly in 2 mM Mg2+ at depolarized potentials; although the average NMDA/AMPA ratio was larger than that observed for mEPSCs, the ratio was similar in the two regions. In nominally 0 Mg2+ and in the presence of CNQX, spontaneous activation of NMDAR increased recording noise and produced a small tonic depolarization which was similar in both areas. We conclude that this basic property of excitatory transmission is conserved across PFC and VC synapses and is therefore unlikely to contribute to differences in firing patterns observed in vivo in the two regions.
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Parisi, Eva, Yolanda Almadén, Mercé Ibarz, Sara Panizo, Anna Cardús, Mariano Rodriguez, Elvira Fernandez, and Jose M. Valdivielso. "N-methyl-d-aspartate receptors are expressed in rat parathyroid gland and regulate PTH secretion." American Journal of Physiology-Renal Physiology 296, no. 6 (June 2009): F1291—F1296. http://dx.doi.org/10.1152/ajprenal.90557.2008.
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N-methyl-d-aspartate receptors (NMDAR) are tetrameric amino acid receptors which act as membrane calcium channels. The presence of the receptor has been detected in the principal organs responsible for calcium homeostasis (kidney and bone), pointing to a possible role in mineral metabolism. In the present work, the presence of the receptor was determined in normal parathyroid glands (PTG) by real-time PCR, immunoprecipitation, and immunohistrochemistry. Healthy animals showed a decrease in blood parathyroid hormone (PTH) levels 15 min after the treatment with NMDA. This effect was also observed in animals with high levels of PTH-induced EDTA injection, but not in uremic animals with secondary hyperparathyroidism (2HPT). Normal rat PTG incubated in media with low calcium concentration (0.8 mM CaCl2) showed a decrease in PTH release when NMDA was added to the media. This effect of NMDA was abolished when glands were coincubated with MK801 (a pharmacological blocker of the NMDA channel) or PD98059 (an inhibitor of the ERK-MAPK pathway). Glands obtained from animals with 2HPT showed no effect of NMDA in the in vitro release of PTH, together with a decrease in the expression of NMDAR1. In conclusion, NMDA receptor is present in PTG and is involved in the regulation of the PTH release. The mechanism by which NMDAR exerts its function is through the activation of the MAPK cascade. In uremic 2HPT animals the receptor expression is downregulated and the treatment with NMDA does not affect PTH secretion.
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Finke, Carsten, Annerose Mengel, Harald Prüss, Winfried Stöcker, Andreas Meisel, and Klemens Ruprecht. "Anti-NMDAR encephalitis mimicking HaNDL syndrome." Cephalalgia 34, no. 12 (March 11, 2014): 1012–14. http://dx.doi.org/10.1177/0333102414526070.
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Background Anti-NMDA receptor encephalitis typically manifests as severe multistage neuropsychiatric syndrome. However, milder or incomplete forms of the disorder have been recognised. Here, we report on a patient with anti-NMDA receptor encephalitis with a clinical phenotype mimicking the syndrome of headache with neurological deficits and cerebrospinal fluid (CSF) lymphocytosis (HaNDL). Case A 67-year-old man presented with recurrent stereotyped episodes of hemianopia, aphasia and right hemiparesis accompanied by throbbing headaches as well as confusion and agitation. CSF analysis showed lymphocytic pleocytosis. Additional analysis revealed NMDA receptor IgG antibodies in the patient’s CSF. Following immunotherapy, no further episodes occurred and NMDAR antibodies became undetectable. No NMDAR or other neuronal antibodies were detected in archived serum and CSF samples of 12 HaNDL patients fulfilling the current diagnostic criteria. Conclusions While anti-NMDAR encephalitis can manifest with a HaNDL-like clinical picture, HaNDL syndrome itself does not appear to be mediated by anti-NMDAR antibodies.
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Li, Yan, Boris Krupa, Jian-Sheng Kang, Vadim Y. Bolshakov, and Guosong Liu. "Glycine Site of NMDA Receptor Serves as a Spatiotemporal Detector of Synaptic Activity Patterns." Journal of Neurophysiology 102, no. 1 (July 2009): 578–89. http://dx.doi.org/10.1152/jn.91342.2008.
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Calcium influx associated with the opening of N-methyl-d-aspartate (NMDA) receptor channels is the major signal triggering synaptic and developmental plasticity. Controlling the NMDA receptor function is therefore critical for many functions of the brain. We explored the mechanisms of synaptic activation of the NMDAR glycine site by endogenous coagonist using whole cell voltage-clamp recordings from hippocampal neurons in mixed cultures, containing both neurons and glial cells, and, under more physiological conditions, in hippocampal slices. Here we show that the glycine site of the NMDA receptor at hippocampal synapses, both in culture and acute brain slices, is not saturated by the ambient coagonist concentration and is modulated through activity-dependent coagonist release. Augmentation of the NMDA receptor-mediated synaptic responses by local glutamate-induced coagonist release is spatially restricted and determined by spatiotemporal summation of synaptic events at neighboring synaptic inputs on a single dendritic branch. Therefore different spatiotemporal patterns of presynaptic activity could be translated into different levels of the NMDAR activation in specific afferent projections. These results suggest that the NMDA receptor glycine site may serve as a detector of the spatiotemporal characteristics of presynaptic activity patterns.
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Massey, S. C., and R. F. Miller. "N-methyl-D-aspartate receptors of ganglion cells in rabbit retina." Journal of Neurophysiology 63, no. 1 (January 1, 1990): 16–30. http://dx.doi.org/10.1152/jn.1990.63.1.16.
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1. Intracellular and extracellular recordings were obtained from ganglion cells in the rabbit retina. The effect of N-methyl-DL-aspartate (NMDLA) and N-methyl-D-aspartate (NMDA) antagonists were studied with the use of a perfusion method for drug application. 2. NMDLA excited all ganglion cell types and caused a characteristic burst firing pattern, which is not typical of physiological responses in the retina. When synaptic transmission was blocked with cobalt, NMDLA still excited ganglion cells, indicating a direct action. 3. A comparison of DL-2-amino-5-phosphonopentanoate (DL-AP-5) and DL-2-amino-7-phosphonoheptanoate (DL-AP-7) revealed that DL-AP-7 was a more specific NMDA antagonist. DL-AP-5 partially blocked the b-wave of the electroretinogram (ERG), an action typical of L-2-amino-4-phosphonobutyrate (L-APB), which specifically blocks on channels in the retina. 4. DL-AP-7 reversibly blocked the action of NMDLA on all ganglion cell types, but the effects of kainate (KA) and carbachol were unchanged. AP-7 was stereospecific and pharmacologically specific, with action typical of a competitive NMDA antagonist in the rabbit retina. 5. DL-AP-7 did not block light responses driven by center or surround stimulation for ON or OFF ganglion cells. Directional selectively was unchanged by DL-AP-7. However, most ganglion cells showed a reduction, typically 20-30%, in the number of action potentials produced by light stimulation. 6. In contrast to a previous report, we found no evidence that DL-AP-7 specifically inhibited sustained ON ganglion cells. The inhibition of sustained ON responses by DL-AP-5, previously attributed to NMDA antagonism, is probably because of the weak APB activity of L-AP-5. 7. We conclude that NMDA receptors do not mediate the major light-driven input to ganglion cells in the rabbit retina. By exclusion, transmission from bipolar cells to ganglion cells appears to be carried mostly by KA or quisqualate (QQ) receptors. However, because NMDA antagonists reduced the number of action potentials produced by light stimulation, it is likely that NMDA receptors carry a portion of the signal transmission to ganglion cells. The presence of NMDA receptors on third-order neurons is consistent with the release of glutamate from presynaptic neurons such as bipolar cells.
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Tong, Gary, Hiroto Takahashi, Shichun Tu, Yeonsook Shin, Maria Talantova, Wagner Zago, Peng Xia, et al. "Modulation of NMDA Receptor Properties and Synaptic Transmission by the NR3A Subunit in Mouse Hippocampal and Cerebrocortical Neurons." Journal of Neurophysiology 99, no. 1 (January 2008): 122–32. http://dx.doi.org/10.1152/jn.01044.2006.
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Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-d-aspartate (NMDA)-induced currents and decreased Mg2+ sensitivity and Ca2+ permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg2+ sensitivity, and decreased Ca2+ permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg2+ sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extrasynaptic receptors, likely composed of NR1, NR2, and NR3 subunits.
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Ormerod, BK, EM Falconer, and LA Galea. "N-methyl-D-aspartate receptor activity and estradiol: separate regulation of cell proliferation in the dentate gyrus of adult female meadow vole." Journal of Endocrinology 179, no. 2 (November 1, 2003): 155–63. http://dx.doi.org/10.1677/joe.0.1790155.
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We have previously found that estradiol increases (within 4 h) but then decreases (within 48 h) cell proliferation in the dentate gyrus of adult female ovariectomized (OVX) rats and of intact meadow voles and that estradiol partially stimulates adrenal activity to suppress cell proliferation in rats. Estradiol enhances N-methyl-D-aspartate receptor (NMDAr) activity and NMDAr activation suppresses cell proliferation in the adult rodent dentate gyrus. Therefore, we tested whether estradiol alters cell proliferation in the dentate gyrus of adult OVX female meadow voles by stimulating NMDAr activity. In experiment 1, OVX females were injected with estradiol (10 micro g) or oil and then with NMDA (30 mg/kg) or vehicle 3 h later and bromodeoxyuridine 4 h later (BrdU; 50 mg/kg). Voles were perfused 1 h after BrdU injection. Relative to oil vehicle, estradiol increased (P</=0.001) and NMDA decreased (P</=0.006) labeled cell number. Coadministration of estradiol/NMDA increased labeled cell numbers relative to NMDA alone (P</=0.03), suggesting that within 4 h estradiol does not influence the effect of NMDA receptors on cell proliferation. In experiment 2, OVX females were injected with either estradiol or oil and then with either MK-801 (1 mg/kg) or vehicle 47 h later and BrdU 48 h later. The animals were perfused 1 h after BrdU was injected. Relative to oil-treated voles, estradiol-treated voles had fewer (P<0.006) and MK-801-treated voles had more labeled cells (P</=0.0001) in the dentate gyrus. However, estradiol did not appear to stimulate NMDA receptors to suppress cell proliferation because estradiol (48 h)/MK-801-treated voles had fewer BrdU-labeled cells than oil (48 h)/MK-801-treated voles (P</=0.06). The results show that estradiol time-dependently influences cell proliferation but that estradiol does not stimulate NMDAr activity to influence cell proliferation in the dentate gyrus of adult voles.
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Li, Yi-Fan, William G. Mayhan, and Kaushik P. Patel. "NMDA-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 6 (December 1, 2001): H2328—H2336. http://dx.doi.org/10.1152/ajpheart.2001.281.6.h2328.
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The paraventricular nucleus (PVN) of the hypothalamus is an important site of integration in the central nervous system for sympathetic outflow. Both glutamate and nitric oxide (NO) play an important role in the regulation of sympathetic nerve activity. The purpose of the present study was to examine the interaction of NO and glutamate within the PVN in the regulation of renal sympathetic nerve activity in rats. Renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR) were measured in response to administration of N-methyl-d-aspartic acid (NMDA) and N G-monomethyl-l-arginine (l-NMMA) into the PVN. We found that microinjection of NMDA (25, 50, and 100 pmol) into the PVN increased RSND, BP, and HR in a dose-dependent manner, reaching 53 ± 9%, 19 ± 3 mmHg, and 32 ± 12 beats/min, respectively, at the highest dose. These responses were significantly enhanced by prior microinjection ofl-NMMA. On the other hand, inhibition of NO within the PVN by microinjection of l-NMMA also induced increases in RSND, BP, and HR in a dose-dependent manner, reaching 48 ± 6.5%, 11 ± 4 mmHg, and 55 ± 16 beats/min, respectively, at the highest dose. This sympathoexcitatory response was eliminated by prior microinjection of dl-2-amino-5-phosphonovaleric acid, an antagonist of the NMDA receptor. Furthermore, with the use of the push-pull technique, perfusion of glutamate (0.5 μmol) or NMDA (0.1 nmol) into the PVN induced an increase in NO release. In conclusion, our data indicate that NMDA receptors within the PVN mediate an excitatory effect on renal sympathetic nerve activity, arterial BP, and HR. NO in the PVN, which is released by activation of the NMDA receptor, also inhibits NMDA-mediated increases in sympathetic nerve activity. This negative feedback of NO on the glutamate system within the PVN may play an important role in maintaining the overall balance and tone of sympathetic outflow in normal and pathophysiological conditions known to have increased sympathetic tone.
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Kabbaj, M., G. Zouiri, H. GHOUDA, and Y. Kriouile. "Anti-NMDA Receptor Encephalitis in Children." Scholars Journal of Medical Case Reports 10, no. 10 (October 9, 2022): 1020–22. http://dx.doi.org/10.36347/sjmcr.2022.v10i10.007.
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Anti-NMDAR encephalitis is a type of neurological syndrome that can be paraneoplastic or non-paraneoplastic in nature. It is a recently discovered that is becoming much more recognized in children. The symptoms of anti-NMDAR encephalitis occur as a result of autoimmune antibody binding to the NMDA receptor on certain neuronal cell surfaces. Patients with anti-NMDAR encephalitis are described as having a change in mental status manifested by abrupt changes from calm behaviors to agitation, aggression or extreme irritability. In children, the first symptom to be recognized is often non-psychiatric: convulsion, status epilepticus, dystonia, verbal reduction or mutism .The diagnosis is clinical and confirmation is easy with demonstration of antibodies in serum and CSF; Early diagnosis and aggressive immunotherapy are imperative. Anti-NMDA receptor encephalitis can be reversible if diagnosed and treated early.
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Nandakumar, DN, P. Ramaswamy, C. Prasad, D. Srinivas, and K. Goswami. "Glioblastoma invasion and NMDA receptors: A novel prospect." Physiology International 106, no. 3 (September 2019): 250–60. http://dx.doi.org/10.1556/2060.106.2019.22.
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Purpose Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored. Main methods LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction. Results We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level. Conclusions This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.
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Gruszczynska-Biegala, Joanna, Klaudia Strucinska, Filip Maciag, Lukasz Majewski, Maria Sladowska, and Jacek Kuznicki. "STIM Protein-NMDA2 Receptor Interaction Decreases NMDA-Dependent Calcium Levels in Cortical Neurons." Cells 9, no. 1 (January 9, 2020): 160. http://dx.doi.org/10.3390/cells9010160.
Full textAbstract:
Neuronal Store-Operated Ca2+ Entry (nSOCE) plays an essential role in refilling endoplasmic reticulum Ca2+ stores and is critical for Ca2+-dependent neuronal processes. SOCE sensors, STIM1 and STIM2, can activate Orai, TRP channels and AMPA receptors, and inhibit voltage-gated channels in the plasma membrane. However, the link between STIM, SOCE, and NMDA receptors, another key cellular entry point for Ca2+ contributing to synaptic plasticity and excitotoxicity, remains unclear. Using Ca2+ imaging, we demonstrated that thapsigargin-induced nSOCE was inhibited in rat cortical neurons following NMDAR inhibitors. Blocking nSOCE by its inhibitor SKF96365 enhanced NMDA-driven [Ca2+]i. Modulating STIM protein level through overexpression or shRNA inhibited or activated NMDA-evoked [Ca2+]i, respectively. Using proximity ligation assays, immunofluorescence, and co-immunoprecipitation methods, we discovered that thapsigargin-dependent effects required interactions between STIMs and the NMDAR2 subunits. Since STIMs modulate NMDAR-mediated Ca2+ levels, we propose targeting this mechanism as a novel therapeutic strategy against neuropathological conditions that feature NMDA-induced Ca2+ overload as a diagnostic criterion.
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Peterson, Cristina D., Kelley F. Kitto, Harsha Verma, Kelsey Pflepsen, Eric Delpire, George L. Wilcox, and Carolyn A. Fairbanks. "Agmatine requires GluN2B-containing NMDA receptors to inhibit the development of neuropathic pain." Molecular Pain 17 (January 2021): 174480692110291. http://dx.doi.org/10.1177/17448069211029171.
Full textAbstract:
A decarboxylated form of L-arginine, agmatine, preferentially antagonizes NMDArs containing Glun2B subunits within the spinal cord and lacks motor side effects commonly associated with non-subunit-selective NMDAr antagonism, namely sedation and motor impairment. Spinally delivered agmatine has been previously shown to reduce the development of tactile hypersensitivity arising from spinal nerve ligation. The present study interrogated the dependence of agmatine’s alleviation of neuropathic pain (spared nerve injury (SNI) model) on GluN2B-containing NMDArs. SNI-induced hypersensitivity was induced in mice with significant reduction of levels of spinal GluN2B subunit of the NMDAr and their floxed controls. Agmatine reduced development of SNI-induced tactile hypersensitivity in controls but had no effect in subjects with reduced levels of GluN2B subunits. Ifenprodil, a known GluN2B-subunit-selective antagonist, similarly reduced tactile hypersensitivity in controls but not in the GluN2B-deficient mice. In contrast, MK-801, an NMDA receptor channel blocker, reduced hypersensitivity in both control and GluN2B-deficient mice, consistent with a pharmacological pattern expected from a NMDAr antagonist that does not have preference for GluN2B subtypes. Additionally, we observed that spinally delivered agmatine, ifenprodil and MK-801 inhibited nociceptive behaviors following intrathecal delivery of NMDA in control mice. By contrast, in GluN2B-deficient mice, MK-801 reduced NMDA-evoked nociceptive behaviors, but agmatine had a blunted effect and ifenprodil had no effect. These results demonstrate that agmatine requires the GluN2B subunit of the NMDA receptor for inhibitory pharmacological actions in pre-clinical models of NMDA receptor-dependent hypersensitivity.
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Arvanian, Victor L., William J. Bowers, Jeffrey C. Petruska, Vladimir Motin, Honeyleen Manuzon, Wade C. Narrow, Howard J. Federoff, and Lorne M. Mendell. "Viral Delivery of NR2D Subunits Reduces Mg2+ Block of NMDA Receptor and Restores NT-3-Induced Potentiation of AMPA-Kainate Responses in Maturing Rat Motoneurons." Journal of Neurophysiology 92, no. 4 (October 2004): 2394–404. http://dx.doi.org/10.1152/jn.00278.2004.
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N-methyl-d-aspartate (NMDA) responsiveness of motoneurons declines during the initial 2 postnatal weeks due to increasing Mg2+ block of NMDA receptors. Using gene chip analyses, RT-PCR, and immunochemistry, we have shown that the NR2D subunit of the NMDA receptor (NMDAR), known to confer resistance to Mg2+ block, also declines in motoneurons during this period. We injected a viral construct (HSVnr2d) into the lumbar spinal cord on postnatal day 2 in an attempt to restore NMDAR function in motoneurons during the second postnatal week. Following HSVnr2d injection, we detected elevated levels of NR2D mRNA in spinal cord samples and NR2D protein specifically in motoneurons. These molecular changes were associated with marked functional alterations whereby NMDAR-mediated responses in motoneurons associated with both dorsal root (DR) and ventrolateral funiculus (VLF) inputs returned to values observed at E18 due to decreased Mg2+ blockade. Viruses carrying the β-galactosidase gene did not induce these effects. NT-3 is known to potentiate AMPA-kainate responses in motoneurons if the response has an NMDAR-mediated component and thus is normally ineffective during the second postnatal week. Restoration of NMDAR-mediated responsiveness in the second postnatal week was accompanied by a return of the ability of neurotrophin-3 (NT-3) to potentiate the AMPA-kainate responses produced by both DR and VLF synaptic inputs. We conclude that delivery of the gene for a specific NMDA subunit can restore properties characteristic of younger animals to spinal cord motoneurons. This approach might be useful for enhancing the function of fibers surviving in the damaged spinal cord.
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Gall, David, and Geneviève Dupont. "Tonic Activation of Extrasynaptic NMDA Receptors Decreases Intrinsic Excitability and Promotes Bistability in a Model of Neuronal Activity." International Journal of Molecular Sciences 21, no. 1 (December 27, 2019): 206. http://dx.doi.org/10.3390/ijms21010206.
Full textAbstract:
NMDA receptors (NMDA-R) typically contribute to excitatory synaptic transmission in the central nervous system. While calcium influx through NMDA-R plays a critical role in synaptic plasticity, experimental evidence indicates that NMDAR-mediated calcium influx also modifies neuronal excitability through the activation of calcium-activated potassium channels. This mechanism has not yet been studied theoretically. Our theoretical model provides a simple description of neuronal electrical activity that takes into account the tonic activity of extrasynaptic NMDA receptors and a cytosolic calcium compartment. We show that calcium influx mediated by the tonic activity of NMDA-R can be coupled directly to the activation of calcium-activated potassium channels, resulting in an overall inhibitory effect on neuronal excitability. Furthermore, the presence of tonic NMDA-R activity promotes bistability in electrical activity by dramatically increasing the stimulus interval where both a stable steady state and repetitive firing can coexist. These results could provide an intrinsic mechanism for the constitution of memory traces in neuronal circuits. They also shed light on the way by which β -amyloids can alter neuronal activity when interfering with NMDA-R in Alzheimer’s disease and cerebral ischemia.
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Sun, Min-Yu, Mariangela Chisari, Lawrence N. Eisenman, Charles F. Zorumski, and Steven J. Mennerick. "Contributions of space-clamp errors to apparent time-dependent loss of Mg2+ block induced by NMDA." Journal of Neurophysiology 118, no. 1 (July 1, 2017): 532–43. http://dx.doi.org/10.1152/jn.00106.2017.
Full textAbstract:
N-methyl-d-aspartate receptors (NMDARs) govern synaptic plasticity, development, and neuronal response to insult. Prolonged activation of NMDARs such as during an insult may activate secondary currents or modulate Mg2+ sensitivity, but the conditions under which these occur are not fully defined. We reexamined the effect of prolonged NMDAR activation in juvenile mouse hippocampal slices. NMDA (10 μM) elicited current with the expected negative-slope conductance in the presence of 1.2 mM Mg2+. However, several minutes of continued NMDA exposure elicited additional inward current at −70 mV. A higher concentration of NMDA (100 µM) elicited the current more rapidly. The additional current was not dependent on Ca2+, network activity, or metabotropic NMDAR function and did not persist on agonist removal. Voltage ramps revealed no alteration of either reversal potential or NMDA-elicited conductance between −30 mV and +50 mV. The result was a more linear NMDA current-voltage relationship. The current linearization was also induced in interneurons and in mature dentate granule neurons but not immature dentate granule cells, dissociated cultured hippocampal neurons, or nucleated patches excised from CA1 pyramidal neurons. Comparative simulations of NMDA application to a CA1 pyramidal neuron and to a cultured neuron revealed that linearization can be explained by space-clamp errors arising from gradual recruitment of distal dendritic NMDARs. We conclude that persistent secondary currents do not strongly contribute to NMDAR responses in juvenile mouse hippocampus and careful discernment is needed to exclude contributions of clamp artifacts to apparent secondary currents. NEW & NOTEWORTHY We report that upon sustained activation of NMDARs in juvenile mouse hippocampal neurons there is apparent loss of Mg2+ block at negative membrane potentials. However, the phenomenon is explained by loss of dendritic voltage clamp, leading to a linear current-voltage relationship. Our results give a specific example of how spatial voltage errors in voltage-clamp recordings can readily be misinterpreted as biological modulation.
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Chen, Xi, Xiao Li, Yin Ting Wong, Xuejiao Zheng, Haitao Wang, Yujie Peng, Hemin Feng, et al. "Cholecystokinin release triggered by NMDA receptors produces LTP and sound–sound associative memory." Proceedings of the National Academy of Sciences 116, no. 13 (March 8, 2019): 6397–406. http://dx.doi.org/10.1073/pnas.1816833116.
Full textAbstract:
Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK−/−mice lacked neocortical LTP and showed deficits in a cue–cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue–cue associative memory.
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Sethuramanujam, Santhosh, and Malcolm M. Slaughter. "Disinhibitory recruitment of NMDA receptor pathways in retina." Journal of Neurophysiology 112, no. 1 (July 1, 2014): 193–203. http://dx.doi.org/10.1152/jn.00817.2013.
Full textAbstract:
Glutamate release at bipolar to ganglion cell synapses activates NMDA and AMPA/kainic acid (KA) ionotropic glutamate receptors. Their relative strength determines the output signals of the retina. We found that this balance is tightly regulated by presynaptic inhibition that preferentially suppresses NMDA receptor (NMDAR) activation. In transient ON-OFF neurons, block of GABA and glycine feedback enhanced total NMDAR charge by 35-fold in the ON response and 9-fold in the OFF compared with a 1.7-fold enhancement of AMPA/KA receptors. Blocking only glycine receptors enhanced the NMDAR excitatory postsynaptic current 10-fold in the ON and 2-fold in the OFF pathway. Blocking GABAA or GABAC receptors (GABACRs or GABAARs) produced small changes in total NMDAR charge. When both GABAARs and GABACRs were blocked, the total NMDAR charge increased ninefold in the ON and fivefold in the OFF pathway. This exposed a strong GABACR feedback to bipolar cells that was suppressed by serial amacrine cell synapses mediated by GABAARs. The results indicate that NMDAR currents are large but latent, held in check by dual GABA and glycine presynaptic inhibition. One example of this controlled NMDAR activation is the cross talk between ON and OFF pathways. Blocking the ON pathway increased NMDAR relative strength in the OFF pathway. Stimulus prolongation similarly increased the NMDAR relative strength in the OFF response. This NMDAR enhancement was produced by a diminution in GABA and glycine feedback. Thus the retinal network recruits NMDAR pathways through presynaptic disinhibition.
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Yan, Jing, C. Peter Bengtson, Bettina Buchthal, Anna M. Hagenston, and Hilmar Bading. "Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants." Science 370, no. 6513 (October 8, 2020): eaay3302. http://dx.doi.org/10.1126/science.aay3302.
Full textAbstract:
Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to TRPM4. This interaction is mediated by intracellular domains located in the near-membrane portions of the receptors. Structure-based computational drug screening using the interaction interface of TRPM4 in complex with NMDARs identified small molecules that spare NMDAR-induced calcium signaling but disrupt the NMDAR/TRPM4 complex. These interaction interface inhibitors strongly reduce NMDA-triggered toxicity and mitochondrial dysfunction, abolish cyclic adenosine monophosphate–responsive element–binding protein (CREB) shutoff, boost gene induction, and reduce neuronal loss in mouse models of stroke and retinal degeneration. Recombinant or small-molecule NMDAR/TRPM4 interface inhibitors may mitigate currently untreatable human neurodegenerative diseases.
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Lumsden, Eric W., Timothy A. Troppoli, Scott J. Myers, Panos Zanos, Yasco Aracava, Jan Kehr, Jacqueline Lovett, et al. "Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function." Proceedings of the National Academy of Sciences 116, no. 11 (February 22, 2019): 5160–69. http://dx.doi.org/10.1073/pnas.1816071116.
Full textAbstract:
Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine’s antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed inXenopusoocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 µM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.
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Bravo, David, Katherine Zepeda-Morales, Carola J. Maturana, Jeffri S. Retamal, Alejandro Hernández, Teresa Pelissier, Rafael Barra, Patricio Sáez-Briones, Héctor Burgos, and Luis Constandil. "NMDA and P2X7 Receptors Require Pannexin 1 Activation to Initiate and Maintain Nociceptive Signaling in the Spinal Cord of Neuropathic Rats." International Journal of Molecular Sciences 23, no. 12 (June 16, 2022): 6705. http://dx.doi.org/10.3390/ijms23126705.
Full textAbstract:
Pannexin 1 (Panx1) is involved in the spinal central sensitization process in rats with neuropathic pain, but its interaction with well-known, pain-related, ligand-dependent receptors, such as NMDA receptors (NMDAR) and P2X7 purinoceptors (P2X7R), remains largely unexplored. Here, we studied whether NMDAR- and P2X7R-dependent nociceptive signaling in neuropathic rats require the activation of Panx1 channels to generate spinal central sensitization, as assessed by behavioral (mechanical hyperalgesia) and electrophysiological (C-reflex wind-up potentiation) indexes. Administration of either a selective NMDAR agonist i.t. (NMDA, 2 mM) or a P2X7R agonist (BzATP, 150 μM) significantly increased both the mechanical hyperalgesia and the C-reflex wind-up potentiation, effects that were rapidly reversed (minutes) by i.t. administration of a selective pannexin 1 antagonist (10panx peptide, 300 μM), with the scores even reaching values of rats without neuropathy. Accordingly, 300 μM 10panx completely prevented the effects of NMDA and BzATP administered 1 h later, on mechanical hyperalgesia and C-reflex wind-up potentiation. Confocal immunofluorescence imaging revealed coexpression of Panx1 with NeuN protein in intrinsic dorsal horn neurons of neuropathic rats. The results indicate that both NMDAR- and P2X7R-mediated increases in mechanical hyperalgesia and C-reflex wind-up potentiation require neuronal Panx1 channel activation to initiate and maintain nociceptive signaling in neuropathic rats.
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ZIBURKUS, JOKUBAS, MARTHA E. BICKFORD, and WILLIAM GUIDO. "NMDAR-1 staining in the lateral geniculate nucleus of normal and visually deprived cats." Visual Neuroscience 17, no. 2 (March 2000): 187–96. http://dx.doi.org/10.1017/s0952523800172013.
Full textAbstract:
In normal adult cats, a monoclonal antibody directed toward the NR-1 subunit of the N-methyl-d-aspartate (NMDA) receptor (Pharmingen, clone 54.1) produced dense cellular and neuropil labeling throughout all layers of the lateral geniculate nucleus (LGN) and adjacent thalamic nuclei, including the thalamic reticular, perigeniculate, medial intralaminar, and ventral lateral geniculate nuclei. Cellular staining revealed well-defined somata, and in some cases proximal dendrites. NMDAR-1 cell labeling was also evident in the LGN of early postnatal kittens, suggesting that developing LGN cells possess this receptor subunit at or before eye opening. Within the A-layers of the adult LGN, staining encompassed a wide range of soma sizes. Soma size comparisons of NMDAR-1 stained cells with those stained with an antibody directed toward a nonphosphorylated neurofilament protein (SMI-32), which selectively stains Y-relay cells (Bickford et al., 1998), or an antibody to glutamic acid decarboxylase (GAD), which stains for GABAergic interneurons, suggested that NMDA receptors are utilized by relay cells and interneurons. NMDAR-1 staining was also observed in the LGN of cats with early monocular lid suture. Although labeling was apparent in both deprived and nondeprived A-layers of LGN, the distribution of soma sizes was significantly different. In the deprived A-layers of LGN, staining was limited to small- and medium-sized cells. Cells with relatively large soma were lacking. However, cell density measurements as well as soma size comparisons with cells stained for Nissl substance suggested these differences were due to deprivation-induced cell shrinkage and not to a loss of NMDAR-1 staining in Y-cells. Taken together, these results suggest that NMDA receptors are utilized by both relay cells and interneurons in LGN and that alterations in early visual experience do not necessarily affect the expression of NMDA receptors in the LGN.
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Jia, Zhengping, YouMing Lu, Jeff Henderson, Franco Taverna, Carmelo Romano, Wanda Abramow-Newerly, J. Martin Wojtowicz, and John Roder. "Selective Abolition of the NMDA Component of Long-Term Potentiation in Mice Lacking mGluR5." Learning & Memory 5, no. 4 (September 1, 1998): 331–43. http://dx.doi.org/10.1101/lm.5.4.331.
Full textAbstract:
The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTPNMDA), but normal LTP of the AMPA-receptor-mediated component (LTPAMPA). This selective loss of LTPNMDA was seen in three different genotypic backgrounds and was apparent at all holding potentials (−70 mV to +20 mV). Furthermore, the LTPNMDA deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4β-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTPAMPA. Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.
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Fatemi, S., E. Qu, and J. Fullmer. "Anti-NMDA-Receptor Encephalitis in a Patient with Ovarian Teratoma, Harboring Brain Histology of Varying Developmental Stages and Regions with Chronic Inflammation." American Journal of Clinical Pathology 156, Supplement_1 (October 1, 2021): S80—S81. http://dx.doi.org/10.1093/ajcp/aqab191.170.
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Abstract Introduction/Objective Anti-NMDA-receptor encephalitis is a subacute, autoimmune disorder thought to be caused by autoantibodies directed against the N-methyl-D-aspartate (NMDA) receptor. Clinical symptoms of anti-NMDAR encephalitis may mimic schizophrenia and psychotic spectrum disorders or substance-induced psychosis. Although initially described in association with ovarian teratomas in women, anti-NMDAR encephalitis has been reported in individuals without paraneoplastic association, as well as in males. Herein, we report a case of a 29-year-old woman with suicidal ideation and other neuropsychiatric manifestations who was found to have a right ovarian cystic mass by imaging study. Microscopically, the resected ovarian mass is composed of mature skin, fat, cartilage and neural tissues. Nerve, ganglions and multiple brain tissues are present. Cerebellum including external granular cell layer (normally only seen in infants), cerebrum-like, choroid plexus and other neural elements are present. There is peripheral lymphoplasmacytic infiltrates around and within the neuroglial matrix. Cerebral spinal fluid was concurrently tested positive for Anti-NMDAR. The combined clinical, histological, and laboratory findings confirmed the above diagnosis. Although Anti-NMDAR encephalitis is a familiar entity to many clinical psychiatrist and neurologists, it is less commonly reported in the pathology literature. Its resultant relationship to cystic teratoma warrants awareness of this condition by pathologists. Methods/Case Report Case Report Results (if a Case Study enter NA) NA Conclusion Anti-NMDA-receptor encephalitis is related to cystic teratoma, therefore pathologists need to be aware of this condition.
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Parisi, Eva, Milica Bozic, Mercé Ibarz, Sara Panizo, Petya Valcheva, Blai Coll, Elvira Fernández, and José M. Valdivielso. "Sustained activation of renal N-methyl-d-aspartate receptors decreases vitamin D synthesis: a possible role for glutamate on the onset of secondary HPT." American Journal of Physiology-Endocrinology and Metabolism 299, no. 5 (November 2010): E825—E831. http://dx.doi.org/10.1152/ajpendo.00428.2010.
Full textAbstract:
N-methyl-d-aspartate (NMDA) receptors (NMDAR) are tetrameric amino acid receptors that act as membrane calcium channels. The presence of the receptor has been detected in the principal organs responsible for calcium homeostasis (kidney, bone, and parathyroid gland), pointing to a possible role in mineral metabolism. The aim of this study was to test the effect of NMDAR activation in the kidney and on 1,25(OH)2D3 synthesis. We determined the presence of NMDAR subunits in HK-2 (human kidney cells) cells and proved its functionality. NMDA treatment for 4 days induced a decrease in 1α-hydroxylase levels and 1,25(OH)2D3 synthesis through the activation of the MAPK/ERK pathway in HK-2 cells. In vivo administration of NMDA for 4 days also caused a decrease in blood 1,25(OH)2D3 levels in healthy animals and an increase in blood PTH levels. This increase in PTH induced a decrease in the urinary excretion of calcium and an increase in urinary excretion of phosphorous and sodium as well as in diuresis. Bone turnover markers also increased. Animals with 5/6 nephrectomy showed low levels of renal 1α-hydroxylase as well as high levels of renal glutamate compared with healthy animals. In conclusion, NMDAR activation in the kidney causes a decrease in 1,25(OH)2D3 synthesis, which induces an increase on PTH synthesis and release. In animals with chronic kidney disease, high renal levels of glutamate could be involved in the downregulation of 1α-hydroxylase expression.
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Mehrotra, Suneet, Marsha L. Pierce, Shashank M. Dravid, and Thomas F. Murray. "Stimulation of Neurite Outgrowth in Cerebrocortical Neurons by Sodium Channel Activator Brevetoxin-2 Requires Both N-Methyl-D-aspartate Receptor 2B (GluN2B) and p21 Protein (Cdc42/Rac)-Activated Kinase 1 (PAK1)." Marine Drugs 20, no. 9 (August 31, 2022): 559. http://dx.doi.org/10.3390/md20090559.
Full textAbstract:
N-methyl-D-aspartate (NMDA) receptors play a critical role in activity-dependent dendritic arborization, spinogenesis, and synapse formation by stimulating calcium-dependent signaling pathways. Previously, we have shown that brevetoxin 2 (PbTx-2), a voltage-gated sodium channel (VGSC) activator, produces a concentration-dependent increase in intracellular sodium [Na+]I and increases NMDA receptor (NMDAR) open probabilities and NMDA-induced calcium (Ca2+) influxes. The objective of this study is to elucidate the downstream signaling mechanisms by which the sodium channel activator PbTx-2 influences neuronal morphology in murine cerebrocortical neurons. PbTx-2 and NMDA triggered distinct Ca2+-influx pathways, both of which involved the NMDA receptor 2B (GluN2B). PbTx-2-induced neurite outgrowth in day in vitro 1 (DIV-1) neurons required the small Rho GTPase Rac1 and was inhibited by both a PAK1 inhibitor and a PAK1 siRNA. PbTx-2 exposure increased the phosphorylation of PAK1 at Thr-212. At DIV-5, PbTx-2 induced increases in dendritic protrusion density, p-cofilin levels, and F-actin throughout the dendritic arbor and soma. Moreover, PbTx-2 increased miniature excitatory post-synaptic currents (mEPSCs). These data suggest that the stimulation of neurite outgrowth, spinogenesis, and synapse formation produced by PbTx-2 are mediated by GluN2B and PAK1 signaling.
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Zhang, Y., and A. Auerbach. "Kinetic properties of NMDA receptors in embryonic Xenopus spinal neurons." Journal of Neurophysiology 74, no. 1 (July 1, 1995): 153–61. http://dx.doi.org/10.1152/jn.1995.74.1.153.
Full textAbstract:
1. The kinetic properties of embryonic Xenopus spinal cord neuron N-methyl-D-aspartate (NMDA)-activated receptors (NMDAR) were examined at the single-channel level. These receptors have a main conductance state of 50 pS and make occasional sojourns to a subconductance level of approximately 40 pS. The open channel lifetime is 1.3 ms at -80 mV and in 1 mM Ca(2+)-, Mg(2+)-free solution. Extracellular Mg2+ blocks the channel at a rate of 2.9 x 10(8) M-1 s-1 and with a Kd of approximately 20 microM at -80 mV. In patches with only one channel active, the closed interval duration distribution requires at least four exponentials to be fit. The time constant of one closed interval component decreases with increasing NMDA concentration. Kinetic modeling indicates that these NMDA receptors open at a rate of 230 s-1 and close at a rate of 167 s-1, that in the absence of desensitization the maximum probability of being open is approximately 0.5, and that this probability is half-maximal at approximately 150 microM NMDA.
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Zhang, Xin, Bin Cheng, Xianghong Jing, Yongfa Qiao, Xinyan Gao, Huijuan Yu, Bing Zhu, and Haifa Qiao. "NMDA Receptors of Gastric-Projecting Neurons in the Dorsal Motor Nucleus of the Vagus Mediate the Regulation of Gastric Emptying by EA at Weishu (BL21)." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/583479.
Full textAbstract:
A large number of studies have been conducted to explore the efficacy of electroacupuncture (EA) for the treatment of gastrointestinal motility. While several lines of evidence addressed the basic mechanism of EA on gastrointestinal motility regarding effects of limb and abdomen points, the mechanism for effects of the back points on gastric motility still remains unclear. Here we report that the NMDA receptor (NMDAR) antagonist kynurenic acid inhibited the gastric emptying increase induced by high-intensity EA at BL21 and agonist NMDA enhanced the effect of the same treatment. EA at BL21 enhanced NMDAR, but not AMPA receptor (AMPAR) component of miniature excitatory postsynaptic current (mEPSC) in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). In sum, our data demonstrate an important role of NMDAR-mediated synaptic transmission of gastric-projecting DMV neurons in mediating EA at BL21-induced enhancement of gastric emptying.
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Liu, Yibin, Yanpeng Tian, Ruoyi Guo, Xin Xu, Mingle Zhang, Zhongkang Li, Yanlai Xiao, et al. "Anti-NMDA Receptor Encephalitis: Retrospective Analysis of 15 Cases, Literature Review, and Implications for Gynecologists." Journal of Healthcare Engineering 2022 (March 15, 2022): 1–9. http://dx.doi.org/10.1155/2022/4299791.
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Background. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare form of autoimmune encephalitis caused by anti-NMDA receptor antibodies. This disease mainly affects women of childbearing age and is commonly associated with ovarian teratoma. However, the relationship between anti-NMDA receptor encephalitis and ovarian teratoma and the role of anti-NMDA receptor antibody in the relationship remain unclear. Objectives. This study aimed to describe 15 cases of anti-NMDA receptor encephalitis (5 with ovarian teratoma), review literature, and reinforce the gynecologist's knowledge of this disorder. Methods. Clinical data of 15 patients from January 2015 to December 2020 admitted to The Second Hospital of Hebei Medical University were collected and analyzed. The diagnosis of anti-NMDA receptor encephalitis was based on the presence of anti-NMDA receptor antibodies in cerebrospinal fluid (CSF) and/or serum. Laparoscopic teratoma removal was performed in patients with ovarian teratoma. All patients had received immunotherapy. In addition, a review of the literature was performed to reinforce the gynecologist's knowledge of this disorder. Results. A total of 15 patients with anti-NMDA receptor encephalitis were screened, of whom 5 patients were confirmed with ovarian teratoma by pathology. The most common symptoms of anti-NMDAR encephalitis with teratoma are fever (5/5, 100%), seizure (5/5, 100%), mental and behavioral disorders (4/5, 80%), and decreased consciousness (4/5, 80%). Conversely, the most common symptoms of patients without teratoma were neuropsychiatric symptoms, including headache (6/10, 60%) and mental and behavioral disorders (7/10, 70%). All patients underwent immunotherapy, including steroids, intravenous immunoglobulin (IVIG), plasma exchange, and cyclophosphamide, and 4 out of 5 patients with ovarian teratomas underwent surgical treatment. All patients had a good outcome after systemic, surgical, and immunotherapy treatment. No patient who underwent surgical treatment developed a recurrence. Conversely, 2 of 10 patients without teratoma developed an anti-NMDA receptor encephalitis recurrence. Conclusions. Patients with anti-NMDA encephalitis show severe mental and neurological symptoms. Resection of teratoma is beneficial to the relief or disappearance of symptoms and has a good prognosis. This disorder should be fully recognized by gynecologists, who play an important role in diagnosis and treatment.
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Kenney, Michael J., Mark L. Weiss, Tammy Mendes, Yan Wang, and Richard J. Fels. "Role of paraventricular nucleus in regulation of sympathetic nerve frequency components." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 5 (May 1, 2003): H1710—H1720. http://dx.doi.org/10.1152/ajpheart.00673.2002.
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Autospectral and coherence analyses were used to determine the role of and interactions between paraventricular nucleus (PVN) nitric oxide, γ-aminobutyric acid (GABA), and the N-methyl-d-aspartic acid (NMDA)-glutamate receptor in regulation of sympathetic nerve discharge (SND) frequency components in anesthetized rats. Four observations were made. First, PVN microinjection of bicuculline (BIC) (GABAAreceptor antagonist), but not single PVN injections of NMDA (excitatory amino acid) or N G-monomethyl-l-arginine (l-NMMA; a nitric oxide synthase inhibitor), altered SND frequency components. Second, combined PVN microinjections ofl-NMMA and NMDA changed the SND bursting pattern; however, the observed pattern change was different from that produced by PVN BIC and not observed after sinoaortic denervation. Third, PVN microinjection of kynurenic acid prevented and reversed BIC-induced changes in the SND bursting pattern. Finally, vascular resistance (renal and splenic) was significantly increased after PVN BIC microinjection despite the lack of change in the level of renal and splenic SND. These data demonstrate that the PVN contains the neural substrate for altering SND frequency components and suggest complex interactions between specific PVN neurotransmitters and between PVN neurotransmitters and the arterial baroreceptor reflex in SND regulation.
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Rosch, Richard E., Sukhvir Wright, Gerald Cooray, Margarita Papadopoulou, Sushma Goyal, Ming Lim, Angela Vincent, A. Louise Upton, Torsten Baldeweg, and Karl J. Friston. "NMDA-receptor antibodies alter cortical microcircuit dynamics." Proceedings of the National Academy of Sciences 115, no. 42 (September 27, 2018): E9916—E9925. http://dx.doi.org/10.1073/pnas.1804846115.
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NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities—or even seizures—is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab–related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.
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Li, Xiaohong, Chen Li, Yiting Tang, Yanhong Huang, Qingmei Cheng, Xiaoting Huang, Feiyan Zhao, et al. "NMDA receptor activation inhibits the antifibrotic effect of BM-MSCs on bleomycin-induced pulmonary fibrosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 3 (September 1, 2018): L404—L421. http://dx.doi.org/10.1152/ajplung.00002.2018.
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Endogenous glutamate (Glu) release and N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation are associated with lung injury in different animal models. However, the underlying mechanism is unclear. Bone marrow-derived mesenchymal stem cells (BM-MSCs), which show potential use for immunomodulation and tissue protection, play a protective role in pulmonary fibrosis (PF) process. Here, we found the increased Glu release from the BM cells of bleomycin (BLM)-induced PF mice in vivo. BLM stimulation also increased the extracellular Glu in BM-MSCs via the antiporter system xc− in vitro. The gene expression of each subunit of NMDAR was detected in BM-MSCs. NMDAR activation inhibited the proliferation, migration, and paracrine function of BM-MSCs in vitro. BM-MSCs were derived from male C57BL/6 mice, transfected with lentiviral vectors carrying the enhanced green fluorescence protein gene, pretreated with NMDA, and transplanted into the female recipient mice that were intratracheally injected with BLM to induce PF. Transplantation of NMDA-pretreated BM-MSCs significantly aggravated PF as compared with that in the normal BM-MSCs transplantation group. The sex determination gene Y chromosome and green fluorescence protein genes of BM-MSCs were detected to observe BM-MSCs homing in the fibrotic lungs. Moreover, NMDAR activation inhibited BM-MSC migration by downregulating the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 signaling axis. NMDAR activation aggravated the transforming growth factor-β1-induced extracellular matrix production in alveolar epithelial cells and fibroblasts through the paracrine effects of BM-MSCs. In summary, these findings suggested that NMDAR activation-mediated Glu excitotoxicity induced by BLM in BM-MSCs abolished the therapeutic effects of normal BM-MSCs transplantation on BLM-induced PF.
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Wang, Yongfu, Janna V. Denisova, Ki Sung Kang, Joseph D. Fontes, Bao Ting Zhu, and Andrei B. Belousov. "Neuronal Gap Junctions Are Required for NMDA Receptor–Mediated Excitotoxicity: Implications in Ischemic Stroke." Journal of Neurophysiology 104, no. 6 (December 2010): 3551–56. http://dx.doi.org/10.1152/jn.00656.2010.
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N-methyl-d-aspartate receptors (NMDARs) play an important role in cell survival versus cell death decisions during neuronal development, ischemia, trauma, and epilepsy. Coupling of neurons by electrical synapses (gap junctions) is high or increases in neuronal networks during all these conditions. In the developing CNS, neuronal gap junctions are critical for two different types of NMDAR-dependent cell death. However, whether neuronal gap junctions play a role in NMDAR-dependent neuronal death in the mature CNS was not known. Using Fluoro-Jade B staining, we show that a single intraperitoneal administration of NMDA (100 mg/kg) to adult wild-type mice induces neurodegeneration in three forebrain regions, including rostral dentate gyrus. However, the NMDAR-mediated neuronal death is prevented by pharmacological blockade of neuronal gap junctions (with mefloquine, 30 mg/kg) and does not occur in mice lacking neuronal gap junction protein, connexin 36. Using Western blots, electrophysiology, calcium imaging, and gas chromatography–mass spectrometry in wild-type and connexin 36 knockout mice, we show that the reduced level of neuronal death in knockout animals is not caused by the reduced expression of NMDARs, activity of NMDARs, or permeability of the blood–brain barrier to NMDA. In wild-type animals, this neuronal death is not caused by upregulation of connexin 36 by NMDA. Finally, pharmacological and genetic inactivation of neuronal gap junctions in mice also dramatically reduces neuronal death caused by photothrombotic focal cerebral ischemia. The results indicate that neuronal gap junctions are required for NMDAR-dependent excitotoxicity and play a critical role in ischemic neuronal death.
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Gonzales, Jerry M., Alex L. Loeb, Peter S. Reichard, and Steven Irvine. "Ketamine Inhibits Glutamate-, N-Methyl-D-Aspartate-, and Quisqualate-stimulated cGMP Production in Cultured Cerebral Neurons." Anesthesiology 82, no. 1 (January 1, 1995): 205–13. http://dx.doi.org/10.1097/00000542-199501000-00025.
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Background Glutamatergic signaling has been linked to the recently discovered neurotransmitter/neuromodulator nitric oxide (NO), and several classes of anesthetics block some step in glutamatergic signaling. This study was designed to determine whether or not ketamine would prevent NO-dependent cGMP production stimulated by glutamate (GLU) and the GLU analogs NMDA, quisqualate (QUIS), and kainate (KAIN). Methods Primary cultures of cortical neurons and glia (prepared from 16-day gestational rat fetuses) were used after 12-16 days in culture. Reactions were carried out in magnesium-free buffer containing 100 microM 3-isobutyl-1-methylxanthine, and cGMP content of cultures was used as a bioassay of NO production. Results Cyclic GMP production stimulated by sodium nitroprusside (100 microM) occurred predominately in neurons and not in glia. Neurons were spontaneously active in these cultures; basal cGMP production was decreased by 50% in the presence of 1 microM tetrodotoxin (TTX). Glutamate (100 microM), NMDA (100 microM), QUIS (300 microM), and KAIN (100 microM) each increased cGMP content of neuronal cultures. L-NMMA (100 microM), a NO synthase inhibitor, prevented the stimulation of cGMP production by GLU or its analogs. Pretreatment with MK-801 (1 microM) or ketamine (10-100 microM) inhibited GLU-, NMDA-, and QUIS-stimulated cGMP production. Quisqualate-stimulated responses were the most sensitive to inhibition by ketamine and NMDA-stimulated responses were the least sensitive to inhibition. MK-801 and ketamine did not significantly inhibit KAIN-stimulated cGMP production. CNQX (10 microns) blocked KAIN-stimulated cGMP production only. Conclusions The authors' data demonstrate that ketamine inhibited NO synthesis stimulated by NMDA- and non-NMDA-receptor specific analogs. Our findings indicate that blockade of QUIS- as well as NMDA-subtypes of GLU- receptor may be important in the development of ketamine-induced anesthesia.
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Chang, Chun-Hung, Hsien-Yuan Lane, Ping-Tao Tseng, Shaw-Ji Chen, Chieh-Yu Liu, and Chieh-Hsin Lin. "Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials." Journal of Psychopharmacology 33, no. 4 (February 7, 2019): 436–48. http://dx.doi.org/10.1177/0269881118822157.
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Background: Multiple N-methyl-d-aspartate (NMDA)-receptor-enhancing agents have demonstrated promising effects for cognition in schizophrenia. However, the results of studies have been conflicting. This updated meta-analysis explored the effect of NMDA-receptor-enhancing agents on cognitive function. Methods: We searched PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials and Cochrane Systematic Reviews for studies on the effect of NMDA-receptor-enhancing agents on cognitive function in patients with schizophrenia up to September 2018. Double-blind randomised placebo trials with cognition rating scales were included. We pooled studies by using a random-effect model for comparisons with add-on NMDA-receptor-enhancing agents. Cognitive function scores were compared between baseline and subsequent levels, and NMDA-receptor-positive modulators were assessed using the standardised mean difference (SMD) with 95% confidence intervals (CIs). We evaluated statistical heterogeneity through visual inspection of funnel plots and by using the I2 statistic. Results: We identified 25 trials with 1951 participants meeting the inclusion criteria. NMDA-receptor-enhancing agents had a small but nonsignificant effect compared with the placebo on overall cognitive function (SMD = 0.068, CI = −0.056 to 0.193, P = 0.283). We identified trials enrolling patients aged between 30 and 39 years old, which reported significant positive effects (SMD: 0.163, 95% CI: 0.016–0.310, P = 0.030). Men were associated with a smaller effect of NMDA-receptor-positive modulators on overall cognitive function. Moreover, subgroup meta-analysis of cognitive domains revealed that N-acetyl cysteine (NAC) had a significant effect on working memory ( P-value for interaction = 0.038; SMD = 0.679, CI = 0.397–0.961, P < 0.001). Conclusions: Our meta-analysis revealed no significant effect of NMDA-enhancing agents on overall cognition. However, subgroup analysis suggested that NMDAR-enhancing agents may benefit young patients with schizophrenia, and NAC may have an effect on working memory. Additional trials with larger samples are suggested to evaluate these cognitive domains and ascertain the possible mechanisms.
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Diao, Xavier, and Milana Mor. "Anti-NMDA Receptor Encephalitis in a Patient with a History of Autism Spectrum Disorder." Adolescent Psychiatry 10, no. 3 (December 21, 2020): 231–35. http://dx.doi.org/10.2174/2211352517666190902144221.
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Background: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune syndrome characterized by a well-described constellation of neuropsychiatric symptoms. Its exact pathophysiology is poorly understood, but it is thought to be mediated by autoantibodies against NMDA (N-methyl-D-aspartate)-type glutamate receptors in the central nervous system. There is ongoing literature to suggest that patients with autism spectrum disorder (ASD) have evidence of neuroinflammation—or by definition, encephalitis. Objective: To investigate the link between autism spectrum disorder and autoimmune encephalitides. Methods: We present a case of anti-NMDA receptor encephalitis in a patient with autism spectrum disorder. “OP” is a 16-year-old male with a history of attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) who presented with a 3-day history of acute-onset altered mental status, electroencephalogram (EEG)-corroborated seizures, and slurred speech. Laboratory studies were significant for serum- and cerebrospinal fluid (CSF)-positive NMDA antibodies. The child psychiatry consult-liaison service was consulted for significant agitation and behavioral dyscontrol. We recommended 1:1 observation for safety, as well as antipsychotic agents titrated to clinical effect. The patient had a protracted hospital course, but was eventually discharged to an acute rehabilitation facility for continued stabilization and therapy. Conclusion: It remains to be seen if the relation between encephalitis and ASD is uni- or bidirectional, that is: whether children with ASD have a genetic diathesis to developing encephalitides (such as those mediated by the NMDAR), or conversely, if deranged or inflamed neuroreceptor processes are implicated in the development of ASD.
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Jafari-Sabet, Majid, Hamed Mofidi, and Mohammad-Sadegh Attarian-Khosroshahi. "NMDA receptors in the dorsal hippocampal area are involved in tramadol state-dependent memory of passive avoidance learning in mice." Canadian Journal of Physiology and Pharmacology 96, no. 1 (January 2018): 45–50. http://dx.doi.org/10.1139/cjpp-2017-0228.
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The precise neurobiological mechanisms of tramadol abuse underlying the cognitive function are still unknown. The aim of the present study was to examine the possible effects of intra-CA1 injections of N-methyl-d-aspartate (NMDA), a glutamate NMDA receptor (NMDAR) agonist, and d,l-2-amino-5-phosphonopentanoic acid (DL-AP5), a competitive NMDAR antagonist, on tramadol state-dependent memory. A single-trial step-down passive avoidance task was used for the assessment of memory retrieval in adult male NMRI mice. Post-training i.p. administration of an atypical μ-opioid receptor agonist, tramadol (2.5 and 5 mg/kg), dose-dependently induced impairment of memory retention. Pre-test injection of tramadol (2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under post-training administration of tramadol (5 mg/kg) influence. Pre-test intra-CA1 injection of NMDA (10−5 and 10−4 μg/mouse) 5 min before the administration of tramadol (5 mg/kg, i.p.) dose-dependently inhibited tramadol state-dependent memory. Pre-test intra-CA1 injection of DL-AP5 (0.25 and 0.5 μg/mouse) reversed the memory impairment induced by post-training administration of tramadol (5 mg/kg). Pre-test administration of DL-AP5 (0.25 and 0.5 μg/mouse) with an ineffective dose of tramadol (1.25 mg/kg) restored the retrieval and induced tramadol state-dependent memory. It can be concluded that dorsal hippocampal NMDAR mechanisms play an important role in the modulation of tramadol state-dependent memory.
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Sun, Min-Yu, Andrew J. Linsenbardt, Christine M. Emnett, Lawrence N. Eisenman, Yukitoshi Izumi, Charles F. Zorumski, and Steve Mennerick. "24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival." Neuroscientist 22, no. 2 (January 27, 2015): 132–44. http://dx.doi.org/10.1177/1073858414568122.
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The major cholesterol metabolite in brain, 24(S)-hydroxycholesterol (24S-HC), serves as a vehicle for cholesterol removal. Its effects on neuronal function, however, have only recently begun to be investigated. Here, we review that nascent work. Our own studies have demonstrated that 24S-HC has potent positive modulatory effects on N-methyl-d-aspartate (NMDA) receptor (NMDAR) function. This could have implications not only for brain plasticity but also for pathological NMDAR overuse. Other work has demonstrated effects of 24S-HC on neuronal survival and as a possible biomarker of neurodegenerative disease. Depending on circumstances, both upregulation/mimicry of 24S-HC signaling and down-regulation/antagonism may have therapeutic potential. We are interested in the possibility that synthetic analogues of 24S-HC with positive effects at NMDARs may hold neurotherapeutic promise, given the role of NMDA receptor hypofunction in certain neuropsychiatric disorders.
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Karanth, S., W. H. Yu, C. A. Mastronardi, and S. M. McCann. "Vitamin E Stimulates Luteinizing Hormone-Releasing Hormone and Ascorbic Acid Release from Medial Basal Hypothalami of Adult Male Rats." Experimental Biology and Medicine 228, no. 7 (July 2003): 779–85. http://dx.doi.org/10.1177/15353702-0322807-02.
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Vitamin E, a dietary factor, is essential for reproduction in animals. It is an antioxidant present in all mammalian cells. Previously, we showed that ascorbic acid (AA) acted as an inhibitory neurotransmitter in the hypothalamus by scavenging nitric oxide (NO). Earlier studies have shown the antioxidant synergism between vitamin E and ascorbic acid (AA). Therefore, it was of interest to evaluate the effect of vitamin E on luteinizing hormone-releasing hormone (LHRH) and AA release. Medial basal hypothalami from adult male rats of the Sprague Dawley strain were incubated with Krebs-Ringer bicarbonate buffer or graded concentrations of a water soluble form of vitamin E, tocopheryl succinate polyethylene glycol 1000 (TPGS, 22–176 μM) for 1 hr. Subsequently, the tissues were incubated with vitamin E or combinations of vitamin. E + N-methyl-D-aspartic acid (NMDA), an excitatory amino acid for 30 min to study the effect of prior and continued exposure to vitamin E on NMDA-induced LHRH release. AA and LHRH released into the incubation media were determined by high-performance liquid chromatography and radioimmunoassay, respectively. Vitamin E stimulated both LHRH and AA release. The minimal effective concentrations were 22 and 88 μM, respectively. NMDA stimulated LHRH release as previously shown and this effect was not altered in the combined presence of vitamin E plus NMDA. However, AA release was significantly reduced in the combined presence of vitamin E plus NMDA. To evaluate the role of NO in vitamin E-induced LHRH and AA release, the tissues were incubated with vitamin E or combinations of vitamin E + NG-monomethyl-L-arginine (NMMA), a competitive inhibitor of NO synthase. NMMA significantly suppressed vitamin E-induced LHRH and AA release indicating a role of NO in the release of both LHRH and AA. The data suggest that vitamin E plays a role in the hypothalamic control of LHRH and AA release and that the release is mediated by NO.
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Sabbula, Bhanu R., Shravya Yemmanur, Raghavendra Sanivarapu, Deepthi Kagolanu, and Ahmed Shadab. "Finding the Cause of Psychosis: A Challenging Case of Anti-NMDAR Encephalitis." Case Reports in Medicine 2020 (October 13, 2020): 1–4. http://dx.doi.org/10.1155/2020/2074704.
Full textAbstract:
An autoimmune response causing inflammation in the brain tissue is called autoimmune encephalitis. Autoantibodies directed against N-methyl-D-aspartate (NMDA) receptors cause a type of autoimmune encephalitis resulting in memory loss, confusion, and psychosis. A 28-year-old male with a history of schizophrenia, seizure disorder, and stroke presented with a 2-day history of bizarre behavior, restlessness, insomnia, agitation, and hallucinations. He was initially managed for acute psychosis without any improvement. Further workup for organic causes revealed positive NMDAR antibodies in both the cerebrospinal fluid and serum, confirming a diagnosis of autoimmune encephalitis. His condition later improved with steroids and intravenous immunoglobulins. This case signifies the importance of ruling out organic causes in patients with unexplained neuropsychiatric symptoms. NMDA encephalitis is more common in young females with underlying malignancies, especially ovarian teratomas. This case is unique, given the extremely rare occurrence of NMDA encephalitis in male patients without any malignancies.
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Gambrill, Abigail C., Granville P. Storey, and Andres Barria. "Dynamic Regulation of NMDA Receptor Transmission." Journal of Neurophysiology 105, no. 1 (January 2011): 162–71. http://dx.doi.org/10.1152/jn.00457.2010.
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N-methyl-d-aspartate receptors (NMDARs) are critical for establishing, maintaining, and modifying glutamatergic synapses in an activity-dependent manner. The subunit composition, synaptic expression, and some of the properties of NMDARs are regulated by synaptic activity, affecting processes like synaptic plasticity. NMDAR transmission is dynamic, and we were interested in studying the effect of acute low or null synaptic activity on NMDA receptors and its implications for synaptic plasticity. Periods of no stimulation or low-frequency stimulation increased NMDAR transmission. Changes became stable after periods of 20 min of low or no stimulation. These changes in transmission have a postsynaptic origin and are explained by incorporation of GluN2B-containing receptors to synapses. Importantly, periods of low or no stimulation facilitate long-term potentiation induction. Moreover, recovery after a weak preconditioning stimulus that normally blocks subsequent potentiation is facilitated by a nonstimulation period. Thus synaptic activity dynamically regulates the level of NMDAR transmission adapting constantly the threshold for plasticity.
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Zheng, Hong, Keshore R. Bidasee, William G. Mayhan, and Kaushik P. Patel. "Lack of central nitric oxide triggers erectile dysfunction in diabetes." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 3 (March 2007): R1158—R1164. http://dx.doi.org/10.1152/ajpregu.00429.2006.
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Erectile dysfunction is a serious and common complication of diabetes mellitus. The proposed mechanisms for erectile dysfunction in diabetes include central and autonomic neuropathy, endothelial dysfunction, and smooth muscle dysfunction. The paraventricular nucleus (PVN) of the hypothalamus is known to be involved in centrally mediated penile erection. This study was designed to examine the role of nitric oxide (NO) within the central nervous system component of the behavioral responses including erection in diabetic rats. N-methyl-d-aspartic acid (NMDA)-induced erection, yawning, and stretch through the PVN can be blocked by prior administration of NO synthase (NOS) blocker, l-NMMA, in freely moving, conscious male normal rats. Four weeks after streptozotocin (STZ) and vehicle injections, NMDA-induced erection, yawning, and stretch responses through the PVN are significantly blunted in diabetic rats compared with control rats. Examination of neuronal NOS (nNOS) protein by Western blot analysis indicated a reduced amount of nNOS protein in the PVN of rats with diabetes compared with control rats. Furthermore, restoring nNOS within the PVN by gene transfer using adenoviral transfection significantly restored the erectile and yawning responses to NMDA in diabetic rats. These data demonstrate that a blunted NO mechanism within the PVN may contribute to NMDA-induced erectile dysfunction observed in diabetes mellitus.
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Levy, Robert B., Alex D. Reyes, and Chiye Aoki. "Nicotinic and Muscarinic Reduction of Unitary Excitatory Postsynaptic Potentials in Sensory Cortex; Dual Intracellular Recording In Vitro." Journal of Neurophysiology 95, no. 4 (April 2006): 2155–66. http://dx.doi.org/10.1152/jn.00603.2005.
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We studied the cholinergic modulation of glutamatergic transmission between neighboring layer 5 regular-spiking pyramidal neurons in somatosensory cortical slices from young rats (P10-P26). Brief bath application of 5–10 μM carbachol, a nonspecific cholinergic agonist, decreased the amplitude of evoked unitary excitatory postsynaptic potentials (EPSPs). This effect was blocked by 1 μM atropine, a muscarinic receptor antagonist. Nicotine (10 μM), in contrast to carbachol, reduced EPSPs in nominally magnesium-free solution but not in the presence of 1 mM Mg+2, indicating the involvement of NMDA receptors. Likewise, when the postsynaptic cell was depolarized under voltage clamp to allow NMDA receptor activation in the presence of 1 mM Mg+2, synaptic currents were reduced by nicotine. Nicotinic EPSP reduction was prevented by the NMDA receptor antagonist d-AP5 (50 μM) and by the nicotinic receptor antagonist mecamylamine (10 μM). Both carbachol and nicotine reduced short-term depression of EPSPs evoked by 10 Hz stimulation, indicating that EPSP reduction happens via reduction of presynaptic glutamate release. In the case of nicotine, several possible mechanisms for NMDAR-dependent EPSP reduction are discussed. As a result of NMDA receptor dependence, nicotinic EPSP reduction may serve to reduce the local spread of cortical excitation during heightened sensory activity.