scholarly journals N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Cristiane Busnardo ◽  
Aline Fassini ◽  
Bruno Rodrigues ◽  
José Antunes-Rodrigues ◽  
Carlos C. Crestani ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Hemorrhagic Shock ◽  
Glutamate Receptor ◽  
Recovery Period ◽  
Intraperitoneal Administration ◽  
Receptor Activation ◽  
Vasopressin Release ◽  
Bed Nucleus ◽  
Nmda Glutamate Receptor ◽  
The Brain

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.

Xenon Acts by Inhibition of Non–N -methyl-d-aspartate Receptor–mediated Glutamatergic Neurotransmission in Caenorhabditis elegans 

2005 ◽  
Vol 103 (3) ◽  
pp. 508-513 ◽  
Author(s):  
Peter Nagele ◽  
Laura B. Metz ◽  
C Michael Crowder
Keyword(s):  
Nitrous Oxide ◽  
Caenorhabditis Elegans ◽  
Nmda Receptor ◽  
Glutamate Receptor ◽  
Glutamatergic Transmission ◽  
Wild Type ◽  
C Elegans ◽  
Aspartate Receptor ◽  
Nmda Glutamate Receptor ◽  
Response Transformation

Background Electrophysiologic experiments in rodents have found that nitrous oxide and xenon inhibit N-methyl-D-aspartate (NMDA)-type glutamate receptors. These findings led to the hypothesis that xenon and nitrous oxide along with ketamine form a class of anesthetics with the identical mechanism, NMDA receptor antagonism. Here, the authors ask in Caenorhabditis elegans whether xenon, like nitrous oxide, acts by a NMDA receptor-mediated mechanism. Methods Xenon:oxygen mixtures were delivered into sealed chambers until the desired concentration was achieved. The effects of xenon on various behaviors were measured on wild-type and mutant C. elegans strains. Results With an EC50 of 15-20 vol% depending on behavioral endpoint, xenon altered C. elegans locomotion in a manner indistinguishable from that of mutants in glutamatergic transmission. Xenon reduced the frequency and duration of backward locomotion without altering its speed or other behaviors tested. Mutation of glr-1, encoding a non-NMDA glutamate receptor subunit, abolished the behavioral effects of xenon; however, mutation of nmr-1, which encodes the pore-forming subunit of an NMDA glutamate receptor previously shown to be required for nitrous oxide action, did not significantly alter xenon response. Transformation of the glr-1 mutant with the wild-type glr-1 gene partially restored xenon sensitivity, confirming that glr-1 was necessary for the full action of xenon. Conclusions Xenon acts in C. elegans to alter locomotion through a mechanism requiring the non-NMDA glutamate receptor encoded by glr-1. Unlike for the action of nitrous oxide in C. elegans, the NMDA receptor encoded by nmr-1 is not essential for sensitivity to xenon.

Distribution, Density, and Clustering of Functional Glutamate Receptors Before and After Synaptogenesis in Hippocampal Neurons

2000 ◽  
Vol 84 (3) ◽  
pp. 1573-1587 ◽  
Author(s):  
Jeffrey R. Cottrell ◽  
Gilles R. Dubé ◽  
Christophe Egles ◽  
Guosong Liu
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Time Course ◽  
Synapse Formation ◽  
Receptor Activation ◽  
Receptor Density

Postsynaptic differentiation during glutamatergic synapse formation is poorly understood. Using a novel biophysical approach, we have investigated the distribution and density of functional glutamate receptors and characterized their clustering during synaptogenesis in cultured hippocampal neurons. We found that functional α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors are evenly distributed in the dendritic membrane before synaptogenesis with an estimated density of 3 receptors/μm2. Following synaptogenesis, functional AMPA and NMDA receptors are clustered at synapses with a density estimated to be on the order of 104 receptors/μm2, which corresponds to ∼400 receptors/synapse. Meanwhile there is no reduction in the extrasynaptic receptor density, which indicates that the aggregation of the existing pool of receptors is not the primary mechanism of glutamate receptor clustering. Furthermore our data suggest that the ratio of AMPA to NMDA receptor density may be regulated to be close to one in all dendritic locations. We also demonstrate that synaptic AMPA and NMDA receptor clusters form with a similar time course during synaptogenesis and that functional AMPA receptors cluster independently of activity and glutamate receptor activation, including following the deletion of the NMDA receptor NR1 subunit. Thus glutamate receptor activation is not necessary for the insertion, clustering, and activation of functional AMPA receptors during synapse formation, and this process is likely controlled by an activity-independent signal.

scholarly journals Impaired Glial Glutamate Uptake Induces Extrasynaptic Glutamate Spillover in the Spinal Sensory Synapses of Neuropathic Rats

2010 ◽  
Vol 103 (5) ◽  
pp. 2570-2580 ◽  
Author(s):  
Hui Nie ◽  
Han-Rong Weng
Keyword(s):  
Nmda Receptor ◽  
Dorsal Horn ◽  
Glutamate Receptor ◽  
Synaptic Input ◽  
Spinal Dorsal Horn ◽  
Glutamate Uptake ◽  
Receptor Activation ◽  
Cell Dysfunction ◽  
Spinal Dorsal ◽  
Nmda Receptor Activation

Glial cell dysfunction and excessive glutamate receptor activation in spinal dorsal horn neurons are hallmark mechanisms of pathological pain. The way in which glial cell dysfunction leads to excessive glutamate receptor activation in the spinal sensory synapses remains unknown. We and others recently reported the downregulation of glial glutamate transporter (GT) protein expression in the spinal dorsal horn of neuropathic rats. In this study, we showed that excitatory postsynaptic currents originating from N-methyl-d-aspartate receptor activation (NMDA EPSCs) elicited by peripheral synaptic input in the spinal sensory synapses were enhanced in neuropathic rats with mechanical allodynia induced by partial sciatic nerve ligation. The enhanced NMDA EPSCs were accompanied by an increased proportion of NR2B receptor activation. Physically blocking the extrasynaptic glutamate with dextran or chemically scavenging the glutamate with glutamic-pyruvic transaminase ameliorated the abnormal NMDA EPSCs in neuropathic rats. Pharmacological blockade of glial GTs with dihydrokainic acid enhanced NMDA receptor activation elicited by synaptic input or puffed glutamate in normal control rats, but this effect was precluded in neuropathic rats. Thus extrasynaptic glutamate spillover and extrasynaptic NMDA receptor activation induced by deficient glial glutamate uptake in the synapses resulted in the excessive activation of NMDA receptors in neuropathic rats. It is suggested that extrasynaptic glutamate spillover may be a key synaptic mechanism related to phenotypic alterations induced by nerve injury in the spinal dorsal horn and that glial GTs are potential new targets in the development of analgesics.

scholarly journals NMDA Receptor Activation Dephosphorylates AMPA Receptor Glutamate Receptor 1 Subunits at Threonine 840

2007 ◽  
Vol 27 (48) ◽  
pp. 13210-13221 ◽  
Author(s):  
J. Y. Delgado ◽  
M. Coba ◽  
C. N. G. Anderson ◽  
K. R. Thompson ◽  
E. E. Gray ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptor ◽  
Ampa Receptor ◽  
Receptor Activation ◽  
Nmda Receptor Activation

scholarly journals Ischemia-Induced Interleukin-6 as a Potential Endogenous Neuroprotective Cytokine against NMDA Receptor-Mediated Excitoxicity in the Brain

2000 ◽  
Vol 20 (6) ◽  
pp. 956-966 ◽  
Author(s):  
Carine Ali ◽  
Olivier Nicole ◽  
Fabian Docagne ◽  
Sylvain Lesne ◽  
Eric T. MacKenzie ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptor ◽  
Interleukin 6 ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Calcium Ionophore ◽  
Receptor Activation ◽  
Neuronal Cultures ◽  
The Brain

In the brain, the expression of the pleiotropic cytokine interleukin-6 (IL-6) is enhanced in various chronic or acute central nervous system disorders. However, the significance of IL-6 production in such neuropathologic states remains controversial. The present study investigated the role of IL-6 after cerebral ischemia. First, the authors showed that focal cerebral ischemia in rats early up-regulated the expression of IL-6 mRNA, without affecting the transcription of its receptors (IL-6Rα: and gp130). Similarly, the striatal injection of N-methyl-d-aspartate (NMDA) in rats, a paradigm of excitotoxic injury, activated the expression of IL-6 mRNA. The involvement of glutamatergic receptor activation was further investigated by incubating cortical neurons with NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). NMDA and ionomycin (a calcium ionophore) up-regulated IL-6 mRNA, suggesting that neurons may produce IL-6 in response to the calcium influx mediated through NMDA receptors. The potential role of IL-6 during ischemic/excitotoxic insults was then studied by testing the effect of IL-6 against apoptotic or excitotoxic challenges in cortical cultures. IL-6 did not prevent serum deprivation- or staurosporine-induced apoptotic neuronal death, or AMPA/kainate-mediated excitotoxicity. However, in both mixed and pure neuronal cultures, IL-6 dose-dependently protected neurons against NMDA toxicity. This effect was blocked by a competitive inhibitor of IL-6. Overall, the results suggest that the up-regulation of IL-6 induced by cerebral ischemia could represent an endogenous neuroprotective mechanism against NMDA receptor-mediated injury.

scholarly journals Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

2021 ◽  
Vol 15 ◽  
Author(s):  
Theresa S. Rimmele ◽  
Shaomin Li ◽  
Jens Velde Andersen ◽  
Emil W. Westi ◽  
Alexander Rotenberg ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Recovery Period ◽  
Glutamate Transporter ◽  
Receptor Activation ◽  
Presynaptic Terminals ◽  
Ca1 Region ◽  
Metabolic Role ◽  
Synaptic Mitochondria ◽  
Old Mice

GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20–25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.

Distinct NMDA and AMPA Receptor–Mediated Responses in Mouse and Human Cajal-Retzius Cells

2001 ◽  
Vol 86 (5) ◽  
pp. 2642-2646 ◽  
Author(s):  
Shao-Ming Lu ◽  
Nada Zecevic ◽  
Hermes H. Yeh
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptor ◽  
Differential Sensitivity ◽  
Voltage Dependent ◽  
Cell Current ◽  
Nmda Glutamate Receptor ◽  
Retzius Cells ◽  
Glutamate Receptor Agonist ◽  
Human And Mouse ◽  
Cortical Slices

This study examined glutamate-activated current responses of mouse and human Cajal-Retzius (C-R) cells. Thin cortical slices were prepared from the brains of mice 4–6 days after birth and from those of midgestational human fetuses. Both human and mouse C-R cells displayed glutamate-induced whole-cell current responses that were voltage-dependent and included an N-methyl-d-aspartate (NMDA) receptor–mediated component that was differentially sensitive to blockade by the NMDA receptor antagonists 2-amino-5-phosphonovaleric acid and ifenprodil. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a non-NMDA glutamate receptor agonist, induced current responses in human but not in mouse C-R cells. These results, taken together, lead us to conclude that human C-R cells express both NMDA and AMPA types of glutamate receptors very early during development of the cortex. In contrast, mouse C-R cells express only the NMDA type of glutamate receptor. Thus we demonstrate a species-dependent sensitivity of C-R cells to glutamate and postulate that this differential sensitivity may account in part for a species-dependent difference in the persistence of C-R cells during cortical development.

Inflammation, Glutamate, and Glia in Depression: A Literature Review

CNS Spectrums ◽  
2008 ◽  
Vol 13 (6) ◽  
pp. 501-510 ◽  
Author(s):  
Leah McNally ◽  
Zubin Bhagwagar ◽  
Jonas Hannestad
Keyword(s):  
Glutamate Receptor ◽  
Inflammatory Mediators ◽  
Microglial Activation ◽  
Acid Metabolism ◽  
Excitatory Amino Acid ◽  
Receptor Activation ◽  
Interferon Α ◽  
Neurotoxic Effects ◽  
Chronic Activation ◽  
The Brain

ABSTRACTMultiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-α treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

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