Biochemical and morphological analysis of non-NMDA receptor mediated excitotoxicity in chick embryo retina

1999 ◽  
Vol 16 (1) ◽  
pp. 131-139 ◽  
Author(s):  
QUAN CHEN ◽  
JOHN W. OLNEY ◽  
MADELON T. PRICE ◽  
CARMELO ROMANO
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Chick Embryo ◽  
Nmda Receptors ◽  
Ampa Receptor ◽  
Neuronal Death ◽  
Receptor Activation ◽  
Metabotropic Receptor ◽  
Receptor Agonists

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate glutamatergic neurotransmission, and when pathologically overstimulated induce excitotoxic neuronal death. Of the two families of iGluRs, the non-NMDA receptors have received less experimental attention than the NMDA receptors as mediators of neuronal death in in vitro systems. We have demonstrated that non-NMDA receptor activation is highly lethal for neurons of the chick embryo retina, and further characterize this phenomenon here. Treatment of isolated retinas with any of the non-NMDA receptor agonists glutamate, AMPA, or KA, in the presence of the NMDA receptor antagonist MK-801, led to pathomorphology and cell death. KA was the most effective toxin. All of KA-induced toxicity could be blocked by selective AMPA receptor blockers. The toxicity of both AMPA and glutamate could be greatly increased using cyclothiazide, which blocks AMPA receptor desensitization. These results indicate that KA is the most powerful toxin because it is a non-desensitizing agonist at the AMPA receptors. Glutamate exhibited a paradoxical ability to prevent KA-induced toxicity as measured by a biochemical assay of cell death. Also, histological studies indicated that glutamate selectively blocked KA-induced pathomorphological changes in bipolar cells. This protective effect of glutamate was not mimicked by AMPA, NMDA, or any of several metabotropic receptor agonists, indicating that it may be mediated by a receptor of undescribed pharmacology.

scholarly journals Cortical Death Caused by Striatal Administration of AMPA and Interleukin-1 is Mediated by Activation of Cortical NMDA Receptors

2000 ◽  
Vol 20 (10) ◽  
pp. 1409-1413 ◽  
Author(s):  
Stuart M. Allan ◽  
Nancy J. Rothwell
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Neuronal Death ◽  
Interleukin 1 ◽  
Cortical Cell ◽  
Nmda Receptor Antagonist ◽  
Interleukin 1Β

Striatal coadministration of interleukin-1β (IL-1β) with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) in rats results in widespread cortical cell death not caused by either treatment alone. This cortical damage was unaffected by cortical infusion of the AMPA-receptor antagonist NBQX. Cortical infusion of an NMDA-receptor antagonist D-AP5 significantly inhibited (57%; P < 0.05) cortical death, but had no effect on the local striatal death. Thus, cortical neuronal death induced by striatal S-AMPA and human recombinant interleukin-1β (hrIL-1β) is mediated by activation of NMDA receptors in the cortex. The authors propose that IL-1β actions on AMPA-receptor mediated cell death may involve the activation of polysynaptic pathways from the striatum to the cortex.

scholarly journals NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

2009 ◽  
Vol 101 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Felipe Espinosa ◽  
Ege T. Kavalali
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Ampa Receptor ◽  
Cortical Neurons ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Receptor Activity ◽  
Resting Membrane Potential ◽  
Nmda Current ◽  
Nmda Receptor Activation

Under physiological conditions N-methyl-d-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg2+. Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately −67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises ∼20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately −50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.

Retinogeniculate EPSPs recorded intracellularly in the ferret lateral geniculate nucleus in vitro: Role of NMDA receptors

1992 ◽  
Vol 8 (6) ◽  
pp. 545-555 ◽  
Author(s):  
Manuel Esguerra ◽  
Young H. Kwon ◽  
Mriganka Sur
Keyword(s):  
Membrane Potential ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Lateral Geniculate Nucleus ◽  
Excitatory Amino Acid ◽  
Optic Tract ◽  
Receptor Activation ◽  
Lateral Geniculate

AbstractWe used an in vitro preparation of the ferret lateral geniculate nucleus (LGN) to examine the role of the NMDA class of excitatory amino acid (EAA) receptors in retinogeniculate transmission. Intracellular recordings revealed that blockade of NMDA receptors both shortened the time course and reduced the amplitude of fast and slow components of excitatory postsynaptic potentials (EPSPs) evoked by optic tract stimulation. The amplitude and width of the EPSPs mediated by NMDA receptors increased as membrane potential was depolarized towards spike threshold. Individual LGN cells were influenced to varying extents by blockade of NMDA receptors; NMDA and non-NMDA receptor blockade together attenuated severely the entire retinogeniculate EPSP. The dependence of all components of retinogeniculate EPSPs (and action potentials) on NMDA receptor activation supports the hypothesis that the NMDA receptor participates in fast (<10 ms) synaptic events underlying conventional retinogeniculate transmission. The voltage dependence of the NMDA receptor-gated conductance suggests strongly that the transmission of retinal information through the LGN is subject to modulation by extraretinal inputs that affect the membrane potential of LGN neurons.

scholarly journals Stretch injury selectively enhances extrasynaptic, GluN2B-containing NMDA receptor function in cortical neurons

2013 ◽  
Vol 110 (1) ◽  
pp. 131-140 ◽  
Author(s):  
Carrie R. Ferrario ◽  
Blaise O. Ndukwe ◽  
Jianhua Ren ◽  
Leslie S. Satin ◽  
Paulette B. Goforth
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Ampa Receptor ◽  
Cortical Neurons ◽  
Mechanical Stretch ◽  
Receptor Activity ◽  
Network Activity ◽  
Stretch Injury

Alterations in the function and expression of NMDA receptors are observed after in vivo and in vitro traumatic brain injury. We recently reported that mechanical stretch injury in cortical neurons transiently increases the contribution of NMDA receptors to network activity and results in an increase in calcium-permeable AMPA (CP-AMPA) receptor-mediated transmission 4 h postinjury ( Goforth et al. 2011 ). Here, we evaluated changes in the function of synaptic vs. extrasynaptic GluN2B-containing NMDA receptors after injury. We also determined whether postinjury treatment with the GluN2B-selective antagonist Ro 25-6981 or memantine prevents injury-induced increases in CP-AMPA receptor activity. We found that injury increased extrasynaptic, GluN2B-containing NMDA receptor-mediated whole cell currents. In contrast, we found no differences in synaptic NMDA receptor-mediated transmission after injury. Furthermore, treatment with Ro 25-6981 or memantine after injury prevented injury-induced increases in CP-AMPA receptor-mediated activity. Together, our data suggest that increased NMDA receptor activity after injury is predominantly due to alterations in extrasynaptic, GluN2B-containing NMDA receptors and that activation of these receptors may contribute to the appearance of CP-AMPA receptors after injury.

Thiopental Inhibits Increases in [Ca2+]iInduced by Membrane Depolarization, NMDA Receptor Activation, and Ischemia in Rat Hippocampal and Cortical Slices 

1998 ◽  
Vol 89 (2) ◽  
pp. 456-466 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
Naoshi Fujiwara ◽  
Hiroshi Endoh ◽  
Tomohiro Yamakura ◽  
Kiichiro Taga ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Membrane Depolarization ◽  
In Vitro Ischemia ◽  
High K ◽  
Nmda Receptor Activation ◽  
Cortical Slices

Background This study examined the effects of thiopental on intracellular calcium ([Ca2+]i) changes induced by membrane depolarization, N-methyl-D-aspartate (NMDA) receptor activation, and ischemia. Methods Experiments were performed in brain slices prepared from Wistar rats. [Ca2+]i measurements were taken on the CA1 pyramidal cell layer of the hippocampus or layers II to III of the somatosensory cortex using the fura-2 fluorescence technique. Membrane depolarization and NMDA receptor activation were induced by exposing slices to 60 mM K+ and 100 microM NMDA, respectively. In vitro ischemia was induced by superfusing slices with glucose-free Krebs solution equilibrated with 95% nitrogen and 5% carbon dioxide. Thiopental was applied 5 min before application of high K+ and NMDA, or before in vitro ischemia. Results Ischemia for 15 min produced a characteristic [Ca2+]i increase in both hippocampal and cortical slices. Thiopental prolonged the latency to the appearance of the [Ca2+]i plateau and reduced the magnitudes of increase in [Ca2+]i 8, 10, and 15 min after the onset of ischemia. Thiopental also suppressed the high K+- and NMDA-induced [Ca2+]i increases. The NMDA-induced [Ca2+]i increases were attenuated to a greater extent in cortical slices than were those in hippocampal slices. The inhibition of thiopental on the 200-microM NMDA-mediated [Ca2+]i response was confirmed in cultured cortical neurons. Conclusions The results indicate that thiopental attenuates ischemia-induced [Ca2+]i increases in the hippocampus and cortex in vitro, probably because of its inhibition of both voltage-gated calcium channels and NMDA receptors. The regionally different inhibition of thiopental on NMDA receptors may relate to its region-specific action against ischemia.

scholarly journals THE CULTIVATION OF TISSUES FOR PROLONGED PERIODS IN SINGLE FLASKS

1936 ◽  
Vol 64 (1) ◽  
pp. 121-130 ◽  
Author(s):  
Raymond C. Parker
Keyword(s):  
Cell Death ◽  
Chick Embryo ◽  
Connective Tissue ◽  
Breast Muscle ◽  
Cell Multiplication ◽  
Tyrode Solution ◽  
Low Level ◽  
Further Development

1. Fragments of breast muscle from a 12 day old chick embryo have been kept alive in single flasks for an entire year without being transferred. The nutrient materials were supplied by frequent applications of adult fowl serum diluted with Tyrode solution. 2. When fragments of fixed tissues are cultivated in serum, cell multiplication and cell death are both reduced to an extremely low level. 3. The presence of a plasma coagulum is not essential to the continued survival and further development of tissues cultivated inserum. 4. The fibrinogen, prothrombin, and fibrin of coagulated plasma are not essential to the development of connective tissue fibers in vitro.

Dynorphin A Elicits an Increase in Intracellular Calcium in Cultured Neurons Via a Non-Opioid, Non-NMDA Mechanism

2000 ◽  
Vol 83 (5) ◽  
pp. 2610-2615 ◽  
Author(s):  
Qingbo Tang ◽  
Ronald M. Lynch ◽  
Frank Porreca ◽  
Josephine Lai
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Intracellular Calcium ◽  
Cortical Neurons ◽  
Excitatory Amino Acid ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Dynorphin A ◽  
Excitatory Effect

The opioid peptide dynorphin A is known to elicit a number of pathological effects that may result from neuronal excitotoxicity. An up-regulation of this peptide has also been causally related to the dysesthesia associated with inflammation and nerve injury. These effects of dynorphin A are not mediated through opioid receptor activation but can be effectively blocked by pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists, thus implicating the excitatory amino acid system as a mediator of the actions of dynorphin A and/or its fragments. A direct interaction between dynorphin A and the NMDA receptors has been well established; however the physiological relevance of this interaction remains equivocal. This study examined whether dynorphin A elicits a neuronal excitatory effect that may underlie its activation of the NMDA receptors. Calcium imaging of individual cultured cortical neurons showed that the nonopioid peptide dynorphin A(2-17) induced a time- and dose-dependent increase in intracellular calcium. This excitatory effect of dynorphin A(2-17) was insensitive to (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]-cyclohepten-5,10-imine (MK-801) pretreatment in NMDA-responsive cells. Thus dynorphin A stimulates neuronal cells via a nonopioid, non-NMDA mechanism. This excitatory action of dynorphin A could modulate NMDA receptor activity in vivo by enhancing excitatory neurotransmitter release or by potentiating NMDA receptor function in a calcium-dependent manner. Further characterization of this novel site of action of dynorphin A may provide new insight into the underlying mechanisms of dynorphin excitotoxicity and its pathological role in neuropathy.

scholarly journals NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

1998 ◽  
Vol 84 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Patricia J. Ohtake ◽  
José E. Torres ◽  
Yair M. Gozal ◽  
Gavin R. Graff ◽  
David Gozal
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Activation ◽  
Sodium Cyanide ◽  
Respiratory Drive ◽  
Peripheral Chemoreceptor ◽  
Cardiorespiratory Control ◽  
Mk 801 ◽  
Ventilatory Responses ◽  
Before And After

N-methyl-d-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (V˙e) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (Vt) decreased while frequency increased, resulting in a modest reduction inV˙e. Inspiratory time (Ti) decreased, whereas expiratory time remained unchanged. TheV˙e responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (Vt/Ti) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas Vt was unaffected. Sodium cyanide doses associated with significantV˙eincreases were 5 and 50 μg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reducedV˙e during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.

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