Electrophysiological studies of NMDA receptors

Ascher, Philippe; Nowak, Linda M.

doi:10.1016/0166-2236(87)90174-3

Cited by 346 publications

(143 citation statements)

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“…Similar results were obtained with all the seventeen neurons examined. The APV-sensitive component was also enhanced by artificial membrane depolarization as well (not shown), in agreement with the previous report by Ascher and Nowak (1987). The actual APV concentration of the perfusate was 100 pM at the recording stage of the chamber.…”

Section: Enhancement Of Apv Sensitive Component By Reducing Mg2+ In Tsupporting

confidence: 81%

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Composition of the Excitatory Postsynaptic Potentials Recorded from Rat Visual Cortical Neurons in Layer II/III: An In Vitro Electrophysiological and Pharmacological Studies.

Takahashi

Ogawa

1991

Tohoku J. Exp. Med.

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Intracellular recordings were performed on layer II/III neurons of rat brain slices. Neuronal responses to electrical stimulation of the white matter was analyzed pharmacologically using D-2-amino-5-phosphonovalerate (APV), a specific antagonist of the N-methyl-D-aspartate (NMDA) receptor, and kynurenate (Kyn), a broad-spectrum antagonist of both the NMDA and the non-NMDA (kainate and quisqualate) receptors. Fifty-five neurons produced an excitatory postsynaptic potential (EPSP) in response to a single shock. In fortyeight neurons (87%) of them, the EPSP consisted of an APV-sensitive component and an APV-insensitive component. While in seven neurons (13%), it consisted of only the APV-insensitive component. The APV-sensitive component was preceded by the APV-insensitive component and was enhanced in amplitude and duration by the following procedures : a) applying repetitive stimulations to the white matter, b) reducing Mg2+ concentration in the bathing solution and c) depolarizing cell membrane. The APV-insensitive component was affected by neither repetitive stimulation nor reduction of Mg2+ concentration. Both APVsensitive and APV-insensitive components were reduced by the treatment of Kyn. These suggest that in bathing medium containing Mg2+, the APV-sensitive (i.e. the NMDA receptor-mediated) EPSP is generated by the non-NMDA receptormediated depolarization, which removes the Mg2+ blockade in NMDA receptorgated channel.visual cortical neuron ; L-glutamate ; N-methyl-Daspartate receptors ; D-2-amino-5-phosphonovalerate ; kynurenate It is well established that in the mammalian CNS the N-methyl-D-aspartate (NMDA) receptor and non-NMDA receptors (kainate and quisqualate) play impor-

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Section: Enhancement Of Apv Sensitive Component By Reducing Mg2+ In Tsupporting

confidence: 81%

“…Cant rolls in mediating neuronal excitation (Watkins and Evans 1981;Ascher and Nowak 1987;Catman and Iverson 1987). The non-NMDA receptors induce the conventional fast component of excitatory post synaptic potentials (EPSPs) while the NMDA receptors mediate the novel slow component of EPSPs (Forsythe and Westbrook 1988).…”

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confidence: 99%

Composition of the Excitatory Postsynaptic Potentials Recorded from Rat Visual Cortical Neurons in Layer II/III: An In Vitro Electrophysiological and Pharmacological Studies.

Takahashi

Ogawa

1991

Tohoku J. Exp. Med.

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“…The higher toxicity of FCS in Locke-25 compared with Locke-5 should probably be ascribed to partial depolarization by the higher KCI concentration, which dampens the Mg2+ blockade of the NMDA channel (25). Fig.…”

Section: Methodsmentioning

confidence: 99%

“…To further define this extreme toxicity, glutamate was tested in the presence of glycine (25,27,28) in Locke-25. Fig.…”

Section: Methodsmentioning

confidence: 99%

Serum and depolarizing agents cause acute neurotoxicity in cultured cerebellar granule cells: role of the glutamate receptor responsive to N-methyl-D-aspartate.

Schramm

Eimerl

Costa

1990

Proc. Natl. Acad. Sci. U.S.A.

147

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The life span of neonatal rat cerebellar granule cells, grown in basal minimal Eagle's medium containing 10% (vol/vol) fetal calf serum, was extended to 21-30 days by weekly supplementation with glucose. Addition of 1% fetal calf serum to the culture at 14 days killed 85% of the cells within 1 hr. This lethal effect could be prevented by the Nmethyl-D-aspartate (NMDA) receptor antagonists dibenzocyclohepteneimine (MK-801) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP). These findings suggested that the glutamate in the serum caused the dramatic neuronal death through action on the NMDA receptor. Indeed, a 5-min incubation in a Locke physiological salt solution containing 20 pM glutamate and 5 pM glycine killed 55-90% of the cells.This acute toxicity could be prevented by a lyso-GM1 ganglioside with N-acetylated sphingosine. The relatively low glutamate content of the sera analyzed suggests that factors in addition to glycine potentiate serum neurotoxicity. The above noted antagonists of the NMDA receptor also greatly reduced the lethal effect of depolarization by 90 mM KCl or 10 FaM veratridine. Therefore, it is likely that the toxicity of the depolarizing agents is mediated by glutamate released from the cells. It is concluded that survival of cerebellar neurons in primary culture may be strongly affected by unsuspected neurotoxic phenomena elicited by brief action of a rather low glutamate concentration.The possibility that primary cultures of brain neurons might be damaged by toxic actions of glutamate has apparently received little attention other than by those specifically studying excitotoxicity (1-5). However, as will be shown, rapid death of neurones may occur under conventional experimental manipulations of neuronal cultures. Similar events may affect neurons in brain slices (6, 7) and could have important implications for pathological processes in the intact brain (1-5).Excitotoxicity mediated by glutamate and its analogs has been ascribed in many instances to excessive activation of the N-methyl-D-aspartate (NMDA) receptor. Two types of processes have been distinguished: (i) an acute reaction apparently requiring action of glutamate at high concentration, which leads to swelling by influx of Na+, Cl-, and water, terminating in lysis within 1-2 hr (8-10); and (ii) a delayed toxicity extending over approximately 20 hr. Though the excitotoxicity is initiated by glutamate, it soon becomes insensitive to glutamate receptor blockers and proceeds even after glutamate removal (11). It requires extracellular Ca2l and is dependent on prolonged elevation of free cytosolic Ca2+ (10)(11)(12)(13)(14)(15)(16) (19,20). The cell concentration was 1.6 x 106 cells per ml, and the medium was not changed throughout the cultivation period. Experiments were conducted on cells grown in a 24-well multiwell dish (Nunc) with 0.5 ml of medium per well and in 35-mm dishes (Nunc) with 2 ml per dish. The life span of the cells was extended up to 31 days in vitro by addition of 1 mg ofglucose (in 40 ,ul) per ml of...

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“…Upon ligand binding, Na + and K + pass through the pore of ionotropic glutamate receptors and cause depolarization of the neuronal membrane (Ascher & Nowak, 1987;Kandel et al, 1991). In addition to depolarizing membranes, iono-tropic glutamate receptors can initiate long-term molecular adaptations in neurons.…”

Section: Pharmacology Of Glutamate Receptorsmentioning

confidence: 99%

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

Konradi

Heckers

2003

Pharmacology & Therapeutics

292

165

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The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.

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Electrophysiological studies of NMDA receptors

Cited by 346 publications

References 31 publications

Composition of the Excitatory Postsynaptic Potentials Recorded from Rat Visual Cortical Neurons in Layer II/III: An In Vitro Electrophysiological and Pharmacological Studies.

Composition of the Excitatory Postsynaptic Potentials Recorded from Rat Visual Cortical Neurons in Layer II/III: An In Vitro Electrophysiological and Pharmacological Studies.

Serum and depolarizing agents cause acute neurotoxicity in cultured cerebellar granule cells: role of the glutamate receptor responsive to N-methyl-D-aspartate.

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

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