Domoic acid, the alleged "mussel toxin," might produce its neurotoxic effect through kainate receptor activation: an electrophysiological study in the rat dorsal hippocampus

1989 ◽  
Vol 67 (1) ◽  
pp. 29-33 ◽  
Author(s):  
Guy Debonnel ◽  
Luc Beauchesne ◽  
Claude de Montigny
Keyword(s):  
Amino Acid ◽  
Domoic Acid ◽  
Pyramidal Neurons ◽  
Excitatory Amino Acid ◽  
Dorsal Hippocampus ◽  
Electrophysiological Study ◽  
Receptor Activation ◽  
Kainate Receptor ◽  
Neurotoxic Effect ◽  
Excitatory Effect

Domoic acid, an excitatory amino acid structurally related to kainate, was recently identified as being presumably responsible for the recent severe intoxication presented by more than 100 people having eaten mussels grown in Prince Edward Island (Canada). The amino acid kainate has been shown to be highly neurotoxic to the hippocampus, which is the most sensitive structure in the central nervous system. The present in vivo electrophysiological studies were undertaken to determine if domoic acid exerts its neurotoxic effect via kainate receptor activation. Unitary extracellular recordings were obtained from pyramidal neurons of the CA1 and the CA3 regions of the rat dorsal hippocampus. The excitatory effect of domoic acid applied by microiontophoresis was compared with that of agonists of the three subtypes of glutamatergic receptors: kainate, quisqualate, and N-methyl-D-aspartate. In CA1, the activation induced by domoic acid was about threefold greater than that induced by kainate; identical concentrations and similar currents were used. In CA3, domoic acid was also three times more potent than kainate. However, the most striking finding was that domoic acid, similar to kainate, was more than 20-fold more potent in the CA3 than in the CA1 region, whereas no such regional difference could be detected with quisqualate and N-methyl-D-aspartate. As the differential regional response of CA1 and CA3 pyramidal neurons to kainate is attributable to the extremely high density of kainate receptors in the CA3 region, these results provide the first electrophysiological evidence that domoic acid may produce its neurotoxic effects through kainate receptor activation.Key words: domoate, kainate, excitotoxin, hippocampus, N-methyl-D-aspartate.

Reduced neuroexcitatory effect of domoic acid following mossy fiber denervation of the rat dorsal hippocampus: further evidence that toxicity of domoic acid involves kainate receptor activation

1989 ◽  
Vol 67 (8) ◽  
pp. 904-908 ◽  
Author(s):  
Guy Debonnel ◽  
Michel Weiss ◽  
Claude de Montigny
Keyword(s):  
Kainic Acid ◽  
Prince Edward Island ◽  
Domoic Acid ◽  
Pyramidal Neurons ◽  
Mossy Fiber ◽  
Excitatory Amino Acid ◽  
Dorsal Hippocampus ◽  
Receptor Activation ◽  
Kainate Receptors ◽  
Quisqualic Acid

Domoic acid, an excitatory amino acid structurally related to kainic acid, has been shown to be responsible for the severe intoxication presented, in 1987, by more than one hundred and fifty people having eaten mussels grown in Prince Edward Island (Canada). Unitary extracellular recordings were obtained from pyramidal neurons of the CA3 region of the rat dorsal hippocampus. The excitatory effects of microiontophoretic applications of domoic acid and of the agonists of the two other subtypes of glutamatergic receptors, quisqualate and N-methyl-D-aspartate, were compared on intact and colchicine-lesioned sides. Similar to what has been previously found for kainate, the colchicine lesion of the mossy fiber projections induced a 95% decrease of the neuronal responsiveness to domoic acid, whereas the effect of quisqualate was unchanged and that of N-methyl-D-aspartate was only slightly decreased. These results provide further electrophysiological evidence that domoic acid is a potent agonist of kainate receptors and that it may produce its neuroexcitatory and neurotoxic effects, in the hippocampal CA3 region, through activation of kainate receptors located on the mossy fiber terminals.Key words: domoic acid, kainic acid, glutamic acid, N-methyl-D-aspartic acid, quisqualic acid, dorsal hippocampus, neurotoxins.

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.

Ionotropic excitatory amino acid receptors in pre-Bötzinger complex play a modulatory role in hypoxia-induced gasping in vivo

2004 ◽  
Vol 96 (5) ◽  
pp. 1643-1650 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Respiratory Rhythm ◽  
Receptor Activation ◽  
Induced Response ◽  
Brain Hypoxia ◽  
Bötzinger Complex ◽  
Before And After ◽  
Additional Support

Activation of ionotropic excitatory amino acid (EAA) receptors in pre-Bötzinger complex (pre-BötC) not only influences the eupneic pattern of phrenic motor output but also modifies hypoxia-induced gasping in vivo by increasing gasp frequency. Although ionotropic EAA receptor activation in this region appears to be required for the generation of eupneic breathing, it remains to be determined whether similar activation is necessary for the production and/or expression of hypoxia-induced gasping. Therefore, we examined the effects of severe brain hypoxia before and after blockade of ionotropic EAA receptors in the pre-BötC in eight chloralose-anesthetized, deafferented, mechanically ventilated cats. In each experiment, before blockade of ionotropic EAA receptors in the pre-BötC, severe brain hypoxia (6% O2 in a balance of N2 for 3-6 min) produced gasping. Although bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (20-100 mM; 40 nl) into the pre-BötC eliminated basal phrenic nerve discharge, severe brain hypoxia still produced gasping. Under these conditions, however, the onset latency to gasping was increased ( P < 0.05), the number of gasps was reduced for the same duration of hypoxic gas exposure ( P < 0.05), the duration of gasps was prolonged ( P < 0.05), and the duration between gasps was increased ( P < 0.05). These findings demonstrate that hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in the pre-BötC, but ionotropic EAA receptor activation in this region may modify the expression of the hypoxia-induced response. The present findings also provide additional support for the pre-BötC as the primary locus of respiratory rhythm generation.

Spider toxin blocks excitatory amino acid responses in isolated hippocampal pyramidal neurons

1987 ◽  
Vol 79 (3) ◽  
pp. 326-330 ◽  
Author(s):  
N. Akaike ◽  
N. Kawai ◽  
N.I. Kiskin ◽  
E.M. Kljuchko ◽  
O.A. Krishtal ◽  
...  
Keyword(s):  
Amino Acid ◽  
Pyramidal Neurons ◽  
Excitatory Amino Acid ◽  
Hippocampal Pyramidal Neurons ◽  
Spider Toxin

Excitatory amino acid antagonists inhibit synaptic responses in the guinea pig hypothalamic paraventricular nucleus

1991 ◽  
Vol 65 (4) ◽  
pp. 946-951 ◽  
Author(s):  
J. P. Wuarin ◽  
F. E. Dudek
Keyword(s):  
Amino Acid ◽  
Nmda Receptor ◽  
Guinea Pig ◽  
Paraventricular Nucleus ◽  
Excitatory Amino Acid ◽  
Hypothalamic Paraventricular Nucleus ◽  
Peak Amplitude ◽  
Kainate Receptor ◽  
Dose Dependent ◽  
Synaptic Responses

1. The effects of specific excitatory amino acid (EAA) antagonists on evoked excitatory synaptic responses were studied in the hypothalamic paraventricular nucleus (PVN) of the guinea pig, by the use of the in vitro slice preparation. Intracellular recordings were obtained from paraventricular neurons, and excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) were induced by perifornical electrical stimulation. To reduce the influence of a potential gamma-aminobutyric acidA (GABAA) inhibitory component on the synaptic responses, all experiments were performed in the presence of 50 microM picrotoxin. 2. Of 20 cells tested, 13 had electrophysiological characteristics similar to magnocellular neuropeptidergic cells (MNCs) and 7 displayed low-threshold Ca2+ spikes (LTSs). No difference was detected in the effect of the antagonists on the synaptic responses of cells with or without LTS potentials. 3. The broad-spectrum EAA antagonist kynurenic acid decreased the amplitude of the EPSPs and EPSCs in a dose-dependent manner: the mean decrease was 5% for 100 microM, 43% for 300 microM, and 70% for 1 mM. 4. The quisqualate/kainate-receptor-selective antagonist 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX) induced a dose-dependent decrease of the EPSPs and EPSCs: 1 microM had no detectable effect, 3 and 10 microM caused 30 and 70% decreases, respectively, and 30 microM blocked the response almost completely. This effect was not accompanied by a change in resting membrane potential or input resistance and was slowly reversible. 5. The N-methyl-D-aspartate (NMDA)-receptor-selective antagonist DL-2-amino-5-phosphonopentanoic acid (AP5), applied at 30 and 300 microM, reduced slightly the amplitude of the decay phase of the EPSP but did not significantly affect the peak amplitude. In some cells, the current-voltage relationship of the decay phase of the EPSC revealed a region of negative slope conductance between -70 and -40 mV. 6. These results suggest that 1) glutamate or a related EAA is responsible for the fast excitatory input to magnocellular and parvocellular neurons in the PVN and probably also for cells around PVN, 2) a quisqualate/kainate receptor type is responsible for the rising phase and peak amplitude of the synaptic current, and 3) an NMDA receptor contributes to the late part of the synaptic response.

Kainate receptor-mediated synaptic currents in mudpuppy inner retinal neurons reduced by D-O-phosphoserine

1989 ◽  
Vol 62 (2) ◽  
pp. 495-500 ◽  
Author(s):  
P. A. Coleman ◽  
R. F. Miller
Keyword(s):  
Amino Acid ◽  
Ganglion Cells ◽  
Excitatory Amino Acid ◽  
Bipolar Cells ◽  
Kainate Receptor ◽  
Retinal Neurons ◽  
Synaptic Currents ◽  
Excitatory Amino Acid Receptor ◽  
Acid Receptor ◽  
Glutamate Agonists

1. The effects of D-O-phosphoserine (DOS) were examined on proximal neurons in the superfused mudpuppy retinal-eyecup preparation by measuring their synaptically evoked whole-cell currents with the use of patch-clamp electrodes. 2. DOS reduced the light-evoked excitatory postsynaptic potentials (EPSPs) of amacrine and ganglion cells. This suppression was present even though the center responses of both ON- and OFF-bipolar cells were unaffected by DOS. 3. When recordings were done under voltage-clamp conditions. DOS diminished the magnitude of light-evoked synaptic currents associated with a reduction in synaptic conductance. 4. To determine which acidic amino acid receptor mediated the network-selective action of DOS, various glutamate agonists were tested against this excitatory amino acid receptor (EAAR) antagonist. DOS blocked the depolarizing effects of kainate (KA), but not those of N-methyl-D-aspartate (NMDA) or quisqualate (QQ). Thus DOS was a selective KA antagonist, and KA receptors appear to be the dominant EAAR subtype that mediates synaptic inputs into the inner retina of the mudpuppy.

Membrane currents evoked by excitatory amino acid agonists in ON bipolar cells of the mudpuppy retina

1993 ◽  
Vol 70 (4) ◽  
pp. 1326-1338 ◽  
Author(s):  
W. B. Thoreson ◽  
R. F. Miller
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Outward Current ◽  
Receptor Activation ◽  
Extracellular Calcium ◽  
Bipolar Cells ◽  
Membrane Currents ◽  
Cation Channels ◽  
Gaba Uptake ◽  
Conductance Increase

1. Whole-cell patch-clamp recordings were obtained from ON bipolar cells in a retinal slice preparation of the mudpuppy, Necturus maculosus. The effects of excitatory amino acid (EAA) agonists applied in the presence of cobalt (2-5 mM) were examined. 2. At the holding potential of -50 mV, L-2-amino-4-phosphonobutanoic acid (L-AP4, 5-10 microM) evoked an outward current accompanied by a conductance decrease. The zero current potential of the L-AP4-evoked current was near 0 mV independent of whether the intracellular Ringer solution contained CsCl or CsCH3SO4. The currents evoked by light were also accompanied by a conductance decrease and reversed near 0 mV. Replacing external sodium with choline or N-methyl-D-glucamine generated an outward current and suppressed the response to L-AP4. The response to L-AP4 was enhanced by removing extracellular calcium and suppressed by increasing extracellular calcium. These results indicate that L-AP4 closes nonspecific cation channels that are blocked by extracellular calcium. 3. In 2 mM cobalt, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 50-100 microM) evoked membrane currents that were accompanied by a conductance increase. AMPA-evoked currents exhibited a significant chloride dependence and were suppressed by gamma-aminobutyric acid-A (GABAA) antagonists bicuculline and picrotoxin; a GABA uptake blocker, nipecotic acid; and a glycine antagonist, strychnine. AMPA-induced currents were virtually absent in the presence of 5 mM cobalt and nominally 0 mM extracellular calcium. These results indicate that the conductance increase induced by AMPA in the presence of 2 mM cobalt is largely the result of calcium-dependent synaptic inputs onto GABAA and glycine receptors of ON bipolar cells. 4. N-methyl-D-aspartic acid (250 microM) was ineffective when applied in the presence of 100 microM cadmium or 2 mM cobalt. 5. 1S,3R/1R,3S-1-aminocyclopentane-1,3-dicarboxylic acid (100-200 microM) evoked an outward current accompanied by a conductance decrease and appears to be an agonist at the L-AP4 receptor. 6. The findings of this study suggest that the only type of EAA receptor in mudpuppy ON bipolar cells is the L-AP4 receptor and that L-AP4 receptor activation results in the closing of nonspecific cation channels that are blocked by extracellular calcium.

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