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
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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 CA 3 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 CA 3 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.Keywords:
Domoic Acid
Kainate receptor
Mossy fiber (hippocampus)
Neurotoxin
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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 CA 3 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 CA 3 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.
Domoic Acid
Kainate receptor
Mossy fiber (hippocampus)
Neurotoxin
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Acute hippocampal slices and primary neuronal cultures are often used with a tacit assumption that basic characteristics of the two models closely resemble each other. The use of the cell cultures, however, may raise controversies because of non-physiological conditions resulting from e.g. glial cells deficit, random neuronal sprouting, lack of specificity in the synaptic connections, impaired homeostasis, etc. Importantly, alteration in neuronal environment, especially when occurring over a prolonged period of time, may give rise to a profound homeostatic modulation. In the present study we have compared the properties of GABAergic and glutamatergic (non-NMDA) currents in pyramidal neurons from hippocampal slices and neuronal cell culture. We show that, most strikingly, amplitude ratio of currents elicited by ultrafast applications of saturating GABA and glutamate was nearly one order of magnitude larger in cultured neurons than that in slices. Miniature IPSCs and EPSCs also showed substantial differences between these two models. In particular, mEPSC amplitudes were larger and more frequent in cultured neurons but their time duration was longer in slices. Miniature IPSCs did not show differences in amplitude when comparing slices and cultures but their time duration was faster and occurrence more frequent in slices. In conclusion, we provide evidence that expression pattern of GABA(A) and glutamate receptors as well as synaptic current properties in the neuronal cell culture show profound differences with respect to that in the physiological conditions.
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Summary Perturbed information processing in the amygdala has been implicated in developmentally originating neuropsychiatric disorders. However, little is known on the mechanisms that guide formation and refinement of intrinsic connections between amygdaloid nuclei. We demonstrate that the glutamatergic connection from basolateral to central amygdala (BLA-CeA) develops rapidly during the first ten postnatal days, before external inputs underlying amygdala dependent behaviors emerge. During this restricted period of synaptic development, kainate-type of ionotropic glutamate receptors (KARs) are highly expressed in the BLA and tonically activated to regulate glutamate release via a G-protein dependent mechanism. Genetic manipulation of this endogenous KAR activity locally in the newborn LA perturbed development of glutamatergic input to CeA, identifying KARs as a physiological mechanism regulating wiring of the intrinsic glutamatergic circuitry in the amygdala.
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Significance Neuronal circuits develop in an activity-dependent manner. In vitro data suggest that the intracellular accumulation of chloride—a universal characteristic of immature nerve cells—drives network maturation through a depolarizing action of the neurotransmitter GABA. We here demonstrate that deletion of the chloride cotransporter NKCC1 from forebrain pyramidal cells severely impairs hippocampal network synchrony in vitro. In contrast, NKCC1 has weak and event type-dependent effects on spontaneous network activity in vivo, and loss of NKCC1 leaves the maturation of synaptic properties, network dynamics, and hippocampus-dependent behaviors largely unaffected. Our data reveal a subtle neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the assertion that NKCC1 in this major cell type is central to hippocampal development.
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Domoic acid (0.6 mg/kg) was injected intravenously through the caudal vein in pregnant female mice on the 13th day of gestation and EEG was monitored in the developing progeny during postnatal days 10–30. No clinical seizure activity was observed during this period. However, these mice demonstrated generalized electrocortical inhibition associated with diffuse spike and wave activity in their basal EEG records. Intrauterine domoic acid-exposed (IUD) mice had significantly reduced seizure thresholds to an additional dose of domoic acid, given postnatally. At the light microscopic level, hippocampus of IUD mice exhibited age related developmental neurotoxicity. No cellular damage was observed on postnatal day 1. On day 14, severe neuronal damage was observed in the hippocampal CA3 and dentate gyrus regions. On day 30, in addition to CA3 and dentate gyrus, CA4 was also involved. Brain regional GABA levels were significantly reduced and glutamate levels increased in IUD mice. Kainate receptor binding to hippocampal synaptosomal membranes from IUD mice at 30 d of age was significantly increased. There was also an enhanced 45Ca influx into cortical and hippocampal slices of these mice. These findings suggest that intrauterine exposure to domoic acid can induce hippocampal excitotoxicity by increasing the neuronal calcium influx through kainate receptor activation. Histological changes suggest progressive hippocampal damage in IUD mice, but without overt clinical seizures.
Domoic Acid
Kainate receptor
Neurotoxicity
Excitotoxicity
Subiculum
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Domoic acid, an excitatory amino acid structurally related to kainic acid, has recently been identified as being responsible for the severe intoxication presented, in 1987, by more than 150 people having eaten mussels grown in Prince Edward Island. The present in vivo electrophysiological studies, using unitary extracellular recordings obtained from pyramidal neurons of the CA1 and of the CA3 regions of the rat dorsal hippocampus, were undertaken to study the effect of kainic acid and domoic acid applied by microiontophoresis and compare their potencies to that of agonists of the 2 other subtypes of glutamatergic receptors or neuropeptides. The activation induced by domoic acid and 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 all the other substances tested. In the CA1 as well as in the CA3 region, domoic acid was about 3 times more potent than kainate. A selective lesion of the mossy fibre system originating from the dentate gyrus and projecting to the CA3 region of the dorsal hippocampus, drastically reduced the excitatory effect of kainic acid and domoic acid in this later area, without affecting the response to the other substances tested. Several class of pharmacological agents were studied in an attempt to find an antagonist of kainate and domoic acid. Only benzodiazepines could selectively suppress the neuronal activation induced by kainate, however, with a lower efficacy in the CA3 than in the CA1 region. These results demonstrate that domoic acid is a potent agonist of kainate receptors and that, in the CA3 region, it might produce its neurotoxic effects through activation of kainate receptors located on mossy fibre terminals. Finally, in the event of a new wave of intoxication, our results suggest that a rapid treatment with high doses of benzodiazepines could possibly prevent the important and irreversible hippocampal damage.
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Kainate receptor
Neurotoxin
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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.
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Domoic Acid
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