Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures

Routbort, Mark J.; Bausch, Suzanne B.; McNamara, James O

doi:10.1016/s0306-4522(99)00358-9

Cited by 78 publications

(71 citation statements)

References 27 publications

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“…Several observations suggest that kainate receptors play an important role in epilepsy and excitotoxicity (Pollard et al, 1994;Mulle et al, 1998;Routbort et al, 1999;Moldrich et al, 2000). Although some studies show that kainate-induced toxicity is mainly due to the activation of AMPA receptors (Ohno et al, 1997;Ferreira et al, 1998;Ambrósio et al, 2000), other reports also demonstrate the presence of functional kainate receptors (Parternain et al, 1995) and their involvement in excitotoxicity (Sánchez-Gómez and Matute, 1999).…”

mentioning

confidence: 97%

Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Silva¹,

Malva²,

Ambrósio³

et al. 2001

J of Neuroscience Research

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We investigated the role of kainate (KA) receptor activation and desensitization in inducing the increase in the intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ) in individual cultured rat hippocampal neurons. The rat hippocampal neurons in the cultures were shown to express kainate receptor subunits, KA2 and GluR6/7, either by immunocytochemistry or by immunoblot analysis. The effect of LY303070, an ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor antagonist, on the alterations in the [Ca 2ϩ ] i caused by kainate showed cell-tocell variability. The [Ca 2ϩ ] i increase caused by kainate was mostly mediated by the activation of AMPA receptors because LY303070 inhibited the response to kainate in a high percentage of neurons. The response to kainate was potentiated by concanavalin A (Con A), which inhibits kainate receptor desensitization, in 82.1% of the neurons, and this potentiation was not reversed by LY303070 in about 38% of the neurons. Also, upon stimulation of the cells with 4-methylglutamate (MGA), a selective kainate receptor agonist, in the presence of Con A, it was possible to observe [Ca 2ϩ ] i changes induced by kainate receptor activation, because LY303070 did not inhibit the response in all neurons analyzed. In toxicity studies, cultured rat hippocampal neurons were exposed to the drugs for 30 min, and the cell viability was evaluated at 24 hr using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The selective activation of kainate receptors with MGA, in the presence of Con A, induced a toxic effect, which was not prevented by LY303070, revealing a contribution of a small subpopulation of neurons expressing kainate receptors that independently mediate cytotoxicity. Taken together, these results indicate that cultured hippocampal neurons express not only AMPA receptors, but also kainate receptors, which can modulate the [Ca 2ϩ ] i and toxicity. J. Neurosci. Res. 65:378 -386, 2001.

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mentioning

confidence: 97%

Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Silva¹,

Malva²,

Ambrósio³

et al. 2001

J of Neuroscience Research

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“…The organotypic slice culture preserves hippocampal circuitry, permitting generation of seizure-like events in vitro (Gutierrez et al, 1999;Routbort et al, 1999). We first examined whether basal expression levels of the HCN1 and HCN2 channel isoforms in the cultures (explanted on P8 then kept in vitro for 3-4 days; DIV 11-12) approximated the in vivo pattern at an equivalent age (P10-12).…”

Section: Hcn Channel Expression In Organotypic Hippocampal Cultures Rmentioning

confidence: 99%

“…Seizure-like events were induced after 3 days in vitro by incubating cultures for 3 hours in medium containing kainic acid (KA 6 μM; Sigma, St. Louis, MO). Seizure-like events were terminated by returning cultures to normal medium, resulting in cessation of epileptiform discharges (Routbort et al, 1999). Controls were treated identically, but media were devoid of convulsants.…”

Section: Organotypic Slice Cultures and Experimental Agentsmentioning

confidence: 99%

Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Richichi

Brewster

Bender

et al. 2008

Neurobiology of Disease

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Epilepsy may result from abnormal function of ion channels, such as those caused by genetic mutations. Recently, pathological alterations of the expression or localization of normal channels have been implicated in epilepsy generation, and termed 'acquired channelopathies'. Altered expression levels of the HCN channels--that conduct the hyperpolarization-activated current, I h --have been demonstrated in hippocampus of patients with severe temporal lobe epilepsy as well as in animal models of temporal lobe and absence epilepsies. Here we probe the mechanisms for the altered expression of HCN channels which is provoked by seizures. In organotypic hippocampal slice cultures, seizure-like events selectively reduced HCN type 1 channel expression and increased HCN2 mRNA levels, as occurs in vivo. The mechanisms for HCN1 reduction involved Ca 2+ -permeable AMPA receptors-mediated Ca 2+ influx, and subsequent activation of Ca 2+ /calmodulin-dependent protein kinase II. In contrast, upregulation of HCN2 expression was independent of these processes. The data demonstrate an orchestrated program for seizure-evoked transcriptional channelopathy involving the HCN channels, that may contribute to certain epilepsies.

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“…In these cultures, synaptic organization, expression of receptors, and intrinsic hippocampal fiber pathways are developed corresponding to their in vivo counterparts (Frotscher et al, 1995;Holopainen and Lauren, 2003). The treat-ment of cultures with the glutamate receptor agonist kainic acid (KA) leads to enhanced excitation and region-selective neuronal death (Fisher and Alger, 1984;Bruce et al, 1995;Routbort et al, 1999;Holopainen et al, 2001;Liu et al, 2001), which largely correspond to that detected in the hippocampus of epileptic animals in experimental conditions (Buckmaster and Dudek, 1997;Lynch and Sutula, 2000;Zhang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

Kukko‐Lukjanov

Soini²,

Taira³

et al. 2006

J. Neurosci.

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The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H 1 ) and histamine 3 (H 3 ) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (

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Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures

Cited by 78 publications

References 27 publications

Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

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Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures

Cited by 78 publications

References 27 publications

Role of kainate receptor activation and desensitization on the [Ca2+]i changes in cultured rat hippocampal neurons

Role of kainate receptor activation and desensitization on the [Ca2+]i changes in cultured rat hippocampal neurons

Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

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Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons