Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures

Smolders, Ilse Julia; Bortolotto, Zuner A.; Clarke, Vernon R. J.; Warre, Ruth; Khan, Ghous M.; O’Neill, Michael; Ornstein, Paul L.; Bleakman, David; Ogden, Ann-Marie; Weiss, Brianne; Stables, James P.; Ho, Ken H.; Ebinger, Guy; Collingridge, Graham L.; Lodge, David; Michotte, Yvette

doi:10.1038/nn880

Cited by 140 publications

(132 citation statements)

References 44 publications

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“…This conclusion is based on both genetic and pharmacological evidence and is consistent with both expression and anatomical data (Bahn et al, 1994;Paternain et al, 2000;Darstein et al, 2003). The apparent absence of GLU K5 from mossy fiber synapses suggests that behavioral effects of GLU K5 -selective drugs (Smolders et al, 2002) are unlikely to be mediated by effects on mossy fiber transmission and may indicate a molecular basis for strategies to selectively affect distinct KAR subpopulations in the hippocampus.…”

Section: Discussionsupporting

confidence: 76%

Assessing the Role of GLU_K5and GLU_K6at Hippocampal Mossy Fiber Synapses

Breustedt

Schmitz²

2004

J. Neurosci.

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It has been suggested recently that presynaptic kainate receptors (KARs) are involved in short-term and long-term synaptic plasticity at hippocampal mossy fiber synapses. Using genetic deletion and pharmacology, we here assess the role of GLU K5 and GLU K6 in synaptic plasticity at hippocampal mossy fiber synapses. We found that the kainate-induced facilitation was completely abolished in the GLU K6 Ϫ/Ϫ mice, whereas it was unaffected in the GLU K5 Ϫ/Ϫ . Consistent with this finding, synaptic facilitation was reduced in the GLU K6 Ϫ/Ϫ and was normal in the GLU K5 Ϫ/Ϫ . In agreement with these results and ruling out any compensatory effects in the genetic deletion models, application of the GLU K5 -specific antagonist LY382884 [(3S,4aR,6S,8aR)-6-(4-carboxyphenyl)methyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid] did not affect short-term and long-term synaptic plasticity at the hippocampal mossy fiber synapses. We therefore conclude that the facilitatory effects of kainate on mossy fiber synaptic transmission are mediated by GLU K6 -containing KARs.

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Section: Discussionsupporting

confidence: 76%

Assessing the Role of GLU_K5and GLU_K6at Hippocampal Mossy Fiber Synapses

Breustedt

Schmitz²

2004

J. Neurosci.

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“…Two compounds have been described recently: LY382884 and NS3763, which appear to show certain specificity for KARs with different subunit compositions (Bortolotto et al, 1999;Smolders et al, 2002;Alt et al 2004;Christensen et al, 2004). To confirm that this was the case, we characterized these compounds in HEK293 cells expressing different combinations of KAR subunits.…”

Section: Resultsmentioning

confidence: 85%

“…In contrast, antagonism of somatic receptors would reduce the inhibition of pyramidal neurons, whereas the antagonism of presynaptic receptors would potentiate it, probably producing an antiepileptic effect. Along these lines, recent results showed that LY382884 and other GluR5 antagonists behave as potent antiepileptic compounds in a model of hippocampal epilepsy (Smolders et al, 2002).…”

mentioning

confidence: 96%

A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

Christensen¹,

Paternain²,

Selak³

et al. 2004

J. Neurosci.

118

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Although some physiological functions of kainate receptors (KARs) still remain unclear, recent advances have highlighted a role in synaptic physiology. In hippocampal slices, kainate depresses GABA-mediated synaptic inhibition and increases the firing rate of interneurons. However, the sensitivity to agonists of these responses differs, suggesting that the presynaptic and somatic KARs have a distinct molecular composition. Hippocampal interneurons express several distinct KAR subunits that can assemble into heteromeric receptors with a variety of pharmacological properties and that, in principle, could fulfill different roles. To address which receptor types mediate each of the effects of kainate in interneurons, we used new compounds and mice deficient for specific KAR subunits. In a recombinant assay, 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) acted exclusively on homomeric glutamate receptor subunit 5 (GluR5), whereas 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl) 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) antagonized homomeric GluR5 and any heteromeric combination containing GluR5 subunits. In hippocampal slices, LY382884, but not NS3763, was able to prevent kainate-induced depression of evoked IPSC. In contrast, neither prevented the concomitant increase in spontaneous IPSC frequency. The selectivity of these compounds was seen additionally in knock-out mice, such that they were inactive in GluR5 Ϫ/Ϫ mice but completely effective in GluR6 Ϫ/Ϫ mice. Our data indicate that in wild-type mice, CA1 interneurons express heteromeric GluR6 -KA2 receptors in their somatic compartments and GluR5-GluR6 or GluR5-KA2 at presynaptic terminals. However, functional compensation appears to take place in the null mutants, a new pharmacological profile emerging more compatible with the activity of homomeric receptors in both compartments: GluR5 in GluR6 Ϫ/Ϫ mice and GluR6 in GluR5 Ϫ/Ϫ mice.

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“…Pharmacologically, the anticonvulsant topiramate can block GluR5-containing KARs and can protect against seizures induced by the GluR5-selective agonist ATPA , Kaminski et al, 2004. Other GluR5 selective antagonists, such as LY377770 & LY382884, can prevent the induction and maintenance of pilocarpine-induced limbic seizures and epileptiform activity induced by electrical stimulation, both in vitro and in vivo (Smolders et al, 2002). Finally, KARs are aberrantly expressed on granule cells after mossy fiber sprouting in epileptic rats (Epsztein et al, 2005).…”

Section: Kainate Receptors Are Involved In Excitotoxicity and Temporamentioning

confidence: 99%

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

2007

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Although in situ hybridization studies have revealed the presence of kainate receptor (KAR) mRNA in neurons of the rat medial entorhinal cortex (mEC), the functional presence and roles of these receptors are only beginning to be examined. To address this deficiency, whole cell voltage clamp recordings of locally evoked EPSCs were made from mEC layer II and III neurons in combined entorhinal cortex -hippocampal brain slices. Three types of neurons were identified by their electroresponsive membrane properties, locations, and morphologies: stellate-like "Sag" neurons in layer II (S), pyramidal-like "No Sag" neurons in layer III (NS), and "Intermediate Sag" neurons with varied morphologies and locations (IS). Non-NMDA EPSCs in these neurons were composed of two components, and the slow decay component in NS neurons had larger amplitudes and contributed more to the combined EPSC than did those observed in S and IS neurons. This slow component was mediated by KARs and was characterized by its resistance to either GYKI 52466 (100 μM) or NBQX (1 μM), relatively slow decay kinetics, and sensitivity to CNQX (10-50 μM). KAR mediated EPSCs in pyramidal-like NS neurons contributed significantly more to the combined non-NMDA EPSC than did those from S and IS neurons. Layer III neurons of the mEC are selectively susceptible to degeneration in human temporal lobe epilepsy (TLE) and animal models of TLE such as kainate-induced status epilepticus. Characterizing differences in the complement of postsynaptic receptors expressed in injury prone versus injury resistant mEC neurons represents an important step toward understanding the vulnerability of layer III neurons seen in TLE.

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Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures

Cited by 140 publications

References 44 publications

Assessing the Role of GLU_K5and GLU_K6at Hippocampal Mossy Fiber Synapses

Assessing the Role of GLU_K5and GLU_K6at Hippocampal Mossy Fiber Synapses

A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

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Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures

Cited by 140 publications

References 44 publications

Assessing the Role of GLUK5and GLUK6at Hippocampal Mossy Fiber Synapses

Assessing the Role of GLUK5and GLUK6at Hippocampal Mossy Fiber Synapses

A Mosaic of Functional Kainate Receptors in Hippocampal Interneurons

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

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Assessing the Role of GLU_K5and GLU_K6at Hippocampal Mossy Fiber Synapses

Assessing the Role of GLU_K5and GLU_K6at Hippocampal Mossy Fiber Synapses