Kainate binding sites in the hippocampal mossy fibers: Localization and plasticity

doi:10.1016/0306-4522(87)90237-5

Neuroscience

Volume 20, Issue 3, March 1987, Pages 739-748

https://doi.org/10.1016/0306-4522(87)90237-5 Get rights and content

Abstract

The regional distribution of high affinity binding sites for kainic acid has been determined in rat hippocampi by quantitative autoradiography. Selective lesions were made in order to determine the exact localization of these sites in the mossy fiber system, and to evaluate whether the sprouting and synaptic reorganization of the mossy fibers are associated with alterations in the distribution of these binding sites.

The results show that kainate binding sites in the stratum lucidum are more vulnerable to destruction of the granules and their mossy fibers by intrahippocampal colchicine injections than to destruction of the CA3/CA4 pyramidal cells by injection of kainate into the amygdala. This suggests that a substantial proportion of the kainate binding sites is associated with the mossy fiber terminals (i.e. the presynaptic elements). Furthermore, in keeping with an earlier study, destruction of the pyramidal neurons of CA3 by intracerebral kainate produced a dark Timm positive band in the supragranular zone which is due to the sprouting of mossy fibers. This was associated with an increase in the density of kainate binding sites, which further stresses the parallelism between the distribution of these sites and mossy fiber terminals.

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Kainate receptors modulate the microstructure of synchrony during dentate gyrus epileptiform activity
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Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults. In TLE, recurrent mossy fiber (rMF) sprouting from dentate gyrus granule cells (DGCs) forms an aberrant epileptogenic network between dentate granule cells (DGCs) that operates via ectopically expressed kainate receptors (KARs). It was previously shown that KARs expressed at the rMF-DGC synapses play a prominent role in epileptiform network events in TLE. However, it is not well understood how KARs influence neuronal network dynamics and contribute to the generation of epileptiform network activity in the dentate gyrus. To address this question, we monitored the activity of DGCs using single-cell resolution calcium imaging performed in a reliable in vitro model of TLE. Under our experimental conditions, the most prominent DGC activity patterns were interictal-like epileptiform network events, which were correlated with high levels of neuronal synchronization. The pharmacological blockade of KARs reduced the frequency as well as the number of neurons involved in these events, without altering their spatiotemporal dynamics. Analysis of the microstructure of synchrony showed that blockade of KARs diminished the fraction of neurons forming the main functional cluster. Therefore, we propose that KARs act as modulators in the epileptic network by facilitating the recruitment of neurons into coactive cell assemblies, thereby contributing to the occurrence of epileptiform network events.
Metabotropic actions of kainate receptors modulating glutamate release
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Presynaptic kainate (KA) receptors (KARs) modulate GABA and glutamate release in the central nervous system of mammals. While some of the actions of KARs are ionotropic, metabotropic actions for these receptors have also been seen to modulate both GABA and glutamate release. In general, presynaptic KARs modulate glutamate release through their metabotropic actions in a biphasic manner, with low KA concentrations producing an increase in glutamate release and higher concentrations of KA driving weaker release of this neurotransmitter. Different molecular mechanisms are involved in this modulation of glutamate release, with a G-protein independent, Ca²⁺-calmodulin adenylate cyclase (AC) and protein kinase A (PKA) dependent mechanism facilitating glutamate release, and a G-protein, AC and PKA dependent mechanism mediating the decrease in neurotransmitter release. Here, we describe the events underlying the KAR modulation of glutamatergic transmission in different brain regions, addressing the possible functions of this modulation and proposing future research lines in this field.
This article is part of the special Issue on ‘Glutamate Receptors – Kainate receptors’.
Kainate and AMPA receptors in epilepsy: Cell biology, signalling pathways and possible crosstalk
2021, Neuropharmacology
Citation Excerpt :
In TLE, dentate granule cells (DGCs) sprout new aberrant MF axons that, rather than synapsing at CA3 neurons, connect back on to DGC dendrites, forming recurrent circuits (Nadler, 2003) (Fig. 4). These anatomical circuit rearrangements are a hallmark of TLE pathogenesis (Artinian et al., 2011, 2015; Epsztein et al., 2005) that increase intrinsic excitability (Represa et al., 1987; Sutula and Dudek, 2007; Tauck and Nadler, 1985) and could represent a potential therapeutic target to reduce uncontrolled network activity (Andre et al., 2018). Importantly, ~50% of excitatory transmission at the aberrant MF-DGC synapses in epilepsy is mediated by newly inserted KARs that generate hyperexcitable circuits and drive seizures in the chronic phase of TLE (Crepel and Mulle, 2015).
Epilepsy is caused when rhythmic neuronal network activity escapes normal control mechanisms, resulting in seizures. There is an extensive and growing body of evidence that the onset and maintenance of epilepsy involves alterations in the trafficking, synaptic surface expression and signalling of kainate and AMPA receptors (KARs and AMPARs). The KAR subunit GluK2 and AMPAR subunit GluA2 are key determinants of the properties of their respective assembled receptors. Both subunits are subject to extensive protein interactions, RNA editing and post-translational modifications. In this review we focus on the cell biology of GluK2-containing KARs and GluA2-containing AMPARs and outline how their regulation and dysregulation is implicated in, and affected by, seizure activity. Further, we discuss role of KARs in regulating AMPAR surface expression and plasticity, and the relevance of this to epilepsy.
This article is part of the special issue on ‘Glutamate Receptors - Kainate receptors’.
A kainate receptor–selective RNA aptamer
2020, Journal of Biological Chemistry
Citation Excerpt :
In vivo co-application of the two aptamers, FB9s-b and FB9s-r, with varying proportions, may be also therapeutically useful. It is known that epilepsy, stroke, and amyotrophic lateral sclerosis have all been linked to excessive activity/elevated surface expression of both AMPA and kainate receptors (29, 61–64). The roles of AMPA and kainate receptors have also been identified to locate outside of the CNS, such as their expression in human arthritis tissue (65).
Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2′-OH group with 2′-fluorine. These 2′-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.
Identification and characterization of RNA aptamers: A long aptamer blocks the AMPA receptor and a short aptamer blocks both AMPA and kainate receptors
2017, Journal of Biological Chemistry
AMPA and kainate receptors, along with NMDA receptors, represent different subtypes of glutamate ion channels. AMPA and kainate receptors share a high degree of sequence and structural similarities, and excessive activity of these receptors has been implicated in neurological diseases such as epilepsy. Therefore, blocking detrimental activity of both receptor types could be therapeutically beneficial. Here, we report the use of an in vitro evolution approach involving systematic evolution of ligands by exponential enrichment with a single AMPA receptor target (i.e. GluA1/2R) to isolate RNA aptamers that can potentially inhibit both AMPA and kainate receptors. A full-length or 101-nucleotide (nt) aptamer selectively inhibited GluA1/2R with a K_I of ∼5 μm, along with GluA1 and GluA2 AMPA receptor subunits. Of note, its shorter version (55 nt) inhibited both AMPA and kainate receptors. In particular, this shorter aptamer blocked equally potently the activity of both the GluK1 and GluK2 kainate receptors. Using homologous binding and whole-cell recording assays, we found that an RNA aptamer most likely binds to the receptor's regulatory site and inhibits it noncompetitively. Our results suggest the potential of using a single receptor target to develop RNA aptamers with dual activity for effectively blocking both AMPA and kainate receptors.
Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor
2016, Cell Reports
Synaptic communication between neurons requires the precise localization of neurotransmitter receptors to the correct synapse type. Kainate-type glutamate receptors restrict synaptic localization that is determined by the afferent presynaptic connection. The mechanisms that govern this input-specific synaptic localization remain unclear. Here, we examine how subunit composition and specific subunit domains contribute to synaptic localization of kainate receptors. The cytoplasmic domain of the GluK2 low-affinity subunit stabilizes kainate receptors at synapses. In contrast, the extracellular domain of the GluK4/5 high-affinity subunit synergistically controls the synaptic specificity of kainate receptors through interaction with C1q-like proteins. Thus, the input-specific synaptic localization of the native kainate receptor complex involves two mechanisms that underlie specificity and stabilization of the receptor at synapses.

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Kainate binding sites in the hippocampal mossy fibers: Localization and plasticity

Abstract

Neuroscience

Brain Res.

Neuroscience

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Neuroscience

Brain Res.

Brain Res.

Brain Res.

Rev. EEG Neurophysiol.

Neuroscience

Brain Res.

Eur. J. Pharmac.

Atlas Ste´re´otaxique du Dience´phale du Rat Blanc

Development of the mossy fibers of the dentate gurus. I. A light and electron microscopic study of the mossy fibers and their extensions

J. comp. Neurol

Limbic seizures and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy

Neuroscience

Autoradiographic visualization of [3H]kainic acid receptor subtypes in the rat hippocampus

Neurosci. Lett.

Autoradiographic visualization of [³H]kainic acid receptor subtypes in the rat hippocampus