Role of Group I Metabotropic Glutamate Receptors in the Patterning of Epileptiform Activities In Vitro

Merlin, Lisa R. and Robert K. S. Wong. Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. J. Neurophysiol. 78: 539–544, 1997. In guinea pig hippocampal slices, picrotoxin elicited spontaneous epileptiform bursts 300–550 ms in duration. Additional application of ( R,S)-3,5-dihydroxyphenylglycine or ( S)-3-hydroxyphenylglycine, agonists specific for group I metabotropic glutamate receptors(mGluRs), or (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylicacid, a broad-spectrum mGluR agonist, converted picrotoxin-induced interictal bursts into prolonged discharges measured on the order of seconds. The prolonged discharges induced by selective group I mGluR agonist continued to be produced for hours after agonist removal. The antagonists ( S)-4-carboxyphenylglycine and (+)-α-methyl-4-carboxyphenylglycine had no effect on the duration of picrotoxin-induced interictal bursts. However, after agonist exposure, the persistent prolonged discharges occurring in the absence of agonist were reversibly suppressed by the antagonists, suggesting that the activity is maintained via endogenous activation of group I mGluRs by synaptically released glutamate. Our results suggest that, under some conditions, activation of group I mGluRs produces long-lasting enhancement of synaptic responses, mediated at least in part by autopotentiation of the group I mGluR response itself, which may result in the production of seizure discharges and contribute to epileptogenesis.

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Role of Synaptic Metabotropic Glutamate Receptors in Epileptiform Discharges in Hippocampal Slices

Journal of Neurophysiology ◽

10.1152/jn.2002.88.4.1625 ◽

2002 ◽

Vol 88 (4) ◽

pp. 1625-1633 ◽

Cited By ~ 32

Author(s):

Angela C. Lee ◽

Robert K. S. Wong ◽

Shih-Chieh Chuang ◽

Hee-Sup Shin ◽

Riccardo Bianchi

Keyword(s):

Metabotropic Glutamate Receptors ◽

Metabotropic Glutamate Receptor ◽

Hippocampal Slices ◽

Brain Slices ◽

Wild Type ◽

Metabotropic Glutamate ◽

Epileptiform Discharges ◽

Group I ◽

Group I Mglurs

Application of group I metabotropic glutamate receptor (mGluR) agonists elicits seizure discharges in vivo and prolonged ictal-like activity in in vitro brain slices. In this study we examined 1) if group I mGluRs are activated by synaptically released glutamate during epileptiform discharges induced by convulsants in hippocampal slices and, if so, 2) whether the synaptically activated mGluRs contribute to the pattern of the epileptiform discharges. The GABAAreceptor antagonist bicuculline (50 μM) was applied to induce short synchronized bursts of ∼250 ms in mouse hippocampal slices. Addition of 4-aminopyridine (4-AP; 100 μM) prolonged these bursts to 0.7–2 s. The mGluR1 antagonist ( S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385; 25–100 μM) and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP; 10–50 μM), applied separately, significantly reduced the duration of the synchronized discharges. The effects of these antagonists were additive when applied together, suggesting that mGluR1 and mGluR5 exert independent actions on the epileptiform bursts. In phospholipase C β1 (PLCβ1) knockout mice, bicuculline and 4-AP elicited prolonged synchronized discharges of comparable duration as those observed in slices from wild-type littermates. Furthermore, mGluR1 and mGluR5 antagonists reduced the duration of the epileptiform discharges to the same extent as they did in the wild-type preparations. The results suggest that mGluR1 and mGluR5 are activated synaptically during prolonged epileptiform discharges induced by bicuculline and 4-AP. Synaptic activation of these receptors extended the duration of synchronized discharges. In addition, the data indicate that the synaptic effects of the group I mGluRs on the duration of epileptiform discharges were mediated by a PLCβ1-independent mechanism.

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Contrasting Roles of Protein Kinase C in Induction Versus Suppression of Group I mGluR-Mediated Epileptogenesis In Vitro

Journal of Neurophysiology ◽

10.1152/jn.00548.2005 ◽

2005 ◽

Vol 94 (5) ◽

pp. 3643-3647 ◽

Cited By ~ 10

Author(s):

John C. Cuellar ◽

Elvin L. Griffith ◽

Lisa R. Merlin

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Metabotropic Glutamate Receptors ◽

Hippocampal Slices ◽

Burst Length ◽

Metabotropic Glutamate ◽

Kinase C ◽

Group I ◽

Group I Mglurs

Activation of group I metabotropic glutamate receptors (mGluRs) elicits persistent ictaform discharges in guinea pig hippocampal slices, providing an in vitro model of epileptogenesis. The induction of these persistent ictaform bursts is prevented by l-cysteine sulfinic acid (CSA), an agonist at phospholipase D (PLD)–coupled mGluRs. Studies described herein examined the role of protein kinase C (PKC) in both the group I mGluR–mediated induction and CSA-mediated suppression of this form of epileptogenesis. Intracellular recordings were performed from CA3 stratum pyramidale and synchronized burst length was monitored. In the presence of 50 μM picrotoxin, a γ-aminobutyric acid type A antagonist, 250- to 500-ms synchronized bursts were elicited. ( S)-3,5-Dihydroxyphenylglycine (DHPG, 50 μM), an agonist at group I mGluRs, increased the burst length to 1–3 s in duration, a change that persisted after agonist washout. This persistent change in burst length was elicited in the presence of 10 μM chelerythrine, a PKC inhibitor, indicating that DHPG-induced epileptogenesis is PKC independent. However, although PLD activation with CSA (100 μM) was highly effective at suppressing group I mGluR–mediated induction of burst prolongation, CSA application in the presence of chelerythrine was no longer effective and resulted in the expression of persistent ictaform bursts. These data suggest that CSA-mediated suppression of group I mGluR–induced epileptogenesis is PKC dependent. We propose that CSA mediates its effect by PLD-driven activation of PKC, which may desensitize the phospholipase C–linked group I mGluRs and thereby prevent group I mGluR–induced epileptogenesis.

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Activity-dependent regulation of synaptic strength by PSD-95 in CA1 neurons

Journal of Neurophysiology ◽

10.1152/jn.00526.2011 ◽

2012 ◽

Vol 107 (4) ◽

pp. 1058-1066 ◽

Cited By ~ 26

Author(s):

Peng Zhang ◽

John E. Lisman

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Synaptic Strength ◽

Ca1 Neurons ◽

Metabotropic Glutamate ◽

Group I ◽

Term Potentiation ◽

Activity Dependent

CaMKII and PSD-95 are the two most abundant postsynaptic proteins in the postsynaptic density (PSD). Overexpression of either can dramatically increase synaptic strength and saturate long-term potentiation (LTP). To do so, CaMKII must be activated, but the same is not true for PSD-95; expressing wild-type PSD-95 is sufficient. This raises the question of whether PSD-95's effects are simply an equilibrium process [increasing the number of AMPA receptor (AMPAR) slots] or whether activity is somehow involved. To examine this question, we blocked activity in cultured hippocampal slices with TTX and found that the effects of PSD-95 overexpression were greatly reduced. We next studied the type of receptors involved. The effects of PSD-95 were prevented by antagonists of group I metabotropic glutamate receptors (mGluRs) but not by antagonists of ionotropic glutamate receptors. The inhibition of PSD-95-induced strengthening was not simply a result of inhibition of PSD-95 synthesis. To understand the mechanisms involved, we tested the role of CaMKII. Overexpression of a CaMKII inhibitor, CN19, greatly reduced the effect of PSD-95. We conclude that PSD-95 cannot itself increase synaptic strength simply by increasing the number of AMPAR slots; rather, PSD-95's effects on synaptic strength require an activity-dependent process involving mGluR and CaMKII.

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Activation of metabotropic glutamate receptors induces long-term depression of GABAergic inhibition in hippocampus

Journal of Neurophysiology ◽

10.1152/jn.1993.69.3.1000 ◽

1993 ◽

Vol 69 (3) ◽

pp. 1000-1004 ◽

Cited By ~ 67

Author(s):

Y. B. Liu ◽

J. F. Disterhoft ◽

N. T. Slater

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Hippocampal Slices ◽

Input Resistance ◽

Nmda Receptor Antagonist ◽

Metabotropic Glutamate ◽

Epileptiform Discharges ◽

Bath Application

1. The long-term enhancement of synaptic excitability in CA1 hippocampal pyramidal neurons produced by activation of metabotropic glutamate receptors (mGluRs) was studied in rabbit hippocampal slices in vitro. 2. Bath application of the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3- dicarboxylic acid (1S,3R-ACPD) (5-20 microM) for 20 min produced a reversible depolarization of membrane potentiatil, blockade of spike accommodation, and increase in input resistance of CA1 neurons. However, a long-lasting increase in synaptic excitability was observed: single stimuli applied to the Schaffer collateral commisural fiber pathway evoked epileptiform discharges in the presence of 1S,3R-ACPD and after the washout of 1S,3R-ACPD, persistent paroxysmal depolarization shifts (PDSs) were evoked by afferent stimulation. A long-lasting enhancement of synaptic excitability was also observed in the presence of the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), which blocked the stimulation-evoked PDS and associated afterdischarges. 3. When biphasic, monosynaptically evoked inhibitory post-synaptic potentials (IPSPs) were recorded in the presence of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10–15 microM) and D-AP5 (20 microM), the bath application of 1S,3R-ACPD produced a significant reduction (approximately 50%) of both components of the IPSP, which persisted after the washout of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

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The post-synaptic scaffolding protein tamalin regulates ligand-mediated trafficking of metabotropic glutamate receptors

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011979 ◽

2020 ◽

Vol 295 (25) ◽

pp. 8575-8588

Author(s):

Saurabh Pandey ◽

Namrata Ramsakha ◽

Rohan Sharma ◽

Ravinder Gulia ◽

Prachi Ojha ◽

...

Keyword(s):

Glutamate Receptors ◽

Protein Trafficking ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Fragile X ◽

Critical Role ◽

Scaffolding Protein ◽

Metabotropic Glutamate ◽

Group I ◽

Group I Mglurs

Group I metabotropic glutamate receptors (mGluRs) play important roles in various neuronal functions and have also been implicated in multiple neuropsychiatric disorders like fragile X syndrome, autism, and others. mGluR trafficking not only plays important roles in controlling the spatiotemporal localization of these receptors in the cell but also regulates the activity of these receptors. Despite this obvious significance, the cellular machineries that control the trafficking of group I metabotropic glutamate receptors in the central nervous system have not been studied in detail. The post-synaptic scaffolding protein tamalin has been shown to interact with group I mGluRs and also with many other proteins involved in protein trafficking in neurons. Using a molecular replacement approach in mouse hippocampal neurons, we show here that tamalin plays a critical role in the ligand-dependent internalization of mGluR1 and mGluR5, members of the group I mGluR family. Specifically, knockdown of endogenous tamalin inhibited the ligand-dependent internalization of these two receptors. Both N-terminal and C-terminal regions of tamalin played critical roles in mGluR1 endocytosis. Furthermore, we found that tamalin regulates mGluR1 internalization by interacting with S-SCAM, a protein that has been implicated in vesicular trafficking. Finally, we demonstrate that tamalin plays a critical role in mGluR-mediated internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, a process believed to be the cellular correlate for mGluR-dependent synaptic plasticity. Taken together, these findings reveal a mechanistic role of tamalin in the trafficking of group I mGluRs and suggest its physiological implications in the brain.

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Role of Intracellular Calcium Stores on the Effect of Metabotropic Glutamate Receptors on Phosphorylation of Glial Fibrillary Acidic Protein in Hippocampal Slices from Immature Rats

Neurochemical Research ◽

10.1023/b:nere.0000029567.68068.ab ◽

2004 ◽

Vol 29 (8) ◽

pp. 1541-1545 ◽

Cited By ~ 4

Author(s):

D. Oppelt ◽

R. Rodnight ◽

J. Horn ◽

D. Fitarelli ◽

T. Kommers ◽

...

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Intracellular Calcium ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Hippocampal Slices ◽

Acidic Protein ◽

Calcium Stores ◽

Metabotropic Glutamate ◽

Immature Rats

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Synaptically Activated Calcium Responses in Dendrites of Hippocampal Oriens-Alveus Interneurons

Journal of Neurophysiology ◽

10.1152/jn.2001.85.4.1603 ◽

2001 ◽

Vol 85 (4) ◽

pp. 1603-1613 ◽

Cited By ~ 6

Author(s):

Christine E. Gee ◽

Gavin Woodhall ◽

Jean-Claude Lacaille

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Hippocampal Slices ◽

Selective Vulnerability ◽

Ionotropic Glutamate Receptors ◽

Repetitive Firing ◽

Metabotropic Glutamate ◽

Group I ◽

Frequency Of Action Potentials ◽

Mglur Antagonist

Activation of metabotropic glutamate receptors (mGluRs) by agonists increases intracellular calcium levels ([Ca2+]i) in interneurons of stratum oriens/alveus (OA) of the hippocampus. We examined the mechanisms that contribute to dendritic Ca2+ increases in these interneurons during agonist activation of mGluRs and during synaptically evoked burst discharges, using simultaneous whole cell recordings and confocal Ca2+ imaging in rat hippocampal slices. First, we found that the group I/II mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 100 μM) increased dendritic [Ca2+]i and depolarized OA interneurons. Dendritic Ca2+ responses were correlated with membrane depolarizations, but Ca2+ responses induced by ACPD were larger in amplitude than those elicited by equivalent somatic depolarization. Next, we used linescans to measure changes in dendritic [Ca2+]i during synaptically evoked burst discharges and somatically elicited repetitive firing in disinhibited slices. Dendritic Ca2+ signals and electrophysiological responses were stable over repeated trials. Peak Ca2+responses were linearly related to number and frequency of action potentials in burst discharges for both synaptic and somatic stimulation, but the slope of the relationship was steeper for responses evoked somatically. Synaptically evoked [Ca2+]i rises and excitatory postsynaptic potentials were abolished by antagonists of ionotropic glutamate receptors. The group I/II mGluR antagonist S-α-methyl-4-carboxyphenylglycine (500 μM) produced a significant partial reduction of synaptically evoked dendritic Ca2+ responses. The mGluR antagonist did not affect synaptically evoked burst discharges and did not reduce either Ca2+ responses or burst discharges evoked somatically. Therefore ionotropic glutamate receptors appear necessary for synaptically evoked dendritic Ca2+ responses, and group I/II mGluRs may contribute partially to these responses. Dendritic [Ca2+]i rises mediated by both ionotropic and metabotropic glutamate receptors may be important for synaptic plasticity and the selective vulnerability to excitotoxicity of OA interneurons.

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Effect of the Group I Metabotropic Glutamate Agonist DHPG on the Visual Cortex

Journal of Neurophysiology ◽

10.1152/jn.2001.86.4.1622 ◽

2001 ◽

Vol 86 (4) ◽

pp. 1622-1631 ◽

Cited By ~ 8

Author(s):

Xiao-Tao Jin ◽

Christopher J. Beaver ◽

Qinghua Ji ◽

Nigel W. Daw

Keyword(s):

Visual Cortex ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Visual Response ◽

Excitatory Effect ◽

Partial Explanation ◽

Metabotropic Glutamate ◽

Cat Visual Cortex ◽

Group I

Metabotropic glutamate receptors have a variety of effects in visual cortex that depend on the age of the animal, the layer of the cortex, and the group of the receptor. Here we describe these effects for group I receptors, using both in vivo and in vitro preparations. The metabotropic group I glutamate receptor agonist 3,5 dihydroxyphenylglycine (DHPG) potentiates the responses to N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in slices of rat visual cortex. It also increases, initially, the visual response in the cat visual cortex. Both these effects are largest at 3–4 wk of age and decline to insignificance by 10 wk of age. Both are also largest in lower layers of cortex, which explains why the facilitatory effects found with the general metabotropic glutamate agonist 1S,3R aminocyclopentane-1,3-dicarboxylic acid (ACPD) are observed only in lower layers. Prolonged application of DHPG in the cat visual cortex, after the initial excitatory effect, produces depression. We also found that DHPG facilitates the NMDA response in fast-spiking cells, which are inhibitory, providing a partial explanation for this. Thus there are multiple effects of group I metabotropic glutamate receptors, which vary with layer and age in visual cortex.

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