Astrocytic group I mGluR-dependent potentiation of astrocytic glutamate and potassium uptake

2013 ◽  
Vol 109 (9) ◽  
pp. 2404-2414 ◽  
Author(s):  
Prakash Devaraju ◽  
Min-Yu Sun ◽  
Timothy L. Myers ◽  
Kelli Lauderdale ◽  
Todd A. Fiacco
Keyword(s):  
Charge Transfer ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Uptake ◽  
Hippocampal Slices ◽  
Glutamate Transporter ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group I Mglurs ◽  
G Protein Coupled

One of the most important functions of astrocytes is removal of glutamate released during synaptic transmission. Surprisingly, the mechanisms by which astrocyte glutamate uptake is acutely modulated remain to be clarified. Astrocytes express metabotropic glutamate receptors (mGluRs) and other G protein-coupled receptors (GPCRs), which are activated during neuronal activity. Here, we test the hypothesis that astrocytic group I mGluRs acutely regulate glutamate uptake by astrocytes in situ. This hypothesis was tested in acute mouse hippocampal slices. Activation of astrocytic mGluRs, using a tetanic high-frequency stimulus (HFS) applied to Schaffer collaterals, led to potentiation of the amplitude of the synaptically evoked glutamate transporter currents (STCs) and associated charge transfer without changes in kinetics. Similar potentiation of STCs was not observed in the presence of group I mGluR antagonists or the PKC inhibitor, PKC 19–36, suggesting that HFS-induced potentiation of astrocyte glutamate uptake is astrocytic group I mGluR and PKC dependent. Pharmacological stimulation of a transgenic GPCR (MrgA1R), expressed exclusively in astrocytes, also potentiated STC amplitude and charge transfer, albeit quicker and shorter lasting compared with HFS-induced potentiation. The amplitude of the slow, inward astrocytic current due to potassium (K+) influx was also enhanced following activation of the endogenous mGluRs or the astrocyte-specific MrgA1 Gq GPCRs. Taken together, these findings suggest that astrocytic group I mGluR activation has a synergistic, modulatory effect on the uptake of glutamate and K+.

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

1997 ◽  
Vol 78 (1) ◽  
pp. 539-544 ◽  
Author(s):  
Lisa R. Merlin ◽  
Robert K. S. Wong
Keyword(s):  
Guinea Pig ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Hippocampal Slices ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group I Mglurs ◽  
Synaptic Responses

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.

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

2002 ◽  
Vol 88 (4) ◽  
pp. 1625-1633 ◽  
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.

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

2005 ◽  
Vol 94 (5) ◽  
pp. 3643-3647 ◽  
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.

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

2012 ◽  
Vol 107 (4) ◽  
pp. 1058-1066 ◽  
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.

Group I mGluRs Increase Excitability of Hippocampal CA1 Pyramidal Neurons by a PLC-Independent Mechanism

2002 ◽  
Vol 88 (1) ◽  
pp. 107-116 ◽  
Author(s):  
David R. Ireland ◽  
Wickliffe C. Abraham
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Receptor Subtypes ◽  
Ca1 Pyramidal Neurons ◽  
Group I ◽  
Hippocampal Ca1 ◽  
Group I Mglurs ◽  
Induced Changes

Previous studies have implicated phospholipase C (PLC)-linked Group I metabotropic glutamate receptors (mGluRs) in regulating the excitability of hippocampal CA1 pyramidal neurons. We used intracellular recordings from rat hippocampal slices and specific antagonists to examine in more detail the mGluR receptor subtypes and signal transduction mechanisms underlying this effect. Application of the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) suppressed slow- and medium-duration afterhyperpolarizations (s- and mAHP) and caused a consequent increase in cell excitability as well as a depolarization of the membrane and an increase in input resistance. Interestingly, with the exception of the suppression of the mAHP, these effects were persistent, and in the case of the sAHP lasting for more than 1 h of drug washout. Preincubation with the specific mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), reduced but did not completely prevent the effects of DHPG. However, preincubation with both MPEP and the mGluR1 antagonist LY367385 completely prevented the DHPG-induced changes. These results demonstrate that the DHPG-induced changes are mediated partly by mGluR5 and partly by mGluR1. Because Group I mGluRs are linked to PLC via G-protein activation, we also investigated pathways downstream of PLC activation, using chelerythrine and cyclopiazonic acid to block protein kinase C (PKC) and inositol 1,4,5-trisphosphate-(IP3)-activated Ca2+ stores, respectively. Neither inhibitor affected the DHPG-induced suppression of the sAHP or the increase in excitability nor did an inhibitor of PLC itself, U-73122. Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP3-independent transduction pathway.

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

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.

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

2001 ◽  
Vol 85 (4) ◽  
pp. 1603-1613 ◽  
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.

scholarly journals Activation of group I metabotropic glutamate receptors modulates locomotor-related motoneuron output in mice

2011 ◽  
Vol 105 (5) ◽  
pp. 2108-2120 ◽  
Author(s):  
Noboru Iwagaki ◽  
Gareth B. Miles
Keyword(s):  
Spinal Cord ◽  
Action Potential ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Motor Behavior ◽  
Resting Membrane Potential ◽  
Metabotropic Glutamate ◽  
Spinal Motor ◽  
Group I ◽  
Group I Mglurs

Fast glutamatergic transmission via ionotropic receptors is critical for the generation of locomotion by spinal motor networks. In addition, glutamate can act via metabotropic glutamate receptors (mGluRs) to modulate the timing of ongoing locomotor activity. In the present study, we investigated whether mGluRs also modulate the intensity of motor output generated by spinal motor networks. Application of the group I mGluR agonist ( S)-3,5-dihydroxyphenylglycine (DHPG) reduced the amplitude and increased the frequency of locomotor-related motoneuron output recorded from the lumbar ventral roots of isolated mouse spinal cord preparations. Whole cell patch-clamp recordings of spinal motoneurons revealed multiple mechanisms by which group I mGluRs modulate motoneuron output. Although DHPG depolarized the resting membrane potential and reduced the voltage threshold for action potential generation, the activation of group I mGluRs had a net inhibitory effect on motoneuron output that appeared to reflect the modulation of fast, inactivating Na+ currents and action potential parameters. In addition, group I mGluR activation decreased the amplitude of locomotor-related excitatory input to motoneurons. Analyses of miniature excitatory postsynaptic currents indicated that mGluRs modulate synaptic drive to motoneurons via both pre- and postsynaptic mechanisms. These data highlight group I mGluRs as a potentially important source of neuromodulation within the spinal cord that, in addition to modulating components of the central pattern generator for locomotion, can modulate the intensity of motoneuron output during motor behavior. Given that group I mGluR activation reduces motoneuron excitability, mGluRs may provide negative feedback control of motoneuron output, particularly during high levels of glutamatergic stimulation.

Determining calmodulin binding to metabotropic glutamate receptors with distinct protein-interaction methods

2004 ◽  
Vol 32 (5) ◽  
pp. 868-870 ◽  
Author(s):  
K. Lidwell ◽  
J. Dillon ◽  
A. Sihota ◽  
V. O'Connor ◽  
B. Pilkington
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Calmodulin Binding ◽  
Group I ◽  
Group Ii ◽  
Receptor Interacting Proteins ◽  
G Protein Coupled ◽  
Two Hybrid

mGluRs (metabotropic glutamate receptors) are G-protein-coupled receptors that modulate synaptic transmission. The eight mammalian mGluRs form three groups based on sequence and functional similarities: group I (1 and 5), group II (2 and 3) and group III (4, 6–8) mGluRs. In the present study, we used a Y2H (yeast two hybrid) screen to identify proteins that interact with the C-terminal intracellular tail of mGluR3. Prominent among the candidate receptor interacting proteins was calmodulin, a Ca2+ sensor known to bind identifiable sequences in group I and III mGluRs. The Y2H method was used to investigate calmodulin binding to mGluRs but failed to confirm the documented interaction with group III mGluRs. Furthermore, subsequent biochemical analysis showed that calmodulin does not interact with group II mGluRs. This illustrates that certain Ca2+-dependent interactions are not recapitulated in yeast. Moreover, it highlights the necessity for supporting biochemical data to substantiate interactions identified with Y2H methods.

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