Group I mGluRs modulate the pattern of non-synaptic epileptiform activity in the hippocampus

2002 ◽  
Vol 43 (2) ◽  
pp. 141-146 ◽  
Author(s):  
Sébastien J Thuault ◽  
Ceri H Davies ◽  
Andy D Randall ◽  
Graham L Collingridge
Keyword(s):  
Epileptiform Activity ◽  
Group I ◽  
Group I Mglurs

Group I mGluR-Mediated Silent Induction of Long-Lasting Epileptiform Discharges

1999 ◽  
Vol 82 (2) ◽  
pp. 1078-1081 ◽  
Author(s):  
Lisa R. Merlin
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Epileptiform Activity ◽  
Metabotropic Glutamate ◽  
Epileptiform Discharges ◽  
Transient Activation ◽  
Group I ◽  
Induction Process ◽  
Group I Mglurs ◽  
Mglur Antagonist

Picrotoxin, an antagonist of GABAAreceptor-mediated activity, elicited 320- to 475-ms synchronized bursts from the CA3 region of the guinea pig hippocampal slice. The addition of the selective group I metabotropic glutamate receptor (mGluR) agonist ( S)-3,5-dihydroxyphenylglycine (DHPG, 50 μM; 20- to 45-min application) gradually increased the burst duration to 1–4 s; this effect persisted 2–3 h after agonist removal. To determine whether the induction of this long-lasting effect required ongoing synchronized activity during mGluR activation, DHPG application in a second set of experiments took place in the presence of CNQX and ( R,S)-CPP, antagonists of AMPA/kainate and NMDA receptors, respectively. In these experiments, synchronized bursting was silenced during the mGluR agonist application, yet after wash out of the DHPG and the ionotropic glutamate receptor (iGluR) blockers, epileptiform discharges 1–10 s in duration appeared and persisted at least 2 h after wash out of the mGluR agonist. The potentiated bursts were reversibly shortened by application of 500–1,000 μM (+)-α-methyl-4-carboxyphenylglycine (MCPG) or ( S)-4-carboxyphenylglycine (4CPG), agents with group I mGluR antagonist activity. These data suggest that transient activation of group I mGluRs, even during silencing of synchronized epileptiform activity, may have an epileptogenic effect, converting brief interictal-length discharges into persistent seizure-length events. The induction process is iGluR independent, and the maintenance is largely mediated by the action of endogenous glutamate on group I mGluRs, suggesting that autopotentiation of the group I mGluR-mediated response may underlie the epileptogenesis seen here.

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 Modulation of Neurological Deficits and Expression of Glutamate Receptors during Experimental Autoimmune Encephalomyelitis after Treatment with Selected Antagonists of Glutamate Receptors

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Grzegorz Sulkowski ◽  
Beata Dąbrowska-Bouta ◽  
Lidia Strużyńska
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Protein Expression ◽  
Mrna Expression ◽  
Glutamate Receptors ◽  
Neurological Deficits ◽  
Autoimmune Encephalomyelitis ◽  
Protein Levels ◽  
Group I ◽  
Group I Mglurs ◽  
Experimental Autoimmune

The aim of our investigation was to characterize the role of group I mGluRs and NMDA receptors in pathomechanisms of experimental autoimmune encephalomyelitis (EAE), the rodent model of MS. We tested the effects of LY 367385 (S-2-methyl-4-carboxyphenylglycine, a competitive antagonist of mGluR1), MPEP (2-methyl-6-(phenylethynyl)-pyridine, an antagonist of mGluR5), and the uncompetitive NMDA receptor antagonists amantadine and memantine on modulation of neurological deficits observed in rats with EAE. The neurological symptoms of EAE started at 10-11 days post-injection (d.p.i.) and peaked after 12-13 d.p.i. The protein levels of mGluRs and NMDA did not increase in early phases of EAE (4 d.p.i.), but starting from 8 d.p.i. to 25 d.p.i., we observed a significant elevation of mGluR1 and mGluR5 protein expression by about 20% and NMDA protein expression by about 10% over the control at 25 d.p.i. The changes in protein levels were accompanied by changes in mRNA expression of group I mGluRs and NMDARs. During the late disease phase (20–25 d.p.i.), the mRNA expression levels reached 300% of control values. In contrast, treatment with individual receptor antagonists resulted in a reduction of mRNA levels relative to untreated animals.

scholarly journals Inhibition of the Group I mGluRs Reduces Acute Brain Damage and Improves Long-Term Histological Outcomes after Photothrombosis-Induced Ischaemia

ASN NEURO ◽  
2013 ◽  
Vol 5 (3) ◽  
pp. AN20130002 ◽  
Author(s):  
Hailong Li ◽  
Nannan Zhang ◽  
Grace Sun ◽  
Shinghua Ding
Keyword(s):  
Brain Damage ◽  
Group I ◽  
Group I Mglurs

scholarly journals Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension

2010 ◽  
Vol 299 (2) ◽  
pp. R552-R561 ◽  
Author(s):  
De-Pei Li ◽  
Hui-Lin Pan
Keyword(s):  
Receptor Antagonist ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve Activity ◽  
Vasomotor Tone ◽  
Nerve Activity ◽  
Metabotropic Glutamate ◽  
Wky Rats ◽  
Group I ◽  
Group I Mglurs ◽  
Sympathetic Vasomotor Tone

The sympathetic nerve activity is elevated in cardiovascular diseases such as hypertension. Enhanced glutamatergic inputs in the paraventricular nucleus (PVN) of the hypothalamus contribute to heightened sympathetic outflow in spontaneously hypertensive rats (SHR). We determined the role of group I metabotropic glutamate receptors (mGluR) in the PVN in the control of sympathetic vasomotor tone in hypertension. Lumbar sympathetic nerve activity (LSNA), arterial blood pressure (ABP), and heart rate (HR) were recorded in anesthetized SHR and Wistar-Kyoto (WKY) rats. Bilateral microinjection of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGluR5 receptor antagonist, or (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), a selective mGluR1 receptor antagonist, into the PVN had no significant effect on LSNA and ABP in WKY rats. Strikingly, MPEP and LY367385 dose dependently decreased LSNA, ABP, and HR in SHR. The MPEP-induced decreases in LSNA and ABP were significantly greater than those inhibited by LY367385 in SHR. Furthermore, bilateral microinjection of (S)-3,5-dihydroxyphenylglycine (S-DHPG), a selective group I mGluR agonist, into the PVN caused a similar dose-dependent increase in LSNA, ABP, and HR in both groups. S-DHPG-induced responses were attenuated by MPEP or LY367385 alone and were abolished by a combination of MPEP and LY367385 in WKY rats and SHR. In addition, microinjection of the NMDA receptor antagonist attenuated the sympathoexcitatory responses induced by S-DHPG in both WKY rats and SHR. Collectively, this study provides important new evidence that the resting sympathetic vasomotor tone is maintained by tonic activation of group I mGluRs in the PVN in hypertension. Activation of NMDA receptors are involved in the sympathoexcitatory effect of group I mGluRs in the PVN.

The induction of long-term plasticity of non-synaptic, synchronized activity by the activation of group I mGluRs

2008 ◽  
Vol 55 (4) ◽  
pp. 459-463 ◽  
Author(s):  
Sonia Piccinin ◽  
Sébastien J. Thuault ◽  
Andrew J. Doherty ◽  
Jon T. Brown ◽  
Andrew D. Randall ◽  
...  
Keyword(s):  
Group I ◽  
Group I Mglurs

scholarly journals Video-EEG monitoring in diagnostics and treatment efficacy evaluation in newly-diagnosed generalized epilepsy in adults

2021 ◽  
Vol 13 (1) ◽  
pp. 21-32
Author(s):  
A. B. Kozhokaru ◽  
V. A. Karlov ◽  
P. N. Vlasov ◽  
A. S. Orlova
Keyword(s):  
Seizure Frequency ◽  
Treatment Efficacy ◽  
Activity Index ◽  
Epileptiform Activity ◽  
Sleep Cycle ◽  
Cycle Duration ◽  
Eeg Monitoring ◽  
Newly Diagnosed ◽  
Group I ◽  
Generalized Epilepsy

Introduction. Video-electroencephalography (EEG) monitoring (VEEGM) is an indispensable functional method in epileptology. However, virtually no trials on assessing efficacy of antiepileptic drugs (AED) by using VEEGM are available.Objective: to improve efficacy of EEG-diagnostics and evaluate the epileptiform activity index (EAI) in newly-diagnosed idiopathic generalized epilepsy in adult patients receiving  alproic acid and levetiracetam.Material and methods. T here w ere e nrolled 130 p atients: 6 0 (46.2%) m ales a nd 7 0 (53.8%) f emales w ith n ewlydiagnosedidiopathic generalized epilepsy (IGE), aged 22.51±8.9 years. All patients underwent VEEGM with quantitative EAI analysis at baseline visit and 1 3, 6 and 12 months later after treatment. Each seizure episode developed during the VEEGM study were assessed for type, time of seizure onset, relation to wake-sleep cycle, duration, ictal EEG pattern followed by diagnosing epileptic syndrome. Valproic acid and levetiracetam were used for initial therapy in groups per 65 patients in each. Treatment efficacy was assessed using parameters such as retention on therapy, absence of seizures, decrease of seizure frequency by >50%, decrease of seizure frequency by <50% – insufficient efficacy.Results. It was found that seizures during baseline VEEGM were recorded in 43.1% (n=56) patients, who were assigned to group 1, whereas remaining 74 (56.9%) patients were assigned to group 2. EAI was significantly higher in patients with seizures recoded at baseline VEEGM, compared to those lacking seizure episodes during initial VEEGM (p<0,001), mean EAI was also higher in group I at second (p<0.001) and third (p<0.001) visits. EAI magnitude at 6 and 12 months of study became virtually comparable in all groups and did not depend on AED prescribed. Treatment efficacy was higher in patients with IGE, with no  eizures recorded during the initial VEEGM.Conclusion. Long-term VEEGM allows unbiased assessment of treatment dynamics based on EAI analysis. The first 6 months of initial treatment titration in represent most crucial period for patients with newly-diagnosed IGE.

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.

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