Heterologous modulation of inhibitory synaptic transmission by metabotropic glutamate receptors in cultured hippocampal neurons

1996 ◽  
Vol 75 (2) ◽  
pp. 885-893 ◽  
Author(s):  
R. M. Fitzsimonds ◽  
M. A. Dichter
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Uptake ◽  
Low Density ◽  
Inhibitory Synaptic Transmission ◽  
Metabotropic Glutamate ◽  
Mglur Antagonist ◽  
Uptake Mechanisms

1. Whole cell patch-clamp recordings of monosynaptically connected pairs of hippocampal neurons in very low-density culture were performed to determine the effects of the activation of metabotropic glutamate receptors (mGluRs) on inhibitory terminals. The mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S, 3R)-ACPD] and the recently described mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) were used. In addition, the glutamate uptake inhibitors L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) and D,L-beta-threo-hydroxyaspartate (THA) were used to determine whether endogenous agents (presumably glutamate) could activate mGluRs at inhibitory terminals. Previous reports of the role of mGluRs on inhibitory terminals were performed in slice preparations; our use of patch-clamp recordings from isolated pairs of hippocampal neurons is uniquely useful for the study of inhibitory synaptic transmission in the absence of polysynaptic connectivity. 2. The mGluR agonist (1S, 3R)-ACPD (100 microM) reversibly decreased the amplitude of evoked inhibitory postsynaptic currents (IPSCs) in all pairs tested; this effect was completely blocked by coapplication of the mGluR antagonist MCPG (500 microM) with (1S, 3R)-ACPD. MCPG (500 microM) alone had no effect on IPSC amplitude. These results indicate that all inhibitory neurons in our cultures express functional mGluRs in their terminals. 3. Examination of the frequency and the distribution of amplitudes of miniature IPSCs (mIPSCs) provide indications of changes in the sensitivity of postsynaptic receptors and/or of changes in the process of presynaptic transmitter release. Recordings of miniature currents from hippocampal neurons cultured at very low density makes possible the analysis of mIPSCs that arise from a single input, whereas in high density or slice preparations, spontaneous miniature currents reflect numerous synaptic inputs. No change in the amplitudes or frequency of the mIPSCs were observed upon application of (1S, 3R)-ACPD (100 microM). Thus we conclude that the depression of the evoked IPSC amplitude by (1S, 3R)-ACPD is mediated by a presynaptic mechanism in these isolated pairs of hippocampal neurons. 4. The glutamate uptake inhibitor L-trans-PDC also reduced IPSC amplitude in 8 of 13 pairs. In these eight pairs, an increase in N-methyl-D-aspartate (NMDA) receptor-mediated membrane noise indicated an increase in ambient concentrations of glutamate induced by L-trans-PDC. In the remaining five pairs, membrane noise remained unaffected by L-trans-PDC, and IPSCs were not attenuated. Similar results were observed with the use of the uptake inhibitor THA. The mGluR antagonist MCPG blocked the effects of L-trans-PDC and THA on IPSC amplitude. We propose that inhibition of glutamate uptake mechanisms results in activation of mGluRs on GABAergic terminals via endogenous sources of glutamate and that the uptake inhibitors (L-trans-PDC and THA) do not directly activate the metabotropic receptor. 5. Presynaptic receptors and active modulation of uptake mechanisms are clearly involved in a wide range of physiological and pathological synaptic events. The data presented here suggest that heterosynaptic modulation of inhibitory synaptic transmission by metabotropic glutamate receptors may be important for the maintenance and plasticity of the balances between excitatory and inhibitory synaptic transmission in the CNS.

scholarly journals Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission

2004 ◽  
Vol 1 (4) ◽  
pp. 307-316 ◽  
Author(s):  
QING-SONG LIU ◽  
QIWU XU ◽  
JIAN KANG ◽  
MAIKEN NEDERGAARD
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Group Iii ◽  
Inhibitory Synaptic Transmission ◽  
Metabotropic Glutamate ◽  
Group Ii ◽  
Mglur Antagonist

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca2+ elevation in astrocytes, by photolysis of caged Ca2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca2+-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.

Frequency-dependent depression of excitatory synaptic transmission is independent of activation of MCPG-sensitive presynaptic metabotropic glutamate receptors in cultured hippocampal neurons

1995 ◽  
Vol 74 (4) ◽  
pp. 1671-1674 ◽  
Author(s):  
R. Maki ◽  
D. D. Cummings ◽  
M. A. Dichter
Keyword(s):  
Glutamate Receptors ◽  
High Frequency ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Frequency Dependent ◽  
Paired Pulse ◽  
Metabotropic Glutamate ◽  
Whole Cell Patch Clamp ◽  
Mglur Antagonist ◽  
Cultured Hippocampal Neurons

1. A paired-pulse paradigm, and a high-frequency train followed by a test pulse, were used to investigate the possible role of presynaptic metabotropic glutamate receptors (mGluRs) in frequency-dependent modulation of the amplitude of excitatory post-synaptic currents (EPSCs). Paired whole cell patch-clamp recordings from monosynaptically connected hippocampal neurons maintained in very low-density cultures were performed, using the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 500 microM) and the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD, 100 microM]. 2. Paired-pulse depression (PPD) was observed in all the excitatory pairs recorded. The average PPD ratio (amplitude of the 2nd EPSC divided by the amplitude of the 1st EPSC) was 0.80 +/- 0.1 (SD) (n = 8). Application of the mGluR antagonist MCPG had no effect on the amplitude of the EPSCs and did not affect the ratio of the two EPSCs (PPD ratio 0.79 +/- 0.2). 3. The amplitudes of 10 successive EPSCs stimulated at a high frequency (20 Hz) decremented on average in both 4 mM extracellular Ca2+ (n = 5) and in 1 mM extracellular Ca2+ (n = 6). In all pairs tested, posttetanic depression (PTD) was observed (PTD ratio 0.7 +/- 0.2). Bath application of MCPG (500 microM) did not affect the amplitudes of the EPSCs during the train; MCPG also did not affect PTD. 4. The mGluR agonist (1S,3R)-ACPD depressed the amplitudes of the EPSCs in both the paired-pulse (1st EPSC, 35 +/- 9%; 2nd EPSC, 36 +/- 10%) and posttetanic pulse (1 and 4 mM extracellular Ca2+) paradigms. The amount of depression observed, both PPD and PTD, remained unaffected by application of (1S,3R)-ACPD. Coapplication of the antagonist MCPG (500 microM) blocked the effects of (1S,3R)-ACPD (100 microM). 5. We conclude that frequency-dependent depression of EPSC amplitudes occurs independent of endogenous activation of MCPG-sensitive mGluRs in cultured hippocampal neurons. Moreover, we demonstrate that exogenous activation of mGluRs by the agonist (1S,3R)-ACPD can produce additional EPSC depression above that already present due to frequency-dependent mechanisms.

Persistent current oscillations produced by activation of metabotropic glutamate receptors in immature rat CA3 hippocampal neurons

1995 ◽  
Vol 73 (4) ◽  
pp. 1422-1429 ◽  
Author(s):  
L. Aniksztejn ◽  
M. Sciancalepore ◽  
Y. Ben Ari ◽  
E. Cherubini
Keyword(s):  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Calcium Release ◽  
Release Process ◽  
Metabotropic Glutamate ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Presynaptic Nerve Terminals ◽  
Calcium Induced Calcium Release

1. The single-electrode voltage-clamp technique was used to study the effects of the metabotropic glutamate receptors (mGluRs) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, ACPD, 3-10 microM) on CA3 hippocampal neurons during the 1st 10 days of postnatal (P) life and in adulthood. 2. Repeated applications of 1S,3R-ACPD, in the presence of tetrodotoxin (TTX, 1 microM), tetraethylammonium chloride (TEACl 10 mM), and CsCl (2 mM), induced in immature but not in adult neurons periodic inward currents (PICs) that persisted for several hours after the last application of the agonist. 3. PICs, which were generated by nonspecific cationic currents, reversed polarity at 2.8 +/- 3 (SD) mV. They were reversibly blocked by kynurenic acid (1 mM), suggesting that they were mediated by glutamate acting on ionotropic receptors. They were also abolished in a nominally Ca(2+)-free medium. 4. PICs were irreversibly abolished by thapsigargin (10 microM) but were unaffected by ryanodine (10-40 microM). Caffeine (2 mM) also reversibly blocked PICs; this effect was independent from adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, inhibition of voltage-dependent Ca2+ current, or blockade of adenosine receptors. 5. We suggest that, in neonatal slices, mGluRs-induced PICs are triggered by elevation of [Ca2+]i, after mobilization of Ca2+ from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores. This will lead to a persistent, pulsatile release of glutamate from presynaptic nerve terminals, a phenomenon that is probably maintained via a calcium-induced-calcium release process.

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.

Postsynaptic Current Mediated by Metabotropic Glutamate Receptors in Cerebellar Purkinje Cells

1998 ◽  
Vol 80 (2) ◽  
pp. 520-528 ◽  
Author(s):  
Filippo Tempia ◽  
Maria Concetta Miniaci ◽  
Davide Anchisi ◽  
Piergiorgio Strata
Keyword(s):  
Glutamate Receptors ◽  
Purkinje Cells ◽  
Metabotropic Glutamate Receptors ◽  
Parallel Fiber ◽  
High Concentration ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Cerebellar Purkinje Cells ◽  
Mglur Antagonist ◽  
Fiber Stimulation

Tempia, Filippo, Maria Concetta Miniaci, Davide Anchisi, and Piergiorgio Strata. Postsynaptic current mediated by metabotropic glutamate receptors in cerebellar Purkinje cells. J. Neurophysiol. 80: 520–528, 1998. In rat cerebellar slices, repetitive parallel fiber stimulation evokes an inward, postsynaptic current in Purkinje cells with a fast component mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and a slower component mediated by metabotropic glutamate receptors (mGluR). The mGluR-mediated excitatory postsynaptic current (mGluR-EPSC) is evoked selectively by parallel fiber stimulation; climbing fiber stimulation is ineffective. The mGluR-EPSC is elicited most effectively with increasing frequencies of parallel fiber stimulation, from a threshold of 10 Hz to a maximum response at ∼100 Hz. The amplitude of the mGluR-EPSC is a linear function of the number of stimulus pulses without any apparent saturation, even with >10 pulses. Thus mGluRs at the parallel fiber-Purkinje cell synapse can function as linear detectors of the number of spikes in a burst of activity in parallel fibers. The mGluR-EPSC is present from postnatal day 15 and persists into adulthood. It is inhibited by the generic mGluR antagonist (RS)-a-methyl-4-carboxyphenylglycine and by the group I mGluR antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid at a concentration selective for mGluR1. Although the intracellular transduction pathway involves a G protein, the putative mediators of mGluR1 (phospholipase C and protein kinase C) are not directly involved, indicating that the mGluR-EPSC studied here is mediated by a different and still unidentified second-messenger pathway. Heparin, a nonselective antagonist of inositol-trisphosphate (IP3) receptors, has no significant effect on the mGluR-EPSC, suggesting that also IP3 might be not required for the response. Buffering intracellular Ca2+ with a high concentration of bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid partially inhibits the mGluR-EPSC, indicating that Ca2+ is not directly responsible for the response but that resting Ca2+ levels exert a tonic potentiating effect on the mGluR-EPSC.

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.

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