Glutamate Uptake Controls Expression of a Slow Postsynaptic Current Mediated by mGluRs in Cerebellar Purkinje Cells

2002 ◽  
Vol 87 (4) ◽  
pp. 1974-1980 ◽  
Author(s):  
W. Reichelt ◽  
T. Knöpfel
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Uptake ◽  
Glutamate Transporter ◽  
Excitatory Postsynaptic Current ◽  
Metabotropic Glutamate ◽  
Glutamatergic Synaptic Transmission ◽  
Cerebellar Purkinje Cells ◽  
Cell Synapse

At the cerebellar parallel fiber-Purkinje cell synapse, isolated presynaptic activity induces fast excitatory postsynaptic currents via ionotropic glutamate receptors while repetitive, high-frequency, presynaptic activity can also induce a slow excitatory postsynaptic current that is mediated by metabotropic glutamate receptors (mGluR1-EPSC). Here we investigated the involvement of glutamate uptake in the expression of the mGluR1-EPSC. Inhibitors of glutamate uptake led to a large increase of the mGluR1-EPSC. d-aspartate (0.4 mM) andl(−)-threo-3-hydroxyaspartate (0.4 mM) increased the mGluR1-EPSC ∼4.5 and ∼9-fold, respectively, while dihydrokainic acid (1 mM), had no significant effect on the mGluR1-EPSC.d-aspartate (0.4 mM) shifted the concentration-response curve of the depression of the mGluR1-EPSC by the low-affinity mGluR1 antagonist ( S)-a-Methyl-4-carboxyphenylglycine [( S)-MCPG] to higher concentrations and decreased the stimulus intensity and the number of necessary stimuli to evoke an mGluR1-EPSC. Depression of the mGluR1-EPSC by rapid pressure application of ( S)-MCPG at varying time intervals after tetanic stimulation of the parallel fibers indicated that the glutamate concentration in the peri- and extrasynaptic space decayed with time constants of 36 and 316 ms under control conditions and with inhibition of glutamate uptake, respectively. These results show that expression of the slow mGluR-mediated excitatory postsynaptic current is controlled by glutamate transporter activity. Thus in contrast to fast glutamatergic synaptic transmission, metabotropic glutamate receptor-mediated transmission is critically dependent on the activity and capacity of glutamate uptake.

Modulation of Multiple Potassium Currents by Metabotropic Glutamate Receptors in Neurons of the Hypothalamic Supraoptic Nucleus

1997 ◽  
Vol 78 (6) ◽  
pp. 3428-3437 ◽  
Author(s):  
L. A. Schrader ◽  
J. G. Tasker
Keyword(s):  
Glutamate Receptors ◽  
Supraoptic Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Outward Current ◽  
Magnocellular Neurons ◽  
Inward Current ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group I

Schrader, L. A. and J. G. Tasker. Modulation of multiple potassium currents by metabotropic glutamate receptors in neurons of the hypothalamic supraoptic nucleus. J. Neurophysiol. 78: 3428–3437, 1997. We studied the effects of activation of the metabotropic glutamate receptors on intrinsic currents of magnocellular neurons of the supraoptic nucleus (SON) with whole cell patch-clamp and conventional intracellular recordings in coronal slices (400 μm) of the rat hypothalamus. Trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid ( trans-ACPD, 10–100 μM), a broad-spectrum metabotropic glutamate receptor agonist, evoked an inward current (18.7 ± 3.45 pA) or a slow depolarization (7.35 ± 4.73 mV) and a 10–30% decrease in whole cell conductance in ∼50% of the magnocellular neurons recorded at resting membrane potential. The decrease in conductance and the inward current were caused largely by the attenuation of a resting potassium conductance because they were reduced by the replacement of intracellular potassium with an equimolar concentration of cesium or by the addition of potassium channel blockers to the extracellular medium. In some cells, trans-ACPD still elicited a small inward current after blockade of potassium currents, which was abolished by the calcium channel blocker, CdCl2. Trans-ACPD also reduced voltage-gated and Ca2+-activated K+ currents in these cells. Trans-ACPD reduced the transient outward current ( I A) by 20–70% and/or the I A-mediated delay to spike generation in ∼60% of magnocellular neurons tested. The cells that showed a reduction of I A generally also showed a 20–60% reduction in a voltage-gated, sustained outward current. Finally, trans-ACPD attenuated the Ca2+-dependent outward current responsible for the afterhyperpolarization ( I AHP) in ∼60% of cells tested. This often revealed an underlying inward current thought to be responsible for the depolarizing afterpotential seen in some magnocellular neurons. (RS)-3,5-dihydroxyphenylglycine, a group I receptor-selective agonist, mimicked the effects of trans-ACPD on the resting and voltage-gated K+ currents. (RS)-α-methyl-4-carboxyphenylglycine, a group I/II metabotropic glutamate receptor antagonist, blocked these effects. A group II receptor agonist, 2S,1′S,2′S-2carboxycyclopropylglycine and a group III receptor agonist, l(+)-2-amino-4-phosphonobutyric acid, had no effect on the resting or voltage-gated K+ currents, indicating that the reduction of K+ currents was mediated by group I receptors. About 80% of the SON cells that were labeled immunohistochemically for vasopressin responded to metabotropic glutamate receptor activation, whereas only 33% of labeled oxytocin cells responded, suggesting that metabotropic receptors are expressed preferentially in vasopressinergic neurons. These data indicate that activation of the group I metabotropic glutamate receptors leads to an increase in the postsynaptic excitability of magnocellular neurons by blocking resting K+ currents as well as by reducing voltage-gated and Ca2+-activated K+ currents.

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 Physiological Evidence for Ionotropic and Metabotropic Glutamate Receptors in Rat Taste Cells

1999 ◽  
Vol 82 (5) ◽  
pp. 2061-2069 ◽  
Author(s):  
Weihong Lin ◽  
Sue C. Kinnamon
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Monosodium Glutamate ◽  
Taste Receptor ◽  
Membrane Properties ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Taste Cells

Monosodium glutamate (MSG) elicits a unique taste in humans called umami. Recent molecular studies suggest that glutamate receptors similar to those in brain are present in taste cells, but their precise role in taste transduction remains to be elucidated. We used giga-seal whole cell recording to examine the effects of MSG and glutamate receptor agonists on membrane properties of taste cells from rat fungiform papillae. MSG (1 mM) induced three subsets of responses in cells voltage-clamped at −80 mV: a decrease in holding current (subset I), an increase in holding current (subset II), and a biphasic response consisting of an increase, followed by a decrease in holding current (subset III). Most subset II glutamate responses were mimicked by the ionotropic glutamate receptor (iGluR) agonist N-methyl-d-aspartate (NMDA). The current was potentiated by glycine and was suppressed by the NMDA receptor antagonist d(−)-2-amino-5-phosphonopentanoic acid (AP5). The group III metabotropic glutamate receptor (mGluR) agonistl-2-amino-4-phosphonobutyric acid (l-AP4) usually mimicked the subset I glutamate response. This hyperpolarizing response was suppressed by the mGluR antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG) and by 8-bromo-cAMP, suggesting a role for cAMP in the transduction pathway. In a small subset of taste cells, l-AP4 elicited an increase in holding current, resulting in taste cell depolarization under current clamp. Taken together, our results suggest that NMDA-like receptors and at least two types of group III mGluRs are present in taste receptor cells, and these may be coactivated by MSG. Further studies are required to determine which receptors are located on the apical membrane and how they contribute to the umami taste.

scholarly journals Metabotropic glutamate receptor agonists for schizophrenia

2008 ◽  
Vol 192 (2) ◽  
pp. 86-87 ◽  
Author(s):  
Paul J. Harrison
Keyword(s):  
Glutamate Receptors ◽  
Dopamine Receptor ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Blocking ◽  
Receptor Agonists ◽  
Metabotropic Glutamate ◽  
Glutamate Receptor Agonists

SummaryA drug acting at metabotropic glutamate receptors has recently been reported to be an effective antipsychotic, breaking the rule that only dopamine receptor-blocking drugs have this property. The finding complements accumulating evidence that glutamatergic abnormalities are important in the pathophysiology of schizophrenia.

Expression of the K + /Cl − cotransporter, KCC2, in cerebellar Purkinje cells is regulated by group-I metabotropic glutamate receptors

2017 ◽  
Vol 115 ◽  
pp. 51-59 ◽  
Author(s):  
Serena Notartomaso ◽  
Giada Mascio ◽  
Pamela Scarselli ◽  
Katiuscia Martinello ◽  
Sergio Fucile ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Purkinje Cells ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Cerebellar Purkinje Cells

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 Apoptosis and Necrosis Occur in Separate Neuronal Populations in Hippocampus and Cerebellum after Ischemia and Are Associated with Differential Alterations in Metabotropic Glutamate Receptor Signaling Pathways

2000 ◽  
Vol 20 (1) ◽  
pp. 153-167 ◽  
Author(s):  
Lee J. Martin ◽  
Frederick E. Sieber ◽  
Richard J. Traystman
Keyword(s):  
Signaling Pathways ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Pyramidal Cells ◽  
Granule Neurons ◽  
Metabotropic Glutamate ◽  
Cerebellar Purkinje Cells

It was evaluated whether postischemic neurodegeneration is apoptosis and occurs with alterations in phosphoinositide-linked metabotropic glutamate receptors (mGluRs) and their associated signaling pathways. A dog model of transient global incomplete cerebral ischemia was used. The CA1 pyramidal cells and cerebellar Purkinje cells underwent progressive delayed degeneration. By in situ end-labeling of DNA, death of CA1 and Purkinje cells was greater at 7 days than 1 day after ischemia, whereas death of granule neurons in dentate gyrus and cerebellar cortex was greater at 1 than at 7 days. Ultrastructurally, degenerating CA1 pyramidal neurons and cerebellar Purkinje cells were necrotic; in contrast, degenerating granule neurons were apoptotic. In agarose gels of regional DNA extracts, random DNA fragmentation coexisted with internucleosomal fragmentation. By immunoblotting of regional homogenates, mGluR1α, mGluR5, phospholipase Cβ (PLCβ), and Gαq/11 protein levels in hippocampus at 1 and 7 days after ischemia were similar to control levels, but in cerebellar cortex, mGluR1α and mGluR5 were decreased but PLCβ was increased. By immunocytochemistry, mGluR and PLCβ immunoreactivity dissipated in CA1 and cerebellar Purkinje cell/ molecular layers, whereas immunoreactivities for these proteins were enhanced in granule neurons. It was concluded that neuronal death after global ischemia exists as two distinct, temporally overlapping forms in hippocampus and cerebellum: necrosis of pyramidal neurons and Purkinje cells and apoptosis of granule neurons. Neuronal necrosis is associated with a loss of phosphoinositide-linked mGluR transduction proteins, whereas neuronal apoptosis occurs with increased mGluR signaling.

scholarly journals Measurement of synaptic vesicle exocytosis in aortic baroreceptor neurons

1998 ◽  
Vol 275 (2) ◽  
pp. H710-H716 ◽  
Author(s):  
Meredith Hay ◽  
Eileen M. Hasser
Keyword(s):  
Synaptic Vesicle ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Time Course ◽  
Metabotropic Glutamate Receptor ◽  
Calcium Influx ◽  
Metabotropic Glutamate ◽  
Synaptic Vesicle Exocytosis ◽  
Bath Application ◽  
Vesicle Exocytosis

The purpose of this study was to evaluate the use of the fluorescent membrane label FM1–43 as a measure of synaptic terminal exocytosis during stimulation of labeled aortic baroreceptor and unlabeled nodose ganglia neurons. Activation of the nerve terminals with electrical stimulation or depolarization with 90 mM KCl in the presence of 2.0 μM FM1–43 resulted in bright, punctate staining of synaptic boutons. Additional depolarization in the absence of dye resulted in destaining with a time course that was consistent and repeatable in multiple boutons within a given terminal. Destaining was dependent on calcium influx and was blocked by bath application of 100 μM CdCl2. Whole cell patch-clamp studies have reported that depolarization-induced calcium influx in aortic baroreceptor cell bodies is predominantly caused by the activation of ω-conotoxin GVIA (ω-CgTx)-sensitive N-type calcium channels. In addition, these N-type channels have been shown to be inhibited by activation of metabotropic glutamate receptors. In the present study, exocytosis in aortic baroreceptor terminals was not affected by bath application of 5 μM nifedipine and only partially inhibited by bath application of 2.0 μM ω-CgTx. However, depolarization-induced exocytosis was significantly inhibited by bath application of 200 μM L-AP4, a type III metabotropic glutamate receptor agonist. Results from this study suggest that 1) FM1–43 can be used to measure synaptic vesicle exocytosis in baroreceptor neurons; 2) the N-type calcium channel may not be involved in the initial phase of vesicle exocytosis; and 3) activation of L-AP4-sensitive metabotropic glutamate receptors inhibits 90 mM KCl-induced vesicle release.

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