Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors.
TL;DR: It is shown that when transmitter release is enhanced at hippocampal mossy fibre synapses, the concentration of glutamate increases and its clearance is delayed; this allows it to spread away from the synapse and to activate presynaptic inhibitory metabotropic glutamate receptors (mGluRs).
Abstract: The classical view of fast chemical synaptic transmission is that released neurotransmitter acts locally on postsynaptic receptors and is cleared from the synaptic cleft within a few milliseconds by diffusion and by specific reuptake mechanisms. This rapid clearance restricts the spread of neurotransmitter and, combined with the low affinities of many ionotropic receptors, ensures that synaptic transmission occurs in a point-to-point fashion. We now show, however, that when transmitter release is enhanced at hippocampal mossy fibre synapses, the concentration of glutamate increases and its clearance is delayed; this allows it to spread away from the synapse and to activate presynaptic inhibitory metabotropic glutamate receptors (mGluRs). At normal levels of glutamate release during low-frequency activity, these presynaptic receptors are not activated. When glutamate concentration is increased by higher-frequency activity or by blocking glutamate uptake, however, these receptors become activated, leading to a rapid inhibition of transmitter release. This effect may be related to the long-term depression of mossy fibre synaptic responses that has recently been shown after prolonged activation of presynaptic mGluRs (refs 2, 3). The use-dependent activation of presynaptic mGluRs that we describe here thus represents a negative feedback mechanism for controlling the strength of synaptic transmission.
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TL;DR: Recent progress in the research for GluRs is reviewed with special emphasis on the molecular diversity of the GluR system and its implications for physiology and pathology of the CNS.
1,141 citations
TL;DR: Subtype-specific antibodies were used for immunohistochemistry combined with lesioning of the three major hippocampal pathways to establish the precise localization of presynaptic mGluRs in the rat hippocampus, suggesting that transmitter release is differentially regulated by 2-amino-4-phosphonobutyrate-sensitive mGLURs in individual synapses on single axons according to the identity of postsynaptic neurons.
Abstract: Neurotransmission in the hippocampus is modulated variously through presynaptic metabotropic glutamate receptors (mGluRs). To establish the precise localization of presynaptic mGluRs in the rat hippocampus, we used subtype-specific antibodies for eight mGluRs (mGluR1–mGluR8) for immunohistochemistry combined with lesioning of the three major hippocampal pathways: the perforant path, mossy fiber, and Schaffer collateral. Immunoreactivity for group II (mGluR2) and group III (mGluR4a, mGluR7a, mGluR7b, and mGluR8) mGluRs was predominantly localized to presynaptic elements, whereas that for group I mGluRs (mGluR1 and mGluR5) was localized to postsynaptic elements. The medial perforant path was strongly immunoreactive for mGluR2 and mGluR7a throughout the hippocampus, and the lateral perforant path was prominently immunoreactive for mGluR8 in the dentate gyrus and CA3 area. The mossy fiber was labeled for mGluR2, mGluR7a, and mGluR7b, whereas the Schaffer collateral was labeled only for mGluR7a. Electron microscopy further revealed the spatial segregation of group II and group III mGluRs within presynaptic elements. Immunolabeling for the group III receptors was predominantly observed in presynaptic active zones of asymmetrical and symmetrical synapses, whereas that for the group II receptor (mGluR2) was found in preterminal rather than terminal portions of axons. Target cell-specific segregation of receptors, first reported for mGluR7a (Shigemoto et al., 1996), was also apparent for the other group III mGluRs, suggesting that transmitter release is differentially regulated by 2-amino-4-phosphonobutyrate-sensitive mGluRs in individual synapses on single axons according to the identity of postsynaptic neurons.
1,128 citations
Cites background from "Use-dependent increases in glutamat..."
...Recent studies showed that glutamate accumulated by repeated stimulations with short intervals, but not by single stimulations, activates presynaptic group II mGluRs in mossy fibers to induce long-term depression (Yokoi et al., 1996) and to suppress excitatory transmission (Scanziani et al., 1997)....
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TL;DR: The neurochemical evidence for mGlu receptor‐mediated regulation of neurotransmitters, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides is addressed.
Abstract: The G protein-coupled metabotropic glutamate (mGlu) receptors are differentially localized at various synapses throughout the brain. Depending on the receptor subtype, they appear to be localized at presynaptic and/or postsynaptic sites, including glial as well as neuronal elements. The heterogeneous distribution of these receptors on glutamate and nonglutamate neurons/cells thus allows modulation of synaptic transmission by a number of different mechanisms. Electrophysiological studies have demonstrated that the activation of mGlu receptors can modulate the activity of Ca(2+) or K(+) channels, or interfere with release processes downstream of Ca(2+) entry, and consequently regulate neuronal synaptic activity. Such changes evoked by mGlu receptors can ultimately regulate transmitter release at both glutamatergic and nonglutamatergic synapses. Increasing neurochemical evidence has emerged, obtained from in vitro and in vivo studies, showing modulation of the release of a variety of transmitters by mGlu receptors. This review addresses the neurochemical evidence for mGlu receptor-mediated regulation of neurotransmitters, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides.
907 citations
Cites methods or result from "Use-dependent increases in glutamat..."
...The preterminal localization of mGlu2 receptors at the hippocampal mossy fiber synapse observed by Yokoi et al. (1996) might predict that the receptor would be activated only under conditions of high neurotransmitter release, and indeed this has been supported by data from Scanziani et al. (1997)....
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...It is interesting that this study also supports previous electrophysiological data regarding the activation of presynaptic mGlu2 receptors by high synaptic concentrations of glutamate (Scanziani et al., 1997)....
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...It is interesting that this study also supports previous electrophysiological data regarding the activation of presynaptic mGlu2 receptors by high synaptic concentrations of glutamate (Scanziani et al., 1997)....
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TL;DR: The role of mGluRs in LTP induction continues to be a source of dispute, and resolution of the question of the exact involvement of m GluR in the induction of LTP will have to await the production of more selective ligands and of selective gene knockouts.
768 citations
Journal Article•
TL;DR: Gi-coupled mGlu receptors also may exist on presynaptic elements of neighboring gamma-aminobutyric acid neurons where they play a role in heterosynaptic suppressions of GABA release, suggesting that these receptors may have evolved to monitor glutamate that has "spilled out of the synapse".
Abstract: Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein-coupled receptors which function to modulate brain excitability via presynaptic, postsynaptic and glial mechanisms. Certain members of this receptor family have been shown to function as presynaptic regulatory mechanisms to control release of neurotransmitters. In general, Gi-coupled mGlu receptor subtypes appear to negatively modulate excitatory (and possibly also inhibitory) neurotransmitter output when activated. Localization studies have shown that mGlu7 is restricted to the presynaptic grid at the site of vesicle fusion. These studies along with other evidence suggest that mGlu7 is the nerve terminal autoreceptor that regulates physiological release of glutamate. Other mGlu subtypes, in particular mGlu2, mGlu8, and possibly mGlu4, are also localized presynaptically, but at perisynaptic sites outside the active zone of neurotransmitter release. Gi-coupled mGlu receptors also may exist on presynaptic elements of neighboring gamma-aminobutyric acid (GABA) neurons where they play a role in heterosynaptic suppressions of GABA release. This suggests that these receptors may have evolved to monitor glutamate that has "spilled" out of the synapse. Thus, they may serve as the brain's evolutionary mechanism to prevent pathological changes in neuronal excitability and thus maintain homeostasis. Recent progress on the molecular and pharmacological aspects of these presynaptic mGlu receptors is unveiling their functions and the therapeutic directions of agents designed for these novel glutamate receptor targets.
706 citations
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TL;DR: Recently, glutamate has been shown to regulate ion channels and enzymes producing second messengers via specific receptors coupled to G-proteins, and the existence of these receptors is changing views on the functioning of fast excitatory synapses.
2,304 citations
737 citations
TL;DR: The inhibition of GABA uptake greatly enhanced both the presynaptic action of GABA and the slow GABAB-mediated inhibitory postsynaptic current, and uptake mechanisms restrict the spatial range of both point-to-point synaptic transmission mediated by GABA and its action at a distance.
660 citations
TL;DR: Dose-response curves for activation of excitatory amino acid receptors on mouse embryonic hippocampal neurons in culture were recorded for 15 exciteatory amino acids, including the L-isomers of glutamate, aspartate, and a family of endogenous sulfur amino acids.
Abstract: Dose-response curves for activation of excitatory amino acid receptors on mouse embryonic hippocampal neurons in culture were recorded for 15 excitatory amino acids, including the L-isomers of glutamate, aspartate, and a family of endogenous sulfur amino acids. In the presence of 3 microM glycine, with no extracellular Mg, micromolar concentrations of 11 of these amino acids produced selective activation of N-methyl-D-aspartate (NMDA) receptors. L-Glutamate was the most potent NMDA agonist (EC50 2.3 microM) and quinolinic acid the least potent (EC50 2.3 mM). Dose-response curves were well fit by the logistic equation, or by a model with 2 independent agonist binding sites. The mean limiting slope of log-log plots of NMDA receptor current versus agonist concentration (1.93) suggests that a 2-site model is appropriate. There was excellent correlation between agonist EC50S determined in voltage clamp experiments and KdS determined for NMDA receptor binding (Olverman et al., 1988). With no added glycine, and 1 mM extracellular Mg, responses to NMDA were completely blocked; responses to kainate and quisqualate were unchanged. Under these conditions, glutamate and the sulfur amino acids activated a rapidly desensitizing response, similar to that evoked by micromolar concentrations of quisqualate and AMPA, but mM concentrations of L- aspartate, homoquinolinic acid, and quinolinic acid failed to elicit a non-NMDA receptor-mediated response. Except for L-glutamate (EC50 480 microM), the low potency of the sulfur amino acids prevented the study of complete dose-response curves for the rapidly desensitizing response at quisqualate receptors. Small-amplitude nondesensitizing quisqualate receptor responses were activated by much lower concentrations of all quisqualate receptor agonists. Full dose-response curves for the nondesensitizing response were obtained for 9 amino acids; L-glutamate was the most potent endogenous agonist (EC50 19 microM). Domoate (EC50 13 microM) and kainate (EC50 143 microM) activated large-amplitude, nondesensitizing responses.
647 citations
TL;DR: The results indicate that metabotropic glutamate receptor agonists suppress excitatory synaptic transmission in CA1 pyramidal cells by an action at a presynaptic site.
Abstract: 1. The effects of metabotropic glutamate receptor agonists on excitatory synaptic transmission in the CA1 region of rat hippocampal slices (11-30 days) were studied using extracellular and whole-cell patch-clamp recording techniques. 2. Trans-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD; 25-100 microM) reversibly depressed excitatory postsynaptic currents (EPSCs) without affecting presynaptic fibre excitability or EPSC reversal potential. 3. Ibotenate (25 microM) or L-glutamate (250 microM), in the presence of the N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovaleric acid (APV, 50-75 microM), depressed the EPSC amplitude while inducing no detectable inward current. L-2-Amino-4-phosphonobutyrate (L-AP4, 25-100 microM), the phosphonic derivative of glutamate, also depressed EPSC amplitude and caused no detectable inward current. 4. The NMDA receptor-mediated component of the EPSC recorded in the presence of the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20-30 microM) was depressed by trans-ACPD, L-AP4, or quisqualate (1-2 microM). 5. The response to ionophoretic application of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was unaffected by trans-ACPD or L-AP4 although the simultaneously recorded EPSC was strongly depressed. In addition, paired-pulse facilitation (50-75 ms interstimulus interval) was reversibly enhanced by trans-ACPD or L-AP4. These results indicate that the depression of synaptic transmission likely was mediated by a presynaptic 'autoreceptor'. 6. The effects of trans-ACPD or L-AP4 on synaptic transmission decreased significantly over ages 12-30 days and were minimal in adult (greater than 80 days) slices. 7. The depression of synaptic transmission caused by trans-ACPD or L-AP4 was not altered following the induction of long-term potentiation (LTP). 8. The results indicate that metabotropic glutamate receptor agonists suppress excitatory synaptic transmission in CA1 pyramidal cells by an action at a presynaptic site. This effect is developmentally regulated and is maximally expressed during the first postnatal month.
445 citations