Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus

doi:10.1016/0014-2999(93)91009-C

European Journal of Pharmacology

Volume 239, Issues 1–3, 3 August 1993, Pages 265-266

https://doi.org/10.1016/0014-2999(93)91009-C Get rights and content

Abstract

Long-term depression of synaptic transmission was induced following the prior induction of long-term potentiation in the CA1 region of rat hippocampal slices. We show that the induction of this form of synaptic depression can be prevented by (+)-α-methyl-4-carboxyphenylglycine, a selective antagonist of metabotropic glutamate receptors.

References (8)

G. Barrionuevo et al.
The effects of repetitive low frequency stimulation on control and ‘potentiated’ synaptic responses in the hippocampus
Life Sci.
(1980)
S.A. Eaton et al.
Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine (CPG) and (RS)-α-methyl-4-carboxyphenylglycine (MCPG)
Eur. J. Pharmacol.
(1993)
R.M. Mulkey et al.
Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus
Neuron
(1992)
Z.I. Bashir et al.
LTP in the hippocampus needs activation of glutamate metabotropic receptors
Nature
(1993)

There are more references available in the full text version of this article.

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The plethora of functions of glutamate in the brain are mediated by the complementary actions of ionotropic and metabotropic glutamate receptors (mGluRs). The ionotropic glutamate receptors carry most of the fast excitatory transmission, while mGluRs modulate transmission on longer timescales by triggering multiple intracellular signaling pathways. As such, mGluRs mediate critical aspects of synaptic transmission and plasticity. Interestingly, at synapses, mGluRs operate at both sides of the cleft, and thus bidirectionally exert the effects of glutamate. At postsynaptic sites, group I mGluRs act to modulate excitability and plasticity. At presynaptic sites, group II and III mGluRs act as auto-receptors, modulating release properties in an activity-dependent manner. Thus, synaptic mGluRs are essential signal integrators that functionally couple presynaptic and postsynaptic mechanisms of transmission and plasticity. Understanding how these receptors reach the membrane and are positioned relative to the presynaptic glutamate release site are therefore important aspects of synapse biology. In this review, we will discuss the currently known mechanisms underlying the trafficking and positioning of mGluRs at and around synapses, and how these mechanisms contribute to synaptic functioning. We will highlight outstanding questions and present an outlook on how recent technological developments will move this exciting research field forward.
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Glutamate receptors are the most abundant excitatory neurotransmitter receptors in the brain, responsible for mediating the vast majority of excitatory transmission in neuronal networks. The AMPA- and NMDA-type ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the fast synaptic responses, while metabotropic glutamate receptors (mGluRs) are coupled to downstream signaling cascades that act on much slower timescales. These functionally distinct receptor sub-types are co-expressed at individual synapses, allowing for the precise temporal modulation of postsynaptic excitability and plasticity. Intriguingly, these receptors are differentially distributed with respect to the presynaptic release site. While iGluRs are enriched in the core of the synapse directly opposing the release site, mGluRs reside preferentially at the border of the synapse. As such, to understand the differential contribution of these receptors to synaptic transmission, it is important to not only consider their signaling properties, but also the mechanisms that control the spatial segregation of these receptor types within synapses. In this review, we will focus on the mechanisms that control the organization of glutamate receptors at the postsynaptic membrane with respect to the release site, and discuss how this organization could regulate synapse physiology.
Do group I metabotropic glutamate receptors mediate LTD?
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Synapses undergo significant structural and functional reorganization in response to varying patterns of stimulation. These forms of plasticity are considered fundamental to cognition and neuronal homeostasis. An increasing number of reports highlight the importance of activity-dependent synaptic strengthening (long term potentiation: LTP) for learning. However, the functional significance of activity-dependent weakening of synapses (long term depression: LTD) remains relatively poorly understood. One form of synaptic weakening, induced by group I metabotropic glutamate receptors (mGluRs), has received significant attention from a mechanistic point of view and because of its augmentation in a murine model of Fragile X Syndrome. Yet, studies of this form of plasticity often yield confusing, contradictory results. These conflicting findings are likely attributable to the bulk stimulation and recording techniques often used to study synaptic plasticity (typically involving evoked extracellular recordings, which represent the summed activity of many synapses). Such studies inherently blur the identity of the synapses undergoing change, thus giving the illusion that synapses per se are being modified when in fact this may only be true of a specific subset of synapses. Indeed, studies employing minimal synaptic activation paint a fundamentally different picture of what is commonly called “mGluR-LTD”. Here, I review the evidence in favour of group I mGluRs as mediators of various forms of synaptic downregulation and attempt to explain discrepancies in the literature. I argue that, while multiple forms of synaptic weakening may be triggered by these receptors, the canonical form of group I mGluR-mediated depression, mGluR-LTD, is in fact not a depression of basal synaptic responses. Rather, it is a reversal of established LTP and thus a form of depotentiation. Far from being arbitrary, this distinction has significant implications for the role of group I mGluRs in cognition, both in the healthy brain and in pathological conditions. Further, the differential actions of group I mGluRs at naïve and potentiated synapses suggest these receptors signal in a state-dependent manner to regulate various stages of the learning process.
Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning
2013, Neuropharmacology
Citation Excerpt :
With regard to hippocampal LTP, chemical forms have been described that are induced by sole activation of mGlu receptors, in the absence of patterned afferent stimulation. Initial studies were conducted in vitro and showed how the group I and II mGlu agonist, 1-amino-1,3-dicarboxycyclopentane (1S,3R ACPD), induces slow-onset potentiation in the CA1 area of rat hippocampus (Bashir et al., 1993; Chinestra et al., 1994; Bortolotto and Collingridge, 1995). Later, this phenomenon was also demonstrated in vivo, where effects endured for over 4 h (Manahan-Vaughan and Reymann, 1995) and were prevented by an antagonist of group I mGlus (Manahan-Vaughan and Reymann, 1997).
Storage and processing of information at the synaptic level is enabled by the ability of synapses to persistently alter their efficacy. This phenomenon, known as synaptic plasticity, is believed to underlie multiple forms of long-term memory in the mammalian brain. It has become apparent that the metabotropic glutamate (mGlu) receptor is critically required for both persistent forms of memory and persistent synaptic plasticity. Persistent forms of synaptic plasticity comprise long-term potentiation (LTP) and long-term depression (LTD) that last at least for 4 h but can be followed in vivo for days and weeks. These types of plasticity are believed to be analogous to forms of memory that persist for similar time-spans. The mGlu receptors are delineated into three distinct groups based on their G-protein coupling and agonist affinity and also exercise distinct roles in the way they regulate both long-term plasticity and long-term hippocampus-dependent memory. Here, the mGlu receptors will be reviewed both in general, and in the particular context of their role in persistent (>4 h) forms of hippocampus-dependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events.
This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.
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The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM_E17). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM_E17 treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA_A receptor (GABA_AR) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.
This article is part of a Special Issue entitled ‘Schizophrenia’.
N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptorsin cerebellar granule neurons
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Changes in synaptic strength mediated by ionotropic glutamate N-methyl-d-asparate (NMDA) receptors is generally considered to be the molecular mechanism underlying memory and learning. NMDA receptors themselves are subject to regulation through signaling pathways that are activated by G-protein-coupled receptors (GPCRs). In this study we investigate the ability of NMDA receptors to regulate the signaling of GPCRs by focusing on the G_q/11-coupled M₃-muscarinic receptor expressed endogenously in mouse cerebellar granule neurons. We show that NMDA receptor activation results in the phosphorylation and desensitization of M₃-muscarinic receptors through a mechanism dependent on NMDA-mediated calcium influx and the activity of calcium-calmodulin-dependent protein kinase II. Our study reveals a complex pattern of regulation where GPCRs (M₃-muscarinic) and NMDA receptors can feedback on each other in a process that is likely to influence the threshold value of signaling networks involved in synaptic plasticity.

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Rapid communicationMetabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus

Abstract

Life Sci.

Eur. J. Pharmacol.

Neuron

LTP in the hippocampus needs activation of glutamate metabotropic receptors

Nature

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Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus