Regular PaperRole of glutamate metabotropic receptors in long-term potentiation in the hippocampus
Abstract
Glutamate metabotropic receptors (mGluRs) are heterogenous G-protein-linked receptors widely distributed in the central nervous system. These receptors, which are coupled to several second messengers, modulate voltage-gated and receptor-operated channels and play an important role in synaptic plasticity, notably in the modulation of long-term potentiation (LTP). In this review, we briefly describe the different electrophysiological effects of mGluRs and discuss the two models which have been proposed in the literature to underline the role of mGluRs in LTP.
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Counteracting roles of metabotropic glutamate receptor subtypes 1 and 5 in regulation of pain-related spatial and temporal synaptic plasticity in rat entorhinal-hippocampal pathways
2012, Neuroscience LettersIt was previously found that persistent inflammatory pain state resulted in enhancement of synaptic connections and efficacy in direct entorhinal–hippocampal (EC-HIP) pathways. In the current study, the roles of two subtypes of group I metabotropic glutamate receptors in the above processes were evaluated. Similarly, pain-related spatial and temporal synaptic enhancement model was stably achieved by the multi-electrode array (8 × 8) recordings in the hippocampal slices of rats pre-treated with intraplantar (i.pl.) bee venom (BV) injection. I.pl. saline injection was used as control. Inhibition of mGluR1 by a selective antagonist 7-hydroxyiminocyclopropan [b] chromen-1α-carboxylic acid ethyl ester (CPCCOEt) resulted in a dramatic increase in synaptic connections in the hippocampal slices of rats treated by BV, but not by saline. However, inhibition of mGluR5 by a selective antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) produced no spatial change from either of the two groups. Temporally, the BV-enhanced LTP could be further incremented by antagonism of mGluR1 with CPCCOEt perfusion when plateau LTP was well established. However, the BV-enhanced LTP was significantly suppressed by antagonism of mGluR5 with MPEP. Neither of the two drugs affected magnitude of LTP in rats treated by i.pl. saline. Taken together with our previous results, it is suggested that mGluR1 be involved in tonic inhibition of EC-HIP synaptic enhancement, while mGluR5 be involved in maintenance of persistent inflammatory pain-associated EC-HIP synaptic enhancement that is largely based upon activation of ionic glutamate receptors.
Group I metabotropic glutamate receptors: Implications for brain diseases
1999, Progress in NeurobiologyGlutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The discovery of the metabotropic receptors (mGluRs), a family of G-protein coupled receptors than can be activated by glutamate, has led to an impressive number of studies in recent years aimed at understanding their biochemical, physiological and pharmacological characteristics.
The eight mGluRs now known are divided into three groups according to their sequence homology, signal transduction mechanisms, and agonist selectivity. Group I mGluRs include mGluR1 and mGluR5, which are linked to the activation of phospholipase C; Groups II and III include all others and are negatively coupled to adenylyl cyclases.
The availability in recent years of agents selective for Group I mGluRs has made possible the study of the physiological roles of these receptors in the CNS. In addition to mediating glutamatergic neurotransmission, Group I mGluRs can modulate other neurotransmitter receptors, including GABA and the ionotropic glutamate receptors.
Group I mGluRs are involved in many CNS functions and may participate in a variety of disorders such as pain, epilepsy, ischemia, and chronic neurodegenerative diseases. This class of receptor may provide important pharmacological therapeutic targets and elucidating its functions will be relevant to develop new treatments for neurological and psychiatric disorders in which glutamatergic neurotransmission is abnormally regulated.
In this review anatomical, physiological and pharmacological results are presented with a special emphasis on the role of Group I mGluRs in functional and pathological processes.
Metabotropic glutamate receptors limit adenylyl cyclase-mediated effects in rat hippocampus via protein kinase C
1998, Neuroscience LettersGlutamate receptors of the metabotropic type (mGluRs) activate protein kinase C in hippocampus, but few physiological functions of this pathway are known. The present data show that mGluRs utilize protein kinase C to inhibit another second messenger system, the adenylyl cyclase pathway, in neurons of the CA1 area of hippocampus. Activation of mGluRs prevented β-adrenergic receptors, which couple to adenylyl cyclase, from blocking the slow Ca2+-dependent afterhyperpolarization (AHP). Since the afterhyperpolarization modulates neuronal responsiveness, crosstalk between protein kinase C and the adenylyl cyclase pathway is likely to have physiological consequences. Moreover, mGluRs themselves block the afterhyperpolarization, so the observed interference with the β-adrenergic response constitutes a hierarchical relationship in which mGluRs are dominant over β-adrenergic receptors.
Metaplasticity: A new vista across the field of synaptic plasticity
1997, Progress in NeurobiologyOver the past 20 years there has been an increasing understanding of the properties and mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy, putative learning and memory mechanisms in the mammalian brain. More recently, however, it has become apparent that synaptic activity can also elicit persistent neuronal responses not manifest as changes in synaptic strength. Some of these changes may nonetheless modify the ability of synapses to undergo strength changes in response to subsequent episodes of synaptic activity. This kind of activity-dependent modulatory plasticity we have termed “metaplasticity”. Metaplasticity has been observed physiologically as an inhibition of LTP and concomitant facilitation of LTD by prior N-methyl-D-aspartate receptor activator or, conversely, a facilitation of LTP induction by prior metabotropic glutamate receptor activation. The examples of metaplasticity described to date are input specific, and last as long as several hours. The mechanisms underlying such phenomena remain to be fully characterized, although some likely possibilities are an altered N-methyl-D-aspartate receptor function, altered calcium buffering, altered states of kinases or phosphatases, and a priming of protein synthesis machinery. While some details vary, experimentally observed metaplasticity bears some similarity to the “sliding theshold” feature of the Bienenstock, Cooper and Munro model of experience-dependent synaptic plasticity. Metaplasticity may serve several functions including (1) providing a way for synapses to integrate a response across temporally spaced episodes of synaptic activity and (2) keeping synapses within a dynamic functional range, and thus preventing them from entering states of saturated LTP or LTD.
Regulation of synaptic plasticity by mGluR<inf>1</inf> studied in vivo in mGluR<inf>1</inf> mutant mice
1997, Brain ResearchThe role of the metabotropic glutamate receptor 1 (mGluR1) in synaptic plasticity was investigated in vivo in the intact hippocampus of mutant mice lacking this receptor. In a previous study we showed reduced long-term potentiation (LTP) in the dentate gyrus of mGluR1 −/− mice in vivo, but not when LTP was studied in a slice preparation. A possible explanation of this difference is that dentate neurons receive more inhibitory synaptic drive in vivo than in slice preparation where many inhibitory axon collaterals are lost. We report here that another form of synaptic plasticity, paired-pulse depression of the population spike, is also abnormal in the dentate gyrus of mGluR1-deficient mice when tested in vivo. In wild-type mice, stimulation of the medial perforant path produced paired-pulse depression of inter-pulse intervals (IPIs) up to 30 ms. Mutant mGluR1, on the other hand, showed a significantly longer IPI depression, up to 50 ms. Paired-pulse depression results from the activation of inhibitory interneurons. The GABAB agonist baclofen, acting presynaptically on the GABA interneurons, attenuated paired-pulse depression and allowed for a normal and stable LTP in mGluR1 mutant mice. These findings suggest an indirect role for mGluR1 in synaptic plasticity via a regulation of GABA inhibition.
Receptor-mediated activation of protein kinase C in hippocampal long-term potentiation: Facts, problems and implications
1997, Progress in Neuro-Psychopharmacology and Biological PsychiatryDuring the last decade hippocampal long-term potentiation has become one of the most frequently used models to study cellular mechanisms of learning and memory. Receptor-mediated activation of protein kinase C is thought to be involved in LTP stabilisation. In the present review
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1. the molecular structure and activation mechanisms of PKC isoenzymes,
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2. the biochemical evidences for PKC activation after induction of LTP using different stimulation paradigms as well as
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3. the involvement of metabotropic glutamate receptors in PKC activation after induction of LTP are critically discussed.
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