Involvement of the mGluR1 Receptor in Hippocampal Synaptic Plasticity and Associative Learning in Behaving Mice (original) (raw)
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An impairment of hippocampal synaptic plasticity in mice lacking mGlu7 receptors
Neuropharmacology, 1996
Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/-mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/-mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/-mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/-mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.
Regulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice
Brain Research, 1997
The role of the metabotropic glutamate receptor 1 mGluR in synaptic plasticity was investigated in vivo in the intact hippocampus 1 Ž. of mutant mice lacking this receptor. In a previous study we showed reduced long-term potentiation LTP in the dentate gyrus of mGluR yry mice in vivo, but not when LTP was studied in a slice preparation. A possible explanation of this difference is that 1 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 mGluR-deficient mice when tested in vivo. In wild-type mice, stimulation of the medial perforant path produced paired-pulse 1 Ž. depression of inter-pulse intervals IPIs up to 30 ms. Mutant mGluR , on the other hand, showed a significantly longer IPI depression, up 1 to 50 ms. Paired-pulse depression results from the activation of inhibitory interneurons. The GABA agonist baclofen, acting B presynaptically on the GABA interneurons, attenuated paired-pulse depression and allowed for a normal and stable LTP in mGluR 1 mutant mice. These findings suggest an indirect role for mGluR in synaptic plasticity via a regulation of GABA inhibition.
Neuroscience, 2008
In this study we evaluated the effects of the novel, potent non-competitive metabotropic glutamate receptor (mGluR) 1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5methyliden-hexahydro-cyclopental[c]furan-1-on (BAY 36-7620) on different types of synaptic plasticity in the hippocampal cornu ammonis (CA) 1-region and on hippocampus-dependent spatial learning. After having confirmed the presence of mGluR1 in the hippocampal CA1 region of our rat strain by confocal microscopy, we tested the effects of BAY 36-7620 on: 1) long-term potentiation (LTP) induced by weak and strong stimulation; 2) 3,5-dihydroxyphenylglycine (DHPG, 30 M)-induced depression of synaptic transmission; and 3) learning of the hidden platform version of the water maze by mice. BAY 36-7620 (10 M) amplified LTP but, like the mGluR1 antagonists 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt, 10 M) and 4-carboxyphenylglycine (4-CPG, 50 M), diminished LTP at 1 M. The mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP, 10 M) had no effect. BAY 36-7620 (10 M) did not affect strong LTP. Thus, mGlu 1, but not mGlu 5, receptors modulate LTP elicited by weak stimulation in vitro. DHPG-induced depression of synaptic transmission was only marginally affected by BAY 36-7620 (1 M) or 4-CPG (100 M). In a mouse water maze study, BAY 36-7620 (10 mg/kg, i.v.) increased the escape latency and impaired water escape task acquisition during the first 4 days. Drug-and vehicle-treated groups showed comparable performance at day 5. Our data support a role for mGluR1 in LTP and in the acquisition of spatial memory.
Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7
TheScientificWorldJournal, 2002
Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less...
Neuropharmacology, 1998
Understanding the roles of metabotropic glutamate (mGlu) receptors has been severely hampered by the lack of potent antagonists. LY341495 (2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid) has been shown to block group II mGlu receptors in low nanomolar concentrations (. LY341495 is a nanomolar potent and selective antagonist at group II metabotropic glutamate receptors. Neuropharmacology 37, 1 -12) but can be used in higher concentrations to block all hippocampal mGlu receptors, identified so far by molecular cloning (mGlu 1-5, 7,8 ). Here we have further characterised the mGlu receptor antagonist activity of LY341495 and have used this compound to investigate roles of mGlu receptors in hippocampal long-term potentiation (LTP) and long-term depression (LTD). LY341495 competitively antagonised DHPG-stimulated PI hydrolysis in AV12-664 cells expressing either human mGlu 1 or mGlu 5 receptors with K i -values of 7.0 and 7.6 mM, respectively. When tested against 10 mM L-glutamate-stimulated Ca 2 + mobilisation in rat mGlu 5 expressing CHO cells, it produced substantial or complete block at a concentration of 100 mM. In rat hippocampal slices, LY341495 eliminated 30 mM DHPG-stimulated PI hydrolysis and 100 mM (1S,3R)-ACPD-inhibition of forskolin-stimulated cAMP formation at concentrations of 100 and 0.03 mM, respectively. In area CA1, it antagonised DHPG-mediated potentiation of NMDA-induced depolarisations and DHPG-induced long-lasting depression of AMPA receptor-mediated synaptic transmission. LY341495 also blocked NMDA receptor-independent depotentiation and setting of a molecular switch involved in the induction of LTP; effects which have previously been shown to be blocked by the mGlu receptor antagonist (S)-MCPG. These effects may therefore be due to activation of cloned mGlu receptors. In contrast, LY341495 did not affect NMDA receptor-dependent homosynaptic LTD; an effect which may therefore be independent of cloned mGlu receptors. Finally, LY341495 failed to antagonise NMDA receptor-dependent LTP and, in area CA3, NMDA receptor-independent, mossy fibre LTP. Since in the same inputs these forms of LTP were blocked by (S)-MCPG, a novel type of mGlu receptor may be involved in their induction.
A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning
Learning & memory (Cold Spring Harbor, N.Y.)
Metabotropic glutamate receptors (mGluRs) have been implicated in long-term potentiation and in learning and memory formation. In this study, we tested the effects of group I mGluR inhibition on synaptic plasticity and learning of rats at different levels of organization (1) in the hippocampal slice preparation; (2) in freely moving animals implanted with chronic hippocampal electrodes; and (3) in different spatial learning paradigms. To allow a direct comparison of the effects obtained the same doses were used in all paradigms. Bath-application of the selective group I mGluR antagonist (S)4-carboxyphenylglycine (4-CPG) impaired a decremental long-term potentiation (LTP) induced by a weak tetanization paradigm, but failed to affect a robust LTP generated by strong tetanization. In contrast, 4-CPG impaired a robust LTP in freely moving animals if applied 30 min before tetanization. The same dose of 4-CPG only impeded spatial learning mildly in the eight-arm radial maze and had no eff...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997
Class I metabotropic glutamate receptors (mGluRs) have been postulated to play a role in synaptic plasticity. To test the involvement of one member of this class, we have recently generated mutant mice that express no mGluR5 but normal levels of other glutamate receptors. The CNS revealed normal development of gross anatomical features. To examine synaptic functions we measured evoked field EPSPs in the hippocampal slice. Measures of presynaptic function, such as paired pulse facilitation in mutant CA1 neurons, were normal. The response of mutant CA1 neurons to low concentrations of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) was missing, which suggests that mGluR5 may be the primary high affinity ACPD receptor in these neurons. Long-term potentiation (LTP) in mGluR5 mutants was significantly reduced in the NMDA receptor (NMDAR)-dependent pathways such as the CA1 region and dentate gyrus of the hippocampus, whereas LTP remained intact in the mossy fiber synapses on the...
Cerebral Cortex, 2011
Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with persistent synaptic plasticity to the coupling of weak afferent stimulation, which is subthreshold for the induction of plasticity, with a spatial learning experience. The metabotropic glutamate receptor subtype 5 (mGluR5) is critically involved in enabling the persistency of multiple forms of hippocampal synaptic plasticity. We compared the effects of pharmacological allosteric antagonism of mGluR5 in learning-facilitated plasticity with plasticity that had been induced solely by patterned afferent stimulation of the Schaffer collateral pathway to the CA1 stratum radiatum of adult freely behaving rats. Intracerebroventricular injection of the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) had no effect on basal synaptic transmission but significantly prevented both long-term depression (LTD) elicited by electrical stimulation and LTD facilitated by novel object-place configuration learning. NMDA receptor antagonism also prevented learning-facilitated LTD. Habituation to the objects was prevented by MPEP application. Whereas reexposure to the object-place configuration (after 7 days) failed to facilitate LTD in control animals, those who had been treated previously with MPEP expressed LTD, suggesting that inhibition of learning contributed to the initial prevention of LTD. These data support a pivotal role for mGluR5 in both hippocampal LTD and the acquisition of object-place configurations.
Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning
Neuropharmacology, 2013
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 hippocampusdependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events.
Intracellular mGluR5 Can Mediate Synaptic Plasticity in the Hippocampus
Journal of Neuroscience, 2014
Metabotropic glutamate receptor 5 (mGluR5) is widely expressed throughout the CNS and participates in regulating neuronal function and synaptic transmission. Recent work in the striatum led to the groundbreaking discovery that intracellular mGluR5 activation drives unique signaling pathways, including upregulation of ERK1/2, Elk-1 (Jong et al., 2009) and Arc (Kumar et al., 2012). To determine whether mGluR5 signals from intracellular membranes of other cell types, such as excitatory pyramidal neurons in the hippocampus, we used dissociated rat CA1 hippocampal cultures and slice preparations to localize and characterize endogenous receptors. As in the striatum, CA1 neurons exhibited an abundance of mGluR5 both on the cell surface and intracellular membranes, including the endoplasmic reticulum and the nucleus where it colocalized with the sodium-dependent excitatory amino acid transporter, EAAT3. Inhibition of EAAT3 or sodium-free buffer conditions prevented accumulations of radiolabeled agonist. Using a pharmacological approach to isolate different pools of mGluR5, both intracellular and cell surface receptors induced oscillatory Ca 2ϩ responses in dissociated CA1 neurons; however, only intracellular mGluR5 activation triggered sustained high amplitude Ca 2ϩ rises in dendrites. Consistent with the notion that mGluR5 can signal from intracellular membranes, uncaging glutamate on a CA1 dendrite led to a local Ca 2ϩ rise, even in the presence of ionotropic and cell surface metabotropic receptor inhibitors. Finally, activation of intracellular mGluR5 alone mediated both electrically induced and chemically induced long-term depression, but not long-term potentiation, in acute hippocampal slices. These data suggest a physiologically relevant and important role for intracellular mGluR5 in hippocampal synaptic plasticity.