Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7 (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.
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.
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...
Metabotropic glutamate receptor 1 (mGluR1) has been related to processes underlying learning in hippocampal circuits, but demonstrating its involvement in synaptic plasticity when measured directly on the relevant circuit of a learning animal has proved to be technically difficult. We have recorded the functional changes taking place at the hippocampal CA3-CA1 synapse during the acquisition of an associative task in conscious mice carrying a targeted disruption of the mGluR1 gene. Animals were classically conditioned to evoke eyelid responses, using a trace (conditioned stimulus [CS], tone; unconditioned stimulus [US], electric shock) paradigm. Acquisition of this task was impaired in mutant mGluR1 1/2 mice and abolished in mGluR1 2/2 mice. A single pulse presented to Schaffer collaterals during the CS-US interval evoked a monosynaptic field excitatory postsynaptic potential at ipsilateral CA1 pyramidal cells, whose slope was linearly related to learning evolution in controls but not in mGluR1 mutants. Long-term potentiation evoked by train stimulation of Schaffer collaterals was also impaired in both mGluR1 1/2 and mGluR1 2/2 animals. Administration of the selective mGluR1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental [c]furan-1-on to wild-type animals mimicked the functional changes associated to mGluR1 insufficiency in mutants. Thus, mGluR1 is required for activity-dependent synaptic plasticity and associative learning in behaving mice.
mGLU Receptors, 2017
In the hippocampus, the metabotropic glutamate (mGlu) receptor, mGlu5, plays a very prominent role in synaptic information storage and memory. This receptor enables persistent (>24 h) forms of synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), and is also required for plasticity forms that are directly modulated by spatial learning. mGlu5 supports hippocampal neuronal oscillations that occur during synaptic plasticity events, supports the stabilization of place fields, and regulates the direction of change in synaptic weights in specific synaptic subcompartments of the hippocampus. Furthermore, dysfunctions in this receptor are associated with potent disturbances of hippocampus-dependent cognition. We propose that the mGlu5 receptor lies at the hub of hippocampal information processing and is pivotal to the accurate, long-term, and reliable acquisition and encoding of new spatial experiences and cognitive representations.
Pharmacological Research, 1990
InsP) formation by ibotenate or trans-1 -aminocyclopentyl-1,3-dicarboxylic acid (t-ACPD) in rat hippocampal slices was enhanced after tetanic stimulation of the SchaRer collaterals projecting to the CA 1 region (in vitro) or the perforant pathway projecting to the dentate gyrus (in freely moving animals). This effect was observed 5 h (but not 2 h) after long-term potentiation (LTP) induction and was abolished if tetanic stimulation was performed in the presence of specific antagonists of N-methyl-D-aspartate receptors. The delayed increase in excitatory amino acid-induced polyphosphoinositide (PPI) hydrolysis was accompanied by an enhanced responsiveness to norepinephrine, whereas the basal and carbamylcholine-stimulated [3H]InsP formation were unchanged. These results suggest that an increased activity of "metabotropic" glutamate receptors may contribute to the synaptic mechanisms enabling the late expression and or maintenance of LTP. Accordingly, LTP decayed more rapidly (within 5 h) in rats repeatedly injected with LiCl (60-120 mg/kg, i.p., for 10 days), a treatment that led to a reduced efficacy of ibotenate and norepinephrine in stimulating PPI hydrolysis in hippocampal slices. Key Words: Glutamate-Phosphoinositides-Long-term potentiation-Hippocampus. Aronica E. et al. Enhanced sensitivity of "metabotropic" glutamate receptors after induction of long-term potentiation in rat hippocampus. Abbreviations used: t-ACPD, trans-aminocyclopentyl-1,3-dicarboxylic acid; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolpro-
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.
Journal of Neurochemistry, 1991
Stimulation of [3H]inositol monophosphate ([3H]InsP) formation by ibotenate or trans-1-aminocyclopentyl-1,3-dicarboxylic acid (t-ACPD) in rat hippocampal slices was enhanced after tetanic stimulation of the SchaRer collaterals projecting to the CA 1 region (in vitro) or the perforant pathway projecting to the dentate gyrus (in freely moving animals). This effect was observed 5 h (but not 2 h) after long-term potentiation (LTP) induction and was abolished if tetanic stimulation was performed in the presence of specific antagonists of N-methyl-D-aspartate receptors. The delayed increase in excitatory amino acid-induced polyphosphoinositide (PPI) hydrolysis was accompanied by an enhanced responsiveness to norepinephrine, whereas the basal and carbamylcholine-stimulated [3H]InsP formation were unchanged. These results suggest that an increased activity of "metabotropic" glutamate receptors may contribute to the synaptic mechanisms enabling the late expression and or maintenance of LTP. Accordingly, LTP decayed more rapidly (within 5 h) in rats repeatedly injected with LiCl (60-120 mg/kg, i.p., for 10 days), a treatment that led to a reduced efficacy of ibotenate and norepinephrine in stimulating PPI hydrolysis in hippocampal slices. Key Words: Glutamate-Phosphoinositides-Long-term potentiation-Hippocampus. Aronica E. et al. Enhanced sensitivity of "metabotropic" glutamate receptors after induction of long-term potentiation in rat hippocampus.
Cerebral Cortex, 2004
Little is known, however, about the contribution of the individual subtypes mGlu1 and mGlu5 to learning processes and LTP. We investigated the involvement of mGlu5 in hippocampal LTP and spatial learning using the selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). Rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from the medial perforant path -dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days subsequent to the implantation procedure.
Experimental Brain Research, 2009
In the intact adult animal, synaptic plasticity in the visual cortex (VC) is a dynamic and naturalistic phenomenon, the mechanisms of which are not yet fully understood. Given its intrinsic role in hippocampal plasticity, we investigated the eVects of pharmacological antagonism of mGluR5 on synaptic plasticity and receptor expression in the VC of freely moving adult pigmented rats, and compared this with hippocampal eVects. Persistent long-term potentiation (LTP, >24 h) in layer II/III of the primary VC, and LTP in the dentate gyrus, were impaired by application of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). Long-term depression in VC was unaVected. Twenty-four hours after MPEP treatment, mGluR1a monomer expression was reduced in the VC but not in the hippocampus, whereas dimer expression was unaVected; mGluR2/3 and mGluR5 monomers were unaVected, but dimers were reduced in the VC. Our data suggest that mGluR5 is engaged in the regulation of synaptic plasticity in the adult VC and hippocampus: the mechanisms for this may be quite distinct, however. While only LTP is aVected by mGluR5-antagonism in the VC, both LTP and LTD are aVected in the hippocampus. Furthermore, the higher sensitivity of mGluR expression to antagonism of mGluR5 in VC compared to the hippocampus suggests that mGluR5 regulates plasticity phenomena in these structures by means of distinct mGluR-dependent processes.