Reduced activity of hippocampal group-I metabotropic glutamate receptors in learning-prone rats (original) (raw)
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Neurobiology of Learning and Memory, 2007
Group I metabotropic glutamate receptors (mGlu1 and 5) have been implicated in synaptic plasticity and learning and memory. However, much of our understanding of how these receptors in different brain regions contribute to distinct memory stages in different learning tasks remains incomplete. The present study investigated the effects of the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and mGlu1 receptor antagonist, (S)-(+)-α-amino-4-carboxy-2methylbenzene-acetic acid (LY 367385) in the dorsal hippocampus on the consolidation and extinction of memory for inhibitory avoidance learning. Male, Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance task. MPEP, LY 367385 or saline were infused bilaterally into the CA1 region immediately after training or immediately after the first retention test which was given 24 hr after training. Rats receiving MPEP (1.5 or 5.0 μg/side) or LY 367385 (0.7 or 2.0 μg/side) infusion exhibited a dose-dependent decrease in retention when tested 24 hr later. MPEP was ineffective while LY 367385 significantly attenuated extinction when injected after the first retention test using an extinction procedure. These findings indicate a selective participation of hippocampal group I mGlu receptors in memory processing in this task.
Neuropharmacology, 2000
Memory formation involves encoding, consolidation and retention. These processes have been the subjects of considerable research, but physiological mechanisms underlying consolidation have proved difficult to dissociate experimentally. Previous reports have indicated a role for metabotropic glutamate receptors (mGluRs) in memory formation, and we here examined the specific role of mGluRs in the consolidation phase of memory formation. Particular weight was given to the hippocampus due to a high expression level for group I mGluRs and its outstanding role in spatial learning. Rats were first trained in a combined context and cue conditioning paradigm. Then, ex vivo analysis of neuronal tissue taken from hippocampal CA1, CA3 or dentate gyrus of behaviourally trained animals showed a 3-fold hyper-expression of mGluR5 protein in CA3 one day after acquisition training. This increase was transient and greatly diminished within ten days. The decline was paralleled by an increase in mGluR5 protein expression in CA1 and, to a lesser extent, in dentate gyrus, ten days posttraining. Overexpression in CA1 was also obtained after 9 days of extinction training. These data provide new insight into the role of the hippocampus and its subregions in memory consolidation. They support the notion that mGluRs in CA3 may play a part in short-term, and those in CA1 may play a part in long-term consolidation of memory.
Journal of Neural Transmission, 1999
The role of ventral hippocampus glutamate receptors on learning mechanisms and memory was studied in the rat. Adult male rats were unilaterally implanted in the ventral hippocampus with microinjection cannulas. The general experimental procedure used was the chemical stimulation of hippocampal neurons with glutamic acid alone or in combination with glutamate receptor antagonists during learning of an active avoidance response. The one-way active response consisted in avoiding an electric shock applied to the feet while an ultrasonic tone of 40 KHz was on. Two series of experiments were performed. In Experiment 1, the possible effect of glutamate on the evocation of the learned avoidance response was studied. In Experiment 2, the possible effect of glutamate on the acquisition of the avoidance response was analyzed. Experiment 1 showed that glutamate in the range 1-10 nmol did not interfere with the recall of the avoidance response, suggesting that glutamate has no effect on the hippocampal evocation processes. Experiment 2 showed that glutamic acid inhibits the acquisition process, increasing the latency time of escape and deteriorating the learning efficiency. This effect was antagonized by AP7, the NMDA-glutamate receptor antagonist, and increased by AP3, the metabotropic glutamate receptor antagonist. Present data suggest that metabotropic glutamate receptors facilitate and NMDA-glutamate receptors inhibit the learning hippocampal mechanisms in the rat.
Life, 2022
Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) naive mice; (ii) control mice exposed to the same environment as learner mice; (iii) leaner mice, trained for four days in a water maze; (iv) mice in which memory extinction was induced by six trials without the platform; (v) mice that spontaneously lost memory. The mGlu5 receptor-mediated PI hydrolysis was significantly reduced in the dorsal hippocampus of learner mice as compared to naive and control mice. The mGlu5 receptor signaling was also reduced in the ventral hippocampus and prefrontal cortex of learner mice, but only with respect to naive mice. Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with incr...
Psychopharmacology, 2006
Rationale: The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-D-aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. Objective: The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. Methods: Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). Results: Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)methanone methanesulfonate (EMQMCM) for mGlu1, [(2methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+) MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+) MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. Conclusion: The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.
Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats
Neurobiology of Learning and Memory, 2011
Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic coadministration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1Hpyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10 mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 hours after training. However, CDPPB (at 3 mg/kg) attenuated the MK-801 (0.2 mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.
Neuropharmacology, 2006
Glutamatergic neurotransmission in the CNS plays a predominant role in learning and memory. While NMDA receptors have been extensively studied, less is known about the involvement of group I metabotropic glutamate receptors in this area. The purpose of the present study was to evaluate the contribution of mGluR1 and mGluR5 to both acquisition and expression of behaviours in contextual and auditory fear conditioning models. The effects of both receptor types were tested using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGluR1, and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGluR5. Their effects on acquisition were compared to those of the NMDA receptor antagonist (+)MK-801, and the unselective muscarinic antagonist scopolamine, while diazepam and citalopram served as reference compounds in the expression experiments. EMQMCM (1.25 to 5mg/kg) impaired acquisition of contextual fear conditioning (CFC), but not auditory fear conditioning (AFC). Similarly, administration of MTEP during the acquisition phase impaired learning in CFC at doses of 2.5 to 10mg/kg, but was ineffective in AFC. When given before the retention test, both EMQMCM (1 and 3mg/kg) and MTEP (3mg/kg) impaired expression of CFC. In contrast, MTEP (2.5 and 5mg/kg) blocked the expression of AFC, while EMQMCM was ineffective. In conclusion, group I mGlu receptors are shown to be involved in the acquisition of hippocampus-dependent CFC, but not hippocampus-independent AFC. Unlike mGluR5, mGluR1 does not seem be involved in expression of AFC.
Learning & Memory, 1995
We examined the effects of both the metabotropic glutamate receptor (mGluR) antagonist MCPG and the agonist tADA in two behavioral paradigms in rats: (1) brightness discrimination and (2) spatial alternation. Compounds were applied intracerebroventricularly at different times, either 30 min prior to training or immediately after training, and rats were tested for retention 24 hr later in the same paradigms. Both MCPG and tADA caused amnesia in the spatial alternation test, when applied pretraining, but no effect was obtained in the brightness discrimination paradigm. Drug-induced amnesia was shown not to be attributable to state-dependent effects of MCPG or tADA. Moreover, the memory inhibiting effect of MCPG was dose dependent, with a low dose (20 raM/5 ml) having no effect on learning and memory and a 10 times higher concentration (200 mM/5 ml) causing complete amnesia. Application of both saline and MCPG immediately post-training prevented memory formation, which may be attributable to an interference by the injection procedure with the process of memory formation. The mGluR agonist tADA, however, facilitated memory formation in the spatial alternation task, when injected immediately after training. 3Corresponding author. Present address:
Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent
Neuropharmacology, 2004
Atrophy of the medial temporal lobes, including the glutamatergic cortical-hippocampal circuitry, is an early event in Alzheimer's disease (AD) and probably contributes to the characteristic short-term mnemonic decline. Pharmacological strategies directly targeted to ameliorating this functional decline may represent a novel approach for the symptomatic treatment of AD. Presynaptic group II metabotropic glutamate receptors (i.e. mGlu2 and mGlu3) exert a powerful modulatory influence on the function of these pathways, in particular the perforant pathway. Using a combination of mGlu2 receptor knockout mice and the group II agonist LY354740, we show that activation of mGlu2 receptors produces a cognitive impairment, i.e. a delay-dependent deficit in delayed matching and non-matching to position, and impaired spatial learning in a Morris water maze. Conversely, a group II antagonist, LY341495, improved acquisition of spatial learning. LY354740 potently reduced field excitatory postsynaptic potentials in hippocampal slices from wild type but not mGlu2 receptor knockout mice. Taken together, these results suggest that activation of mGlu2 receptors evokes a powerful inhibitory effect on hippocampal synaptic transmission and mGlu2 agonists produce a cognitive deficit consistent with this change. Conversely, mGlu2 receptor antagonists may improve certain aspects of cognition and thus represent a novel approach for the symptomatic treatment of AD. #
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.