Research reportRegulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice
Introduction
Long-term potentiation (LTP) is a synaptic model of memory and neuronal plasticity 7, 8that in the CA1 and dentate gyrus regions of the hippocampus requires the activation of postsynaptic N-methyl-d-aspartate (NMDA) receptors. Metabotropic glutamate receptors (mGluRs) have also been implicated in the induction of LTP in these regions. There are at least eight different subtypes of mGluR (mGluR1–8) which can be placed in three groups on the basis of sequence homology, agonist pharmacology, and coupling to intracellular transduction mechanisms 35, 41. The receptors belonging to group I (mGluR1 and mGluR5), which are coupled to postsynaptic inositol phosphate metabolism, have been implicated in synaptic plasticity 4, 41, although pharmacological evidence that activation of these receptors are required is still lacking.
While NMDA receptor antagonists clearly block induction of LTP both in vitro [18]and in vivo [31], the group I antagonist (+)-α-methyl-4-carboxyphenylglycine (MCPG) has been reported to have mixed effects, sometimes depending on the technique used [6]. Bashir et al. [4]showed that MCPG blocked induction of LTP in hippocampal slices, but this result has not been confirmed by other investigators 16, 28, 39. Similarly, Riedel and Reymann [38]found that MCPG blocked induction of LTP in vivo, but others 6, 11found no effect.
Using a complementary strategy, we [19]and others [1]have examined LTP in hippocampal slices from mice lacking mGluR1 receptors. These studies, however, found contrasting results and did not resolve the role of mGluR1 in LTP [27].
Recently this question was addressed by measuring LTP in the intact hippocampus. Mice lacking mGluR1 were found to have reduced LTP in the dentate gyrus compared to littermate wild-type mice [9], in contrast to earlier results in vitro [19]. A possible explanation for this difference is that inhibitory circuits involving mGluR1 normally influence LTP in vivo but this circuitry is lost in the slice preparation [13].
To investigate this possibility, we studied paired-pulse depression of the population spike in normal and mGluR1 −/− mice, using an in vivo preparation. Paired-pulse depression is a short-term form of plasticity due to inhibitory feedback where the second response of a pair of pulses delivered to afferent fibers is depressed [30]. If mGluR1s are involved in this inhibition, then the depression should be abnormal in mice lacking these receptors. We examined the extracellular field potentials associated with excitatory population spike elicited by paired pulses with varying interpulse intervals (IPIs).
Section snippets
Materials and methods
Male mice lacking (−/−) mGluR1 and with normal (+/+) mGluR1 weighing 17–28 g obtained from the Glaxo-Wellcome Institute for Molecular Biology (Geneva, Switzerland) were anesthetized with urethane (1.2 g/kg body weight) and placed in a Kopf stereotaxic frame. Body temperature was regulated at 37±1°C by means of a heating pad. A bipolar stimulating electrode (tip diameter 150 μm) was placed in the perforant path (AP 0.5 mm anterior to lambda, ML 2.5 mm to midline, DV 1.7–2.2 mm to brain surface)
Results
The relationship between input stimulation and output spike amplitude (I-O curve) was first determined with single pulses. No difference in the I-O curve was found between control (n=12) and mutant −/− mice (n=10) in the amplitude of the population spike with stimulus intensities between 100 and 1000 μA, suggesting a similar level of excitability of the neuronal population in the two groups of mice (Fig. 1). For the paired-pulse experiment, the intensity of the pulse was adjusted to evoke a
Discussion
This study suggests an important, although indirect, role for mGluR1 in synaptic plasticity; the effect is probably mediated via an inhibitory feedback loop onto granule cells. Decreasing the level of feedback inhibition by activation of GABAB receptors on GABA terminals made it possible to induce normal LTP in mGluR1-deficient mice. But in the absence of baclofen, inhibitory interneurons in mGluR1 −/− mice provide too much inhibition to granule cells for LTP to be induced (see Fig. 2).
References (41)
- et al.
Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice
Cell
(1994) - et al.
The functional role of metabotropic glutamate receptors in epileptiform activity induced by 4-aminopyridine in the rat amygdala slice
Brain Res.
(1995) - et al.
Blockade of both epileptogenesis and glutamate release by (1S,3S)-ACPD, a presynaptic glutamate receptor agonist
Brain Res.
(1995) - et al.
A comparison of the ontogeny of excitatory and inhibitory neurotransmission in the CA1 region and dentate gyrus of the rat hippocampal formation
Dev. Brain Res.
(1991) - et al.
Role of glutamate metabotropic receptors in long-term potentiation in the hippocampus
Semin. Neurosci.
(1995) - et al.
Effects of the mGluR antagonist MCPG on spatial and context-specific learning
Neuropharmacology
(1996) - et al.
Antagonists of the metabotropic glutamate receptor do not prevent induction of long-term potentiation in the dentate gyrus of rats
Eur. J. Pharmacol.
(1995) - et al.
GABAB receptors modulate synaptically-evoked responses in the rat dentate gyrus, in vivo
Brain Res.
(1995) - et al.
Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat
Mol. Brain Res.
(1994) Evidence for two physiologically distinct perforant pathways to the fascia dentata
Brain Res.
(1980)
Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity
Neuron
Effects of baclofen and bicuculline on inhibition in the fascia dentata and hippocampus regio superior
Brain Res.
Phenylglycine derivatives as antagonists of metabotropic glutamate receptors
Trends Pharmacol.
Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors
Nature
A synaptic model of memory: long-term potentiation in the hippocampus
Nature
Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path
J. Physiol.
Reduced long-term potentiation in the dentate gyrus of mGlu1 receptor mutant mice in vivo
Eur. J. Pharmacol.
Interneurons and inhibition in the dentate gyrus of the rat in vivo
J. Neurosci.
Long-lasting potentiation and epileptiform activity produced by GABAB receptor activation in the dentate gyrus of rat hippocampal slice
J. Neurosci.
Modulation of epileptiform activity by metabotropic glutamate receptors in immature rat neocortex
J. Neurophysiol.
Cited by (34)
Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice
2021, Chemico-Biological InteractionsCitation Excerpt :Following the SR phase, reversal probe trial (RPT) removed the platform and trial details were same as PT phase. After the behavioral experiment, the long-term potentiation (LTP) and depotentiation (DEP) were used to reflect the synaptic plasticity [39,40]. We chose the neural pathway to record neural signal from perforant pathway (PP) to the dentate gyrus (DG) region.
Distribution of glutamate receptor, ionotropic, kainate 1 and neuropeptide calcitonin gene-related peptide mRNAs during formation of the embryonic and postnatal mouse molar in the maxilla
2020, Annals of AnatomyCitation Excerpt :In particular, the specific reaction of CGRP mRNA in the tip of the tooth germ around mesenchymal cells and alveolar bone indicated the preparation of tooth eruption during development. In general, metabotropic glutamate receptor 1 (mGrik1) was related to learning and memory using mGrik1 knockout mice (Bordi et al., 1997). Recently, mGrik1 has been reported to promote proliferation in neural progenitor cells, and glutamate receptor and cell proliferation promotion may correlate with development.
Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo
2012, Neurobiology of Learning and MemoryCitation Excerpt :We observed an enhanced GABAergic feedback onto dentate gyrus granule cells and elevated levels of LTP in the dentate gyrus of anesthetised CB1-ko mice. Paired-pulse facilitation of population spike develops at longer inter-pulse intervals and this effect can be promoted by an augmentation in glutamatergic and a reduction in GABAergic transmission, respectively (Bordi et al., 1997; Brucato, Morrisett, Wilson, & Swartzwelder, 1992; Canning & Leung, 2000; Joy & Albertson, 1993; Steffensen & Henriksen, 1991). Our results suggest that CB1 might suppress inhibitory output of GABAergic neurons onto granule cells in the dentate gyrus.
Pharmacological reversal of synaptic plasticity deficits in the mouse model of Fragile X syndrome by group II mGluR antagonist or lithium treatment
2011, Brain ResearchCitation Excerpt :Unlike group I mGluRs antagonists, which impair induction of NMDAR-dependent LTP, and L-LTP (late phase LTP), group II mGluR antagonists inhibit only LTD at CA1 synapses. Both L-LTP and LTD require de novo protein synthesis and may utilize overlapping cellular machinery involved in protein synthesis (Altinbilek and Manahan-Vaughan, 2007; Altinbilek and Manahan-Vaughan, 2009; Balschun and Wetzel, 2002; Bordi et al., 1997; Kulla and Manahan-Vaughan, 2008; Manahan-Vaughan and Reymann, 1997; ManahanVaughan, 1997; Naie and Manahan-Vaughan, 2005; Neyman and Manahan-Vaughan, 2008; Santschi et al., 2006). Group II mGluRs are expressed predominantly presynaptically but are also expressed postsynaptically (Lujan et al., 1997; Tanabe et al., 1992, 1993).
Bidirectional synaptic plasticity in the dentate gyrus of the awake freely behaving mouse
2008, Journal of Neuroscience Methods