Elsevier

Brain Research

Volume 761, Issue 1, 27 June 1997, Pages 121-126
Brain Research

Research report
Regulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice

https://doi.org/10.1016/S0006-8993(97)00320-XGet rights and content

Abstract

The 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.

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).

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