Activity-dependent presynaptic autoinhibition by group II metabotropic glutamate receptors at the perforant path inputs to the dentate gyrus and CA1

doi:10.1016/S0028-3908(00)00118-0

Neuropharmacology

Volume 40, Issue 1, 2001, Pages 20-27

https://doi.org/10.1016/S0028-3908(00)00118-0 Get rights and content

Abstract

Pharmacological activation of metabotropic glutamate receptors (mGluRs) can inhibit synaptic transmission; however, relatively little evidence exists regarding the physiological conditions under which such autoreceptors are activated by synaptically released glutamate. Bath application of selective group II mGluR agonists profoundly inhibited field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the perforant path inputs to both the mid-molecular layer of the dentate gyrus and the stratum lacunosum moleculare of the CA1. Application of the group II selective mGluR antagonist LY341495 resulted in an increase in the relative amplitude of a test fEPSP evoked 200 ms after a conditioning burst, but not after a single conditioning stimulus, in both pathways. Antagonist application also resulted in a marked increase in the relative amplitude of test population spikes evoked in the dentate gyrus following a conditioning burst. These observations are consistent with a presynaptic autoinhibitory action of group II metabotropic receptors that is revealed following burst stimulation of the pathway, consistent with their localisation in the preterminal zone. Activation of group II mGluRs during theta–gamma pattern discharge of projection neurones in the entorhinal cortex is likely to play an important role in the regulation of synaptic transmission and plasticity in the perforant pathway.

Introduction

Whilst fast glutamatergic synaptic transmission is mediated by ionotropic receptors, consisting of the AMPA (α-amino-3-hydroxy-5-methylisoxazole propionic acid), kainate and NMDA (N-methyl-d-aspartate) receptor families, glutamate also activates a family of G-protein-coupled receptors, termed metabotropic glutamate receptors (mGluRs), which can modulate neuronal excitability and synaptic transmission. Eight mGluRs have now been cloned, which can be divided into three groups according to their amino-acid sequence identity: group I receptors, mGluR 1 and 5; group II receptors, mGluR 2 and 3; and group III receptors, mGluR 4, 6, 7 and 8 (reviewed in Conn and Pin, 1997). In heterologous expression systems, group I receptors couple primarily to phosphatidylinositol hydrolysis, whereas group II and group III receptors couple to the inhibition of adenylate cyclase (Conn and Pin, 1997).

Immunohistochemical studies indicate that group II mGluRs are highly expressed in the terminal fields of the perforant path input from the entorhinal cortex in the mid-molecular layer of the dentate gyrus and the stratum lacunosum moleculare of the CA1 (Neki et al., 1996, Petralia et al., 1996, Shigemoto et al., 1997, Ohishi et al., 1998). In agreement, autoradiography studies have demonstrated high binding densities of the group II selective agonists [³H]-DCG IV (Mutel et al., 1998) and [³H]-LY354740 (Schaffhauser et al., 1998a) in these regions. Interestingly, these receptors appear to be localised in the preterminal zone rather than in the terminal portions of axons (Shigemoto et al., 1997). Considerable pharmacological evidence suggests that group II mGluRs might serve as autoreceptors that can inhibit transmission at medial perforant path synapses (Ugolini and Bordi, 1995, Macek et al., 1996, Kilbride et al., 1998). Presynaptic mGluRs are believed to inhibit synaptic transmission by inhibition of voltage-gated calcium channels (Takahashi et al., 1996) and/or via direct activity on the release machinery (Scanziani et al., 1995, Schaffhauser et al., 1998b). Activation of group II mGluRs has been shown to result in the inhibition of calcium currents in heterologous expression systems (McCool et al., 1996) and group II selective agonists also inhibit neuronal calcium currents (Chavis et al., 1994, Choi and Lovinger, 1996, Knoflach and Kemp, 1998, Schaffhauser et al., 1998b). Two recent reports have described the inhibition of GABAergic transmission via activation of presynaptic mGluRs by glutamate spillover from neighbouring excitatory synapses (Mitchell and Silver, 2000, Semyanov and Kullmann, 2000). However, activation of presumptive presynaptic metabotropic autoreceptors by synaptically released glutamate has, to date, only been demonstrated at hippocampal mossy fibre synapses (Scanziani et al., 1997).

In this study we have investigated the effects of group II mGluR agonists and antagonists on synaptic transmission at the perforant path inputs to the mid-molecular layer of the dentate gyrus and the stratum lacunosum moleculare of the CA1. We have shown that synaptic transmission in both pathways is inhibited by exogenous group II mGluR selective agonists and that this inhibition can be blocked by the selective group II receptor antagonist LY341495 (Kingston et al., 1998). Furthermore, application of antagonist resulted in an increase in the relative amplitude of a test field excitatory postsynaptic potential (fEPSP) evoked following a conditioning burst, but not following a single conditioning stimulus. Antagonist application produced a relatively larger increase in the amplitude of a test population spike (PS) recorded in the dentate gyrus following a burst conditioning stimulus. These observations are consistent with a presynaptic autoinhibitory action of group II metabotropic receptors that is revealed following burst stimulation of the pathway.

Section snippets

Methods

Hippocampal slices (400 μm) were cut from 90–140 g rats (Roro specific pathogen-free) with a Sorvall tissue chopper. Slices were maintained in a submerged chamber and perfused at 35°C with a simple salt solution containing (mM): NaCl, 124; KCl, 2.5; MgSO₄, 2; CaCl₂, 2.5; KH₂PO₄, 1.25; NaHCO₃, 26; glucose, 10; sucrose, 4; gassed with 95% O₂/5% CO₂ (pH 7.4, 307 mOsm). The perforant path input to the mid-molecular layer of the dentate gyrus was stimulated (0.033 Hz, 100 μs) at a stimulus strength

Pharmacological effects of metabotropic receptor agonists and antagonists

The selective group II metabotropic receptor ligands DCG-IV and LY354740 (reviewed in Schoepp et al., 1999) inhibited fEPSPs evoked by stimulation of the perforant path input to either to the mid-molecular layer of the dentate gyrus [Fig. 1(a)] or the stratum lacunosum moleculare of the CA1 [Fig. 1(b)] in a concentration-dependent manner. The inhibition by LY354740 was antagonised competitively by the group II selective antagonist LY341495 in both pathways [Fig. 1(c) and (d)] (pK_B: dentate

Discussion

To date, there have been relatively few reports describing the activation of mGluRs by synaptic release of glutamate. The terminal fields of the perforant path in both the mid-molecular layer of the dentate gyrus and the stratum lacunosum moleculare of the CA1 exhibit high expression levels of group II mGluRs as revealed by both immunohistochemistry (Neki et al., 1996, Petralia et al., 1996, Shigemoto et al., 1997, Ohishi et al., 1998) and autoradiographic studies (Mutel et al., 1998,

Acknowledgements

We thank Drs Geo Adam and Thomas Woltering for the synthesis and provision of LY341495 and LY354740.

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To validate our assay, DCG-IV, a prototypical mixed mGlu2 and mGlu3 agonist (Hayashi et al., 1993) was tested on fEPSPs in CA1 stratum lacunosum moleculare (CA1-SLM) following stimulation of the temporo-ammonic pathway (TAP) in hippocampal slices from wild-type CD-1 mice aged 5–6 weeks (Fig. 1A, B). This pathway was chosen initially as it has one of the highest expression levels of group II mGlu receptors in the brain (Petralia et al., 1996; Shigemoto et al., 1997) and is inhibited by group II agonists such as DCG-IV (Kew et al., 2001; Kew and Kemp, 2005; Price et al., 2005). DCG-IV (1 nM–1 μM) produced a concentration-dependent inhibition of the TAP evoked fEPSPs in CA1-SLM (Fig. 1A, B and C) with an EC50 of 20 nM; 1 μM inducing a near complete inhibition of the fEPSP (Emax 97 ± 1%; n = 5).
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Activity-dependent presynaptic autoinhibition by group II metabotropic glutamate receptors at the perforant path inputs to the dentate gyrus and CA1

Abstract

Introduction

Section snippets

Methods

Pharmacological effects of metabotropic receptor agonists and antagonists

Discussion

Acknowledgements

European Journal of Pharmacology

Neuropharmacology

Brain Research

Brain Research

Neuroscience Letters

Neuroscience Research

Neuroscience

Neuropharmacology

Brain Research

Neuropharmacology

Neuron

European Journal of Pharmacology

The metabotropic glutamate receptor types 2/3 inhibit L-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells

Journal of Neuroscience

Metabotropic glutamate receptor modulation of voltage-gated Ca2+ channels involves multiple receptor subtypes in cortical neurons

Journal of Neuroscience

Metabotropic glutamate receptor modulation of voltage-gated Ca²⁺ channels involves multiple receptor subtypes in cortical neurons