Presynaptic inhibitory action of the group II metabotropic glutamate receptor agonists, LY354740 and DCG-IV
Introduction
The mediation of presynaptic inhibition by metabotropic glutamate (mGlu) receptors was first established in studies in which 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) was shown to reversibly depress excitatory synaptic transmission in hippocampal CA1 (Baskys and Malenka, 1991; Desai and Conn, 1991; McGuinness et al., 1991; Pacelli and Kelso, 1991). A large number of studies have subsequently confirmed the presence of presynaptic mGlu receptors in many other areas of the brain, such as the hippocampal dentate gyrus (Macek et al., 1996; Bushell et al., 1996), neocortex (Sladeczek et al., 1993; Burke and Hablitz, 1994) and the striatum (Lovinger, 1991, Calabresi et al., 1992). Strong evidence that the inhibition of excitatory synaptic transmission was mediated presynaptically was shown by several lines of evidence. Firstly, inhibition by mGlu receptor agonists occurred without postsynaptic changes (Lovinger, 1991; Baskys and Malenka, 1991; Calabresi et al., 1992; Glaum et al., 1992; Lovinger et al., 1993; Burke and Hablitz, 1994); secondly, mGlu receptor activation reduced the AMPA- and NMDA-receptor mediated excitatory synaptic transmission with a similar potency (Baskys and Malenka, 1991; Lovinger, 1991; Pacelli and Kelso, 1991). Thirdly a change in paired-pulse facilitation or depression (indicative of a presynaptic modulation of transmitter release), was evoked by mGlu receptor agonists. Thus paired-pulse facilitation in CA1 was enhanced by mGlu receptor agonists (Baskys and Malenka, 1991; Burke and Hablitz, 1994; Gereau and Conn, 1995; Manzoni et al., 1997) and paired-pulse depression in the medial perforant path of the dentate gyrus being reduced by mGlu receptor agonists (Kahle and Cotman, 1993; Brown and Reymann, 1995).
Recent studies using a number of agonists selective for mGlu receptor group subtypes have shown the widespread presence of presynaptic group II mGlu receptors. In the hippocampus, a number of group II mGlu receptor selective agonists have been found to inhibit excitatory synaptic transmission, including (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid {(1S,3S)-ACPD} (Vignes et al., 1995) and (2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) (Yokoi et al., 1996) in young CA1; (2S,1′S,2′S)-2-carboxycyclopropyglycine (LCCG-1) (Ugolini and Bordi, 1995) and DCG-IV (Macek et al., 1996; Huang et al., 1997) in the medial perforant path of adult dentate gyrus, and DCG-IV (Macek et al., 1996; Bushell et al., 1996) and (1S,3S)-ACPD (Bushell et al., 1996) in the lateral perforant path of neonatal (Bushell et al., 1996) and adult (Macek et al., 1996) dentate gyrus.
(+)-2-Aminobicyclo[3.1.0]hexane-2-6-dicarboxylic acid (LY354740) is a recently synthesised high affinity efficacious and selective group II mGlu receptor agonist. (Bond et al., 1997; Monn et al., 1997; Schoepp et al., 1997a, Schoepp et al., 1997b). LY354740 suppressed forskolin-stimulated cyclic 3′,5′-adenosine monophosphate (cAMP) formation at group II mGlu receptor with nanomolar potency, but had little or no agonist or antagonist action at group I mGlu receptor or group III mGlu receptor. The agent has potentially important clinical uses—it was found to prevent anxiety in the elevated plus maze and also prevent ACPD-induced limbic seizures. Moreover, it is orally active.
In the present study, we have investigated the presynaptic inhibitory action of LY354740 in the medial and lateral perforant path of the hippocampal dentate gyrus, and also CA1 hippocampus, comparing its action with the well established group II mGlu receptor agonist, DCG-IV.
Section snippets
Materials and methods
All experiments were carried out on hippocampal slices obtained from Wistar rats (50–70 g) (BioResources Unit, Trinity College, Dublin, Ireland). Slices were obtained as described previously (Huang et al., 1997). Briefly, the brain was rapidly removed after decapitation and placed in cold (5°C) oxygenated (95% O2, 5% CO2) artificial cerebro-spinal fluid (ACSF) containing in mM: NaCl, 120; NaHCO3, 26; NaH2PO4, 1.25; KCl, 2.5; Mg2SO4, 2; CaCl2, 2; glucose, 10). Hippocampal slices (350 μM) were
LY354740 and DCG-IV inhibit the EPSP in the medial perforant path
The placement of the recording and stimulating electrodes in the medial perforant path was verified by the presence of paired-pulse depression of EPSPs in response to paired-pulse stimulation.
After establishing a stable amplitude test EPSP for at least 20 min, bath application of LY354740 (20–25 min) caused a dose-dependent and reversible inhibition of the EPSP amplitude in the medial perforant path. The approximate threshold concentration of LY354740 was 10 nM, which induced a small inhibition
Discussion
The present electrophysiological study has shown that LY354740 is a potent agonist at the group II mGlu receptor responsible for mediating inhibition of EPSPs at the medial perforant path in the dentate gyrus in vitro, with the threshold dose about 10 nM and the EC50 close to 100 nM. This is the most potent agonist action at group II mGlu receptors, demonstrated in electrophysiological studies, in this pathway. In comparison with other agonists, electrophysiological studies have shown that
Acknowledgements
This work was supported by grants from the Health Research Board, Ireland, the Wellcome Trust and the European Union.
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