Group III metabotropic glutamate (mGlu) receptors (mGlu4/6/7/8) are presynaptic G-protein coupled receptors which act as auto- and hetero-receptors throughout the central nervous system. The development of mGlu8 receptor-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG), and antagonist (RS)-a-methyl-3,4- dicarboxyphenylglycine (MDCPG), in 2001 (Thomas et al., 2001), has led to a body of research investigating the possible function of this receptor subtype, and linking it to a number of pathological conditions including anxiety and epilepsy. The aim of the current work was to explore the role of mGlu8 within the hippocampal formation specifically, employing DCPG and MDCPG to assess its function in synaptic transmission and plasticity. The mGlu8-selectivity of these compounds was first assessed in the lateral perforant path (LPP) input to the dentate gyrus, a pathway known to express high levels of mGlu8 receptors. Field recordings in hippocampal slices from rat, and mGlu8 receptor knock-out (KO) mice revealed non-selective effects of DCPG at concentrations > 1 μM. Further experiments in slices from mGlu4, mGlu7 and mGlu2 KO mice, as well as a mGlu2-deficient substrain of Wistar rat, indicated that higher concentrations of the agonist activate the group II receptor subtype, mGlu2. Conversely, MDCPG appeared to be selective for mGlu8 at up to the highest concentration tested (30 μM). During this work in the LPP, DCPG was found to induce a novel form of mGlu8-mediated chemical long-term depression (LTD). This was induced by prolonged application of a high concentration (100 μM) of the agonist, and was more pronounced in older animals. Importantly, the LTD could be transiently reversed by application of MDCPG, up to two hours after washout of DCPG. Finally, patch-clamp recordings revealed inhibitory effects of DCPG on glutamatergic and GABAergic transmission onto subsets of CAl interneurons, but not pyramidal cells. This. is consistent with the known target-cell specific expression of mGlu8 within the hippocampus.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:665156 |
| Date | January 2014 |
| Creators | Mercier, Marion |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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