Elsevier

Neuropharmacology

Volume 38, Issue 10, October 1999, Pages 1585-1596
Neuropharmacology

An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus

https://doi.org/10.1016/S0028-3908(99)00062-3Get rights and content

Abstract

Previously, we have found that activation of mGlu receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-DHPG, can induce long-term depression (LTD) in the CA1 region of the hippocampus and that, once established, this synaptic depression can be reversed by application of the mGlu receptor antagonist, (S)-MCPG [Palmer et al., 1997. Neuropharmacology 36, 1517–1532]. We have started to investigate the signal transduction mechanisms involved in these effects. Group I mGlu receptors couple to phospholipase C and therefore can activate protein kinase C and mobilise Ca2+ from intracellular stores. However, neither protein kinase C inhibitors (chelerythrine or Ro 31-8220) nor agents which deplete intracellular Ca2+ stores (thapsigargin or cyclopiazonic acid) were able to prevent DHPG-induced LTD. Furthermore, the ability of MCPG to reverse DHPG-induced LTD was not prevented by these compounds. These results suggest that it is unlikely that DHPG-induced LTD, or its reversal by MCPG, is produced via activation of either protein kinase C or by release of Ca2+ from intracellular stores.

Introduction

The mechanisms of long-term depression (LTD) and long-term potentiation (LTP) are under intense investigation as these forms of synaptic plasticity are thought to underlie learning and memory formation (Bliss and Collingridge, 1993, Bear and Abraham, 1996). In the hippocampus, ‘low-frequency’ stimulation (LFS) can reverse LTP (Barrionuevo et al., 1980, Staubli and Lynch, 1990, Fujii et al., 1991, Bashir and Collingridge, 1994) by a process known as depotentiation. In addition, LFS can, under certain circumstances, induce homosynaptic LTD without the need to first induce LTP, a process which is more readily induced in young animals compared to adults (Dudek and Bear, 1992, Mulkey and Malenka, 1992).

It is known that under certain conditions, activation of mGlu receptors is required for the induction of depotentiation and ‘de novo’ LTD (Bashir et al., 1993, Bashir and Collingridge, 1994, Bolshakov and Siegelbaum, 1994, O’Mara et al., 1995, Oliet et al., 1997) since their induction can be blocked by the mGlu receptor antagonist, (S)-α-methyl-4-carboxyphenylglycine ((S)-MCPG). In addition, forms of LTD can be induced by activation of mGlu receptors using the broad-spectrum mGlu receptor agonist, (1S,3R)-ACPD (Bolshakov and Siegelbaum, 1994, O’Mara et al., 1995, Overstreet et al., 1997).

Recent work in our laboratory has demonstrated that the activation of group I mGlu receptors (probably mGlu5 receptors), by application of the specific agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG; Ito et al., 1992), can induce LTD in the CA1 region of the adult (Palmer et al., 1997) and the juvenile (Fitzjohn et al., 1996) rat hippocampus. In adult tissue, the LTD was small but was enhanced when the tissue was made hyperexcitable by omitting Mg2+ ions from the superfusate. Surprisingly, DHPG-induced LTD once expressed could be transiently reversed by (S)-MCPG and re-established following washout of (S)-MCPG.

We have started to investigate the signal transduction mechanisms involved in DHPG-induced LTD at CA1 synapses in the adult rat hippocampus. Since group I mGlu receptors couple to phosphatidylinositol-specific phospholipase C (PLC), potential mediators of DHPG-induced LTD include the activation of protein kinase C (PKC) and/or inositol-(1,4,5)-trisphosphate-mediated release of Ca2+ from intracellular stores. We therefore tested the ability of established inhibitors of these processes to antagonise both DHPG-induced LTD and its MCPG-induced reversal.

Section snippets

Materials and methods

Experiments were performed as described previously (Palmer et al., 1997). In brief, 400 μm transverse hippocampal slices were obtained from adult female Wistar rats of 170–200 g in weight (approx. 8–10 weeks of age) which had been decapitated whilst under halothane anaesthesia. The CA3 region was removed and slices were then left to stabilise for at least 30 min in an artificial cerebrospinal fluid (aCSF), consisting of (mM): NaCl 124; KCl 3; NaHCO3 26; NaH2PO4 1.25; CaCl2 2; d-glucose 10

DHPG-induced LTD and its MCPG-induced reversal

Superfusion with Mg2+-free medium caused a potentiation of the fEPSPs which stabilised after approx. 30 min. Subsequently, the stimulus intensity was reduced and a baseline was obtained. Consistent with previous studies (Palmer et al., 1997, Fitzjohn et al., 1998), application of DHPG (100 μM, 10 min) under these conditions caused a large, initial depression of synaptic transmission with only partial reversibility upon washout (n=13). A stable response was obtained approx. 15 min after washout

Discussion

The present study suggests that neither activation of PKC nor release of Ca2+ from intracellular stores is required for DHPG-induced LTD or its reversal by MCPG.

Concluding remarks

The present study has revealed several differences between the signalling processes involved in DHPG-induced LTD and those reported for LFS-induced LTD (Hrabetova and Sacktor, 1996, Reyes and Stanton, 1996, Wang et al., 1997). However, at least two forms of LFS-induced LTD exist; one activated by NMDA receptors (Dudek and Bear, 1992, Mulkey and Malenka, 1992, Oliet et al., 1997), the other by mGlu receptors (Stanton et al., 1991, Bashir et al., 1993, Bolshakov and Siegelbaum, 1994, Yang et al.,

Acknowledgements

Supported by the MRC and Knoll Pharmaceuticals.

References (35)

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