Induction of LTD by activation of group I mGluR in the dentate gyrus in vitro

Abstract

The ability of activation of group I metabotropic glutamate receptors (mGluR) to induce long-term depression (LTD) was investigated in the medial perforant path of the dentate gyrus in vitro. Application of the group I agonists (RS)-3,5-dihydroxyphenylglycine (DHPG) and (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), and also the partial agonist (S)-(+)-2-(3′-Carboxybicyclo[1.1.1]pentyl)-glycine (UPF 596), induced LTD of the field EPSP. The induction of LTD is likely to be mediated via mGluR5 since CHPG and UPF 596 are selective agonists/partial agonists at that receptor. Further evidence for the involvement of group I mGluR in LTD induction was the finding that the DHPG and low frequency stimulation induced LTD were inhibited by the group I mGluR antagonist [CRS]-1-aminoindan-1,5-dicarboxylic acid (AIDA). Investigation of the intracellular mechanisms underlying the induction of the group I mGluR-mediated LTD showed an inhibition of the LTD by the protein kinase C (PKC) inhibitor bisindolylmaleimide I and the protein tyrosine kinase inhibitor lavendustin A, but not the PKA inhibitor H89. These studies demonstrate that DHPG-induced LTD can be induced by the activation of mGluR5 followed by intracellular stimulation of PKC and tyrosine kinase.

Introduction

Long-term depression (LTD) is a long-lasting activity-dependent reduction in excitatory glutamatergic transmission which can be induced by a period of low frequency presynaptic stimulation (LFS) (reviewed by Bear and Abraham, 1996). The standard protocol for the induction of homosynaptic LTD of field excitatory potentials (EPSPs) is several minutes of LFS at 1-5 Hz in vitro in CA1 (Dudek and Bear, 1992, Mulkey and Malenka, 1992) and in the dentate gyrus of the hippocampus (O’Mara et al., 1995, Wang et al., 1997).

Initial studies on the involvement of mGluR in the induction of LTD and depotentiation (DP) in the hippocampus led to controversy. While certain studies showed that the induction of LTD/DP was mGluR-dependent, with a block of the induction of LTD by the mGluR antagonist (+)-α-methyl-4-carboxyphenylglycine (MCPG) in both CA1 (Bashir and Collingridge, 1994, Bolshakov and Siegelbaum, 1994, Yang et al., 1994) and in the dentate gyrus (O’Mara et al., 1995), other studies did not find a block of LTD induction by MCPG in CA1 (Selig et al., 1995). One possible resolution of the controversy was the finding of an mGluR dependent and an mGluR-independent form of LTD induction in both CA1 (Oliet et al., 1997) and dentate gyrus (Wang et al., 1997). In the dentate gyrus, mGluR-dependent LTD can be induced in ‘normal’ media (O’Mara et al., 1995, Wang et al., 1997), but in CA1, a high Ca²⁺/Mg²⁺ (4 mM/4 mM) is required for the induction of the mGluR-dependent LTD (Oliet et al., 1997). Further evidence for the involvement of mGluRs in LTD induction was the induction of LTD by the mGluR agonist ACPD, which induced LTD in CA1 (Bolshakov and Siegelbaum, 1994, Bolshakov and Siegelbaum, 1995) and in the dentate gyrus (O’Mara et al., 1995), although in the former, the ACPD application had to be accompanied by a train of postsynaptic depolarising pulses (Bolshakov and Siegelbaum, 1994), or by release of Ca²⁺ from a caged compound (Bolshakov and Siegelbaum, 1995).

The studies investigating the effects of MCPG and ACPD do not reveal which group of mGluR is involved in LTD induction, as MCPG and ACPD are non-selective mGluR ligands. Some evidence has been found for the involvement of group I mGluR in the induction of LTD in CA1. The selective group I antagonist (CRS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) prevented the induction of the mGluR-mediated component (Oliet et al., 1997). Moreover, the group I agonist DHPG induced LTD, particularly under hyperexcitable conditions such as low Mg²⁺ or picrotoxin (Palmer et al., 1997), although such LTD did not occlude with LFS-induced LTD.

In the present study, we have investigated the ability of group I agonists to induce LTD in the dentate gyrus, and the involvement of intracellular messengers in that LTD.