The activation of group I metabotropic glutamate receptors (mGluR) by the selective agonist (S)-3, 5-dihydroxyphenylglycine (DHPG) has previously been shown to induce long-term depression (LTD) of EPSPs in the CA1 and dentate gyrus of the hippocampus. In the present study, we demonstrate that the DHPG-induced LTD is inhibited by prior physiological activation of group I mGluR. Rat hippocampal slices were prepared humanely according to local guidelines using standard methods. Field EPSPs were recorded from the middle molecular layer in response to stimulation of the medial perforant path of the dentate gyrus. Values are expressed as means ± S.E.M. for n slices. Student’s t test was used for statistical comparison (probability level shown in text). DHPG (20 µM, 15 min) induced LTD of field EPSPs with an amplitude of 27 ± 5% n = 4; P < 0.01 in control slices. However, following brief high-frequency stimulation (HFS)-induced long-term potentiation (LTP), DHPG failed to induce depotentiation (DP) from the long-term potentiated level when applied at 15 min post-HFS (145 ± 6% n = 4, compared with 144 ± 4% n = 4 in control; P > 0.05). The involvement of activation of NMDAR and mGluR in the preconditioning HFS block of the DHPG-induced DP by prior preconditioning HFS were investigated using the antagonists AP5 and LY341495, respectively. D-AP5 (100 µM), applied during the HFS, inhibited the induction of LTP but did not reverse the block of the DHPG-induced LTD (102 ± 4% n = 5; P > 0.05), i.e. no DHPG-induced LTD was observed from the baseline level following pre-conditioning HFS in AP5. In contrast, the mGluR antagonist LY341495 (20 µM) reversed the pre-conditioning HFS block of DHPG-induced DP/LTD. Thus in the presence of LY341495, HFS-induced LTP was not inhibited, but subsequent DHPG application induced DP of 26 ± 12% n = 5; P < 0.02 from the long-term potentiated level. Moreover, DHPG induced LTD (17 ± 3% n = 5; P < 0.01) from the baseline level when perfused following the application of preconditioning HFS in the presence of both AP5 and LY341495. The preconditioning HFS block of DHPG-induced LTD was mediated by PKC. Thus the presence of the PKC inhibitor BIS-1 (2 µM) during the preconditioning HFS resulted in a reversal of the block of the LTD, with DHPG inducing LTD of 24 ± 5% n = 5; P < 0.01. In contrast, the DHPG-induced LTD itself was not mediated via PKC stimulation as it was not inhibited by BIS-1 (17 ± 4% n = 4; P < 0.01). We suggest that activation of mGluR during the preconditioning HFS results in stimulation of PKC, which desensitises the group I mGluR and thereby prevents their activation by subsequent application of DHPG.

We would like to thank The Wellcome Trust and Enterprise Ireland for financial support.