The induction of long-term potentiation (LTP) under conditions of blockade of the N-methyl-D-aspartate receptor (NMDAR) was studied in the medial perforant path to granule cell synapse in the rat dentate gyrus.

Animals were killed humanely. A single brief high frequency stimulation (HFS) induced a small amplitude NMDAR-independent potentiation (115 ± 6 %, n = 11, P < 0.01, mean ± S.E.M., Student’s unpaired t test) at 10 min post-HFS in 100 µM AP5. Further HFS applied at 10 min intervals increased the amplitude of LTP induction such that after the 3rd HFS, NMDAR-independent LTP was induced measuring 139 ± 7 % (n = 11, P < 0.01) at 30 min post-HFS. The NMDAR-independent LTP was most likely to be mediated by activation of group II mGluR. Thus the NMDAR-independent LTP induced by three spaced HFS was inhibited by the group I/II antagonist LY341495 (5 µM), with HFS-inducing long-term depression (LTD) measuring 38 ± 6 % (n = 6, P < 0.01), and by the group II mGluR antagonist EGLU (100 µM), with HFS-inducing LTD measuring 32 ± 8 % (n = 5, P < 0.01). The mGluR5 antagonist MPEP did not inhibit the LTP induction, which measured 131 ± 6 % (n = 5). Perfusion of the group II mGluR agonist DCG-IV induced NMDAR-independent LTP measuring 126 ± 9 % (n = 6, P < 0.01) in media containing the NMDAR antagonist AP5, although LTD was induced in control media. The NMDAR-independent LTP induced by three spaced HFS was mediated via activation of p42/44 MAP kinase as it was blocked by the selective inhibitor PD98059, with LTD being induced by HFS measuring 37 ± 5 % (n = 8, P < 0.01).

We would like to thank the Wellcome Trust for financial support.