Mechanisms underlying the inhibition of long-term potentiation by preconditioning stimulation in the hippocampus in vitro

We have investigated the mechanisms underlying a form of metaplasticity, namely the inhibition by preconditioning stimulation of high frequency stimulation (HFS)-induced long-term potentiation (LTP) in the medial perforant path of the dentate gyrus. Preconditioning stimulation (weak 50 Hz) was found to inhibit subsequent LTP induction if applied 10-20 min, but not 2 or 45 min, prior to the HFS. Preconditioning stimulation in the form of low frequency stimulation did not block LTP induction. The inhibition of LTP was not caused by a reduction in N-methyl-D-aspartate receptor (NMDAR) transmission, as the preconditioning stimulation did not reduce isolated NMDAR-mediated EPSPs. The involvement of group I and group II metabotropic glutamate receptor (mGluR) activation in the inhibition of LTP was demonstrated by experiments in which the inhibition of LTP by the preconditioning stimulation was prevented by the presence of antagonists of group I or group II mGluR during the preconditioning stimulation. Moreover, group I and group II mGluR agonists directly inhibited subsequent LTP induction. The involvement of NMDAR in the preconditioning stimulation was shown by the ability of an NMDAR antagonist to prevent the inhibition of LTP by the preconditioning stimulation. The preconditioning inhibition of LTP induction was shown by the use of kinase inhibitors to involve activation of PKC and p38 MAP kinase, but not p42 MAP kinase or tyrosine kinase. We conclude that the preconditioning inhibition of LTP induction is a complex process which involves activation of NMDAR, group I and group II mGluR, and intracellular cascades activating PKC and p38 MAP kinase. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.