The mechanism responsible for long-term depression (LTD) of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSPnmda) was studied. Intracellular recordings were made from CAI cells of rat hippocampal slices in the presence of 6-cyano- 7-nitroquinoxaline-2,3-dione (10 μM) and picrotoxin (50 μM), which block non-NMDA and GABAa receptors, respectively. Intracellular injections of depolarizing pulses (500 ms, 0.3-0.7 nA) at 1 Hz for 5 min in the absence of synaptic stimulation caused a persistent increase in the amplitude of EPSPnmda- However, coupling postsynaptic depolarization with synaptic activity induced LTD. The EPSP(NMDA) LTD could be blocked by L-2-amino-3-phos- phonopropionic acid (50 μM) or (RS)-a-methyl-4-carboxyphenylglycine (200 μM), specific antagonists for metabotropic glutamate receptors (mGluR). Furthermore, application of /ram--1-aminocyclopentane-1,3-dicar- boxylic acid (t-ACPD, 50 μM), a specific mGluR agonist, in conjunction with postsynaptic depolarizing elicited LTD. In contrast, the mGluR agonists quisqualate or t-ACPD when given alone produced a sustained enhancement of EPSPnmda- Finally, coupled depolarization did not evoke LTD in slices pretreated with the protein kinase C (PKC) inhibitor calphostin c (60 nM). The present results demonstrate that activation of mGluR is necessary for the induction of LTD of EPSPnmda and suggest that NMDA receptors are subject to bidirectional regulation by mGluR. Furthermore, the induction of LTD is likely to involve the stimulation of PKC.

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