Two distinct forms of long-term depression coexist at the mossy fiber-CA3 synapse in the hippocampus during development.

During a critical period of postnatal development, between postnatal days 6 and 14, a high-frequency stimulation train (100 Hz for 1 s) to the mossy fibers induces a long-term depression (LTD) of synaptic efficacy of 29 +/- 5.2%. This form of LTD is homosynaptic. It is independent of the activation of N-methyl-D-aspartate or metabotropic glutamate receptors but needs an increase in calcium into the postsynaptic cell for its induction. At the same synapse LTD also could be induced by low-frequency stimulation of the mossy fibers (1 Hz for 15 min). In this case the magnitude of the depression is 37 +/- 4.2%. This form of LTD is N-methyl-D-aspartate independent but requires the activation of metabotropic glutamate receptors because it is prevented by (S)-alpha-methyl-4-carboxyphenylglycine (1 mM). Moreover its induction appears to be presynaptic, because, in contrast with the high-frequency one, it is not blocked by loading the postsynaptic cell with the calcium chelator EGTA or bis-(-o-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid (BAPTA). Saturation of one form of LTD does not occlude the other, suggesting that high and low frequency-induced LTD depend on distinct mechanisms of induction and expression. Quantal (noise deconvolution) analysis of minimal excitatory postsynaptic potentials shows, similarly to high-frequency LTD, a decrease in quantal content without any change in quantal size after low-frequency LTD, suggesting that in both forms of LTD the site where maintenance mechanisms are located is presynaptic.