Low-frequency stimulation of the Schaffer-commissural pathways in slices prepared from juvenile rats (postnatal day 10–15) results in a long-term depression (LTD) of synaptic transmission. 30 min after 5 min of stimulation at 5 Hz, the response to the stimulated pathway was decreased by 36%, whereas the response to an unstimulated pathway projecting to the same neuronal population was decreased by 20%. Stimulation in the presence of the NMDA receptor antagonist AP5 completely prevented homosynaptic LTD. The phospholipase A 2 inhibitor, bromophenacylbromide, also significantly reduced the extent of LTD in both the stimulated and control pathways. LTD was accompanied by a decrease in paired-pulse facilitation, suggesting a change in transmitter release. It also resulted in an increased effect of iontophoretically applied perchlorate, an ion which increases both the affinity of glutamate for the synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and synaptic responses, suggesting a change in postsynaptic receptors. These findings indicate that certain stimulation paradigms produce a combination of pre- and postsynaptic modifications that could underlie changes in synaptic efficacy.