HCN channel blocker ZD7288 depressed synaptic transmission at medial perforant path (MPP) synapses. Low-frequency stimulation (LFS) delivered to these fibers resulted in enhanced LTD after ZD7288 in P9-15 rats, but not in P30-60 rats. Hence, HCN channel activation during neuronal activity may compromise the propensity of LTD at these synapses. Results obtained with L-NAME iterated the effect of HCN channel inhibition on LTD, suggesting that retrograde signaling with NO might play a major role in the linkage between postsynaptic NMDAR activation and presynaptic HCN channel function.