Long-term potentiation (LTP), a synaptic mechanism thought to underlie memory formation, has been studied extensively at hippocampal Schaffer collateral (SC) synapses. The SC pathway transmits information to area CA1 that originates in entorhinal cortex and is processed by the dentate gyrus and area CA3. CA1 also receives direct excitatory input from entorhinal cortex via the perforant path (PP), but the role of this cortical input is less certain. Here, we report that low-frequency stimulation of PP inputs to CA1 has no lasting effect on basal SC transmission, but effectively depotentiates SC synapses that have undergone LTP in a manner that can be reversed by subsequent high-frequency stimulation of SC inputs. This depotentiation does not require NMDA receptors, group I metabotropic glutamate receptors, or L-type calcium channels, but involves adenosine acting at A(1) receptors. Given the limited storage capacity of the hippocampus, these observations provide a mechanism by which input from cortex can help to reset synaptic transmission in the hippocampus and facilitate additional information processing.