Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5-HT4-receptor contributes to processes underlying cognition. It was previously shown that in the CA1-region, 5-HT4-receptors regulate the frequency-response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a Θm-frequency), will result in LTP or LTD, when given in the presence of a 5-HT4-agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5-HT4-receptors do not influence responses generated at Θm-frequencies, but activation of 5-HT4-receptors prevents persistent LTD in mossy fiber (mf)-CA3, or perforant path-DG synapses. Furthermore, the regulation by 5-HT4-receptors of LTP is subfield-specific: 5-HT4-receptor-activation prevents mf-CA3-LTP, but does not strongly affect DG-potentiation. These data suggest that 5-HT4-receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf-CA3 synapses. Thus, 5-HT4-receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience-dependent encoding. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.