High pressure (>1.5 MPa) induces a series of disturbances of the nervous system that are generically termed high-pressure nervous syndrome (HPNS). HPNS is characterized by motor and cognitive impairments. The neocortex and the hippocampus are presumably involved in this last disorder. The medial perforant path (MPP) synapse onto the granule cells of the dentate gyrus is the main connection between these structures. We have studied high-pressure (HP) effects on single and frequency response of this synapse. Since effects of HP on various synapses were mimicked by reducing [Ca²⁺]_o results under these conditions were compared. Medial perforant path-evoked field-EPSPs (fEPSPs) were recorded from granule cells in rat brain slices. Slices were exposed to high pressure of helium (0.1 to 10.1 MPa) at 30° C. HP depressed single fEPSP by 35 and 55 % at 5.1 and 10.1 MPa respectively and increased paired-pulse-facilitation (PPF) at 10-40 ms inter-stimulus intervals. Frequency-dependent-depression (FDD) was enhanced by HP during trains of stimuli at 50 Hz but not at 25 Hz. Depression of single fEPSP by reduction of [Ca²⁺]_o from 2 mM control to 1 mM at normal pressure was equivalent to the effect of 10.1 MPa at control [Ca²⁺]_o. However, this low [Ca²⁺]_o induced greater enhancement of PPF and in contrast, turned FDD at 25-50 Hz into frequency-dependent-potentiation. These results suggest that HP depresses single synaptic release by reducing Ca²⁺-entry, whereas slowing of synaptic frequency response is independent of Ca²⁺. These findings increase our understanding of HPNS experienced by deep divers.