High pressure, which induces central nervous system (CNS) dysfunction (high pressure neurological syndrome - HPNS) depresses synaptic transmission at all synapses examined to date. Several lines of evidence indicate an inhibitory effect of pressure on Ca²⁺ entry into the presynaptic terminal. In the present work we studied for the first time the effect of pressure on the cerebellar climbing fibers (CF) synaptic responses. Pressure modulation of cerebellar synaptic plasticity was tested both in the CF and parallel fibers (PF) pathways using paired pulse protocols. CF synapses which normally operate at a high baseline release probability, demonstrate paired pulse depression (PPD). High pressure reduced CF synaptic responses at 5.1 MPa and 10.1 MPa, but did not affect its PPD. High [Ca²⁺]_o could not antagonize the effect of pressure on the CF response, whereas low [Ca²⁺]_o in contrast to pressure, decreased both the response amplitude and the observed PPD. PF synapses which usually operate at low release probability, exhibit paired pulse facilitation (PPF). Pressure increased PF PPF at all inter stimulus intervals (ISIs) tested (20 - 200 ms). Several Ca²⁺ channel blockers as well as low [Ca²⁺]_o could mimic the effect of pressure on the PF response, but significantly increased the PPF only at 20 ms ISI. These results, together with previous data, show that the CF synapse is relatively resistant to pressure. The lack of pressure effect on CF PPD is surprising, and may suggest that the PPD is not directly linked to synaptic depletion, as generally suggested. The increase in PPF of the PF at pressure which is mimicked by Ca²⁺ channel blockers or low [Ca²⁺]_o further support pressure involvement in synaptic release mechanism(s). These results also indicate that pressure effects may be selective for various types of synapses in the CNS.