- High pressure, which induces central nervous system (CNS) dysfunction (high-pressure neurological syndrome) depresses synaptic transmission at all synapses examined to date. Several lines of evidence indicate an inhibitory effect of pressure on Ca(2+) entry into the presynaptic terminal. In the present work we studied for the first time the effect of pressure on the cerebellar climbing fiber (CF) synaptic responses. Pressure modulation of cerebellar synaptic plasticity was tested in both the CF and parallel fiber (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 and 10.1 MPa but did not affect its PPD. High extracellular Ca(2+) concentration ([Ca(2+)](o)) could not antagonize the effect of pressure on the CF response, whereas low [Ca(2+)](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 interstimulus intervals (ISIs) tested (20-200 ms). Several Ca(2+) channel blockers as well as low [Ca(2+)](o) could mimic the effect of pressure on the PF response but significantly increased the PPF only at the 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 Ca(2+) channel blockers or low [Ca(2+)](o), further supports 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.