Modulation of transmission during trains at a cerebellar synapse

Activity-dependent processes dynamically regulate synapses on the time scal e of milliseconds to seconds. Here, we examine the factors governing synapt ic strength during repetitive stimulation, both in control conditions and d uring presynaptic inhibition. Field recordings of presynaptic volleys, opti cal measurements of presynaptic calcium, and voltage-clamp recordings of po stsynaptic currents were used to examine parallel fiber to Purkinje cell sy napses in cerebellar brain slices at 34 degrees C. In control conditions, r egular stimulus trains (1-50 Hz) evoked up to a 250% peak synaptic enhancem ent, whereas during irregular stimulation, a threefold variability in EPSC amplitude was observed. When initial EPSC amplitudes were reduced by 50%, e ither by lowering external calcium or by activating adenosine A(1) or GABA( B) receptors, the peak enhancement during regular trains was 500%, and syna ptic variability during irregular trains was nearly sixfold. By contrast, c hanges in fiber excitability and calcium influx per pulse were small during trains. Presynaptic calcium measurements indicated that by pulse 10, stimu lus-evoked calcium influx had increased by similar to 15%, which on the bas is of the measured relationship between calcium influx and release correspo nds to an EPSC enhancement of 50%. This enhancement was the same in all exp erimental conditions, even in the presence of N-6-cyclopentyladenosine or b aclofen, suggesting that repetitive stimulation does not relieve the G-prot ein inhibition of calcium channels by these modulators. Therefore, for our experimental conditions, changes in synaptic strength during trains are pri marily attributable to residual calcium (Ca-res)-dependent short-term plast icities, and the actions of neuromodulators during repetitive stimulation r esult from their inhibition of initial calcium influx and the resulting eff ects on Ca-res and calcium-driven processes.