A high-frequency action potential train induces post-tetanic potentiation (PTP) of transmission at many synapses by increasing the intra-terminal calcium concentration, which may increase the quantal content by activation of protein kinase C (PKC). A recent study found that an increase of the mEPSC size, caused by compound vesicle fusion, parallels PTP, suggesting that the quantal size increase also contributes to the PTP generation. However, the strength of this suggestion is somewhat undermined by recent studies suggesting that vesicles responsible for spontaneous and evoked EPSCs may originate from different pools. Furthermore, it is unclear whether the quantal size increase is also mediated by PKC. The present work addressed these issues at a large calyx of Held synapse. We found that PTP was caused by both a PKC-dependent increase of the quantal content and a PKC-independent increase of the quantal size. In addition, we found that mEPSCs and EPSCs were subjected to similar up- and down-regulation, which verifies the basic assumption of quantal analysis – the same mechanism controls the quantal size of spontaneous and evoked release. This verification supports the use of quantal analysis at central synapses. However, unlike the traditional quantal analysis that attributes the quantal size change to a postsynaptic mechanism, the present work, together with one of our previous studies, suggests that the quantal size increase is caused by a presynaptic mechanism, the compound fusion among vesicles that forms large compound vesicles.