Some of the most abundant synapses in the brain such as the synapses formed by the hippocampal mossy fibers, cerebellar parallel fibers and several types of cortical afferents express presynaptic forms of long-term potentiation (LTP), a putative cellular model for spatial, motor and fear learning. Those synapses often display presynaptic mechanisms of LTP induction, which are either NMDA receptor independent of dependent of presynaptic NMDA receptors. Recent investigations on the molecular mechanisms of neurotransmitter release modulation in short- and long-term synaptic plasticity in central synapses give a preponderant role to active zone proteins as Munc-13 and RIM1-alpha, and point toward the maturation process of synaptic vesicles prior to Ca(2+)-dependent fusion as a key regulatory step of presynaptic plasticity.