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The mechanism of chemical synaptic transmission was elucidated at the frog neuromuscular junction (NMJ) and at the squid giant synapse by Katz, Miledi and other researchers. Later progress in molecular biology revealed numerous types of proteins in mammalian central synapses. To establish molecular-functional correlation in synaptic transmission, it now seems essential to re-address the fundamental mechanisms at mammalian central synapses. Using patch-clamp whole-cell recording at the calyx of Held in slices of rodent brainstem, we have identified quantal EPSCs and reproduced the quantal analysis established at the NMJ. Intra-terminal whole-cell loading of the neurotransmitter, glutamate, revealed that vesicular transmitter content is an important determinant of quantal size and its variation. Regarding the Ca 2+ -dependence of transmitter release, the average coupling distance between Ca 2+ entry sites and exocytic vesicles was estimated as tens of nanometers and was found to undergo developmental tightening at the calyx of Held. Numerical simulations suggested that this distance can determine the synaptic delay, synchronicity of vesicular transmitter release, and release probability. The super-linear input (presynaptic)-output (postsynaptic) relationship of neurotransmission is an important physiological feature discovered at squid giant synapses. However, at the calyx of Held, unlike at the squid synapse, the input-output relationship had a wide safety margin, protecting transmitter release from a diminishment of presynaptic action potentials. As in the NMJ, Ca 2+ remaining in the cytosol after action potential facilitates subsequent release. As a downstream mechanism of this residual Ca 2+ , a Ca 2+ -induced Ca 2+ channel activation via high-affinity Ca 2+ binding proteins was discovered at mammalian central synapses., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)