The Hodgkin–Huxley–Katz Prize Lecture

During the last decade, advances in experimental techniques and quantitative modelling have resulted in the development of the calyx of Held as one of the best preparations in which to study synaptic transmission. Here we review some of these advances, including simultaneous recording of pre‐ and postsynaptic currents, measuring the Ca2+ sensitivity of transmitter release, reconstructing the 3‐D anatomy at the electron microscope (EM) level, and modelling the buffered diffusion of Ca2+ in the nerve terminal. An important outcome of these studies is an improved understanding of the Ca2+ signal that controls phasic transmitter release. This article illustrates the spatial and temporal aspects of the three main steps in the presynaptic signalling cascade: Ca2+ influx through voltage‐gated calcium channels, buffered Ca2+ diffusion from the channels to releasable vesicles, and activation of the Ca2+ sensor for release. Particular emphasis is placed on how presynaptic Ca2+ buffers affect the Ca2+ signal and thus the amplitude and time course of the release probability. Since many aspects of the signalling cascade were first conceived with reference to the squid giant presynaptic terminal, we include comparisons with the squid model and revisit some of its implications. Whilst the characteristics of buffered Ca2+ diffusion presented here are based on the calyx of Held, we demonstrate the circumstances under which they may be valid for other nerve terminals at mammalian CNS synapses.