Synaptic transmission is a multi-step process, which involves Ca++ influx into the nerve terminal, Ca-dependent exocytosis, and postsynaptic transmitter action. When synaptic strength changes during 'plasticity' this can be a consequence of changes in any of these steps. Unfortunately, most nerve terminals are very small and not readily accessible to detailed investigation, such that it is usually very difficult to assign a given change to one of the molecular steps involved. More recently, however, it was discovered that a specialized synapse in the auditory pathway, the 'Calyx of Held', has presynaptic terminals, which are large enough that quantitative biophysical techniques can be applied. Particularly, the postsynaptic current can be measured precisely, while the presynaptic calcium concentration ([Ca++]) can be manipulated in a controlled fashion – either by opening and closing of Ca++ channels or by photoreleasing Ca++ from a chemically caged form. Furthermore, [Ca++] can be measured by introducing fluorescent Ca++ indicators into the terminal.

Using these experimental possibilities, we have studied the role of Ca++ and other second messengers in short-term changes of synaptic strength. We found that the concentration of free calcium ([Ca++]i) has at least three roles in neurotransmitter release and its modulation: i) it triggers release within microdomains of highly elevated [Ca++]i around open channels ii) it enhances the supply of new vesicles during ongoing activity and after short-term depression iii) during high-frequency stimulation action potentials become more efficient in eliciting exocytosis due to the buildup of 'residual Calcium', and to facilitation of Ca-current.

Recently, we concentrated on the question on the nature of the rate-limiting step of vesicle recruitment during ongoing activity. Surprisingly, we found that vesicle availability is not limited by vesicle docking and the buildup of a release machinery. These steps can be very fast. Rather, an ultrastructural reorganization at the active zone seems to be the rate-limiting step, which either establishes a close spatial relationship between primed vesicles and Ca-channels or else creates sites for vesicles to dock in the vicinity of such channels.

Erwin Neher serves as Director of the Membrane Biophysics Department at the Max-Planck-Institut für Biophysikalische Chemie in Göttingen, Germany. He received his Ph.D. in Physics from the Institute of Technology in Munich. His research interests have focused on studies of ion channels in nervous signaling and exocytosis. For his development of the patch clamp technique for recording ion channel activity, he received the 1991 Nobel Prize in Physiology or Medicine (together with Bert Sakmann) as well as several other national and international awards. More recently Erwin Neher has been working on neurotransmitter release and on the mechanisms responsible for short-term synaptic plasticity.

He is a Foreign Associate member of the National Academy of Sciences (USA), and of the Royal Society (London). He co-chairs the Board of the European Neuroscience Institute, Göttingen.

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http://nobelprize.org/nobel_prizes/medicine/laureates/1991/neher-autobio.html

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