Erwin Neher

On the Mechanism of Neurotransmitter Release


Abstract

The unique capabilities of our brain as an information processor are critically dependent on the correct function of some 10 billions of neurons, each of which is connected to about 10 000 other neurons by way of synapses. Unlike electronic computers these connections are not rigid but adapt their coupling strengths in response to the information flow in the system – a phenomenon called synaptic plasticity. An understanding of the process of synaptic transmission as well as of the mechanisms underlying plasticity is essential.

It has been known since the early fifties, that synaptic transmission is initiated by the release of a signalling substance, the neurotransmitter, from the presynaptic neuron. This, in turn, is triggered by an influx of Calcium ions (Ca++) into the nerve terminal. The neurotransmitter, once liberated, induces an increase in the conductance of the postsynaptic membrane. Work in my laboratory has concentrated on the process of transmitter release and on the shortest forms of synaptic plasticity, which are called ‘short term depression’ (STD) and short term ‘facilitation’ (STF). In STD the response of a postsynaptic neuron decreases, successively, if the presynaptic neuron is stimulated at constant strength, and is typically seen in some types of synapses at simulation frequencies between 5 Hz and 100 Hz. At other synapses the opposite can be observed, namely STF, particularly for the first few stimuli in a train. The two types of responses may superimpose in complicated ways. Early work by Bernhard Katz and collaborators has already shown that both STD and STF result primarily from changes in the quantity of transmitter released. STD was attributed to the depletion of releasable neurotransmitter from the presynaptic terminal, while STF was interpreted as a buildup of presynaptic calcium during repetitive stimulation. Unfortunately, most nerve terminals are very small and not readily accessible to detailed investigation, such that progress in the understanding of these events was slow.

Quite recently, it was discovered that a specialized synapse in the auditory pathway, the ‘Calyx of Held’, has presynaptic terminals, which are large enough that ‘patch clamp techniques’ can be applied (I.D. Forsythe, J. Physiol. 479, pp. 381-387). In fact, Borst and Sakmann (Nature, 383, pp. 431-434) were able to show that both pre- and postsynaptic compartments can be voltage-clamped simultaneously. This means that the postsynaptic current can be measured precisely, while the presynaptic calcium concentration ([Ca++]) can be increased or decreased – either by opening and closing of Ca++ channels or by releasing Ca++ from a chemically caged form by photolysis. Furthermore, [Ca++] can be measured by introducing fluorescent Ca++ indicators into the terminal. Using these experimental possibilities, we have measured how high [Ca++] has to rise in the presynaptic terminal in order to elicit release. We have determined the size of the ‘pool’ of neurotransmitter, which is used up during STD, and we have studied the ‘buildup’ of [Ca++] during STF. Surprisingly, it turned out that the pool of neurotransmitter is heterogeneous, some component of which reacting very sensitively to an increase in [Ca++], the remainder releasing only reluctantly. These features offer explanations for some properties of transmitter release, which have long been a puzzle.


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