Erwin Neher

Biophysics of Neutrotransmitter 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 in 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 signaling substance, the neurotransmitter, from the presynaptic neuron. Signaling substances are stored in the nerve endings within so-called synaptic vesicles – small membrane-bound containers, which fuse with the plasma membrane, thereby releasing their contents. 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.

When synaptic strength changes during ‘plasticity‘ this can be a consequence of changes in any of the steps of this complicated process. Unfortunately, most nerve terminals are very small and not readily accessible to detailed investigation, such that usually it is very difficult to assign a given change to one of these molecular mechanisms. Quite recently, however, it was discovered that a specialized synapse in the auditory pathway, the ‘Calyx of Held‘, has presynaptic terminals, which are large enough such that quantitative biophysical techniques can be applied. Particularly, 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++ by photolysis from a chemically caged form of Ca++. Furthermore, [Ca++] can be measured by introducing fluorescent Ca++ indicators into the terminal. Using these experimental possibilities, we have established a ‘dose-response-curve’ – the relationship between transmitter release rate and [Ca++]. Also, we have studied the role of Ca++ and other second messengers in short-term changes of synaptic strength. We found that there are two steps, which are strongly modulated: i) action potential waveform and Ca++ influx is modulated in multiple ways by second messengers ii) during ongoing activity new synaptic vesicles have to be recruited, to replace those that have undergone exocytosis. This step of recruitment is also modulated strongly by [Ca++], cAMP and other second messengers. The release process itself – although steeply dependent on [Ca++] – is relatively immune to other forms of modulation.

A question of particular recent interest has been: what happens with vesicles before and after releasing their contents. Some synapses fire at high rates, which implies that vesicles have to be recycled rapidly. This happens by the process of ‘endocytosis’ – the formation and pinching off of new vesicles from the plasma membrane. These vesicles have to be filled with neurotransmitter, before they are ready for reuse. Kinetic modeling of all these processes – [Ca++]-dynamics, release, endocytosis, recycling, and priming for release – is a challenging task.


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