During synaptic transmission, the arrival of a nervous impulse at a nerve terminal triggers synaptic vesicles containing neurotransmitter molecules to release their cargo into the synaptic cleft. This occurs by exocytosis – the membrane-bound vesicles fuse with the presynaptic membrane, so that the interior of the vesicle exposed to the synapse, into which the contents of the vesicle are released. Neurotransmitter release is widely believed to be quantized, with each vesicle contains a certain number of transmitter molecules. The fusion of synaptic vesicles with the presynaptic membrane can be measured as an increase in the capacitance (the ability to store electrical charge) of the membrane.
Exactly how synaptic vesicles are recycled once they have released their contents is still unclear, but it appears that a number of things can happen. The difference between the various models of synaptic vesicle fusion is the extent to which the vesicles fuse with the presynaptic membrane.
In the ‘original’ model (left), proposed by John Heuser and Tom Reese in 1973, complete fusion leads to the flattening of the vesicle, which is then fully integrated into the presynaptic membrane. This was based on experiments in which horseradish peroxidase (HRP) was used to stain and trace the fate of vesicles in the frog neuro- muscular junction. Nerve terminals were stimulated while bathed in a solution of HRP. The tracer was then observed first in vesicles at the nerve terminal, then in endosomes, and finally in newly formed vesicles. Heuser named this ‘recycling,’ because it was the most appropriate description of the process, and as a nod to the emerging environmentalist movement: “The synaptic vesicle is not like a cola bottle that never loses its integrity when returned to the factory to be filled again. Instead, it melts into the plasma membrane and is completely reformed, like an aluminium beer can.”
In a paper published back-to-back with that of Heuser and Reese, Bruno Ceccarelli and his colleagues proposed the ‘kiss-and-run’ model of neurotransmitter release, whereby a partial, reversible fusion of the vesicle with the membrane forms a transient aqueous pore through which the neurotransmitter molecules are released. The kiss-and-run mode of vesicle fusion has remained controversial; although it has been measured at the neuromuscular junction and in hippocampal synapses and chromaffin cells, many researchers doubt that it takes place because until now there has been little direct evidence of the process.
In an advance online publication at Nature, He et al, of the National Institute of Neurological Disorders and Stroke, now provide some direct evidence of kiss-and-run exocytosis. They carried out their experiments in rats, using the calyx of Held, a giant synaptic terminal that forms around the cell bodies of neurons in the superior olive, and which contains vesicles that release glutamate. Because of its size, is the calyx of Held is more accessible than other synapses in the brain, and serves as a model for neurobiologists investigating synaptic transmission.
He’s team developed a technique whereby they can expose the sites at the calyx of Held where neurotransmitter molecules are released. The technique involves using a microelectrode to suck and pull the postsynaptic neuron, while leaving the morphology of the calyx intact. To these preparations, neurotransmitter release was elicited by the addition of concentrated potassium solutions.
After application of the potassium solution, smallflickers of increased membrane capacitance, which lasted less than 2 seconds, were measured. The frequency and amplitude of the capacitance flickers that they were caused by the fusion of single rather than multiple vesicles to the presynaptic membrane. The size of the flickers was also consistent with predictions based on the size of vesicles. The researchers also measured the conductance of the transient pores produced during the kiss-and-run exocytosis, and determined that they had a diameter of >2.3 nanometres.
The conductance flickers corresponding to kiss-and-run exocytosis accounted for only ~20% of the transmitter release events observed in the study. Thus, the cells appear to utilize both full vesicular fusion and kiss-and-run, with the latter enabling faster transmitter release and vesicle recycling than the former. This may be essential in small synapses which contain only small numbers of synaptic vesicles.
Mo Costandi 
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