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  Item 3

"Kiss and run" synaptic vesicles?

For almost thirty years there have been two competing hypotheses about how synaptic vesicles discharge transmitter molecules into the synapse and then are recycled for further activity. Recent experiments and reviews indicate that both hypotheses are correct, each applying to a different pool of vesicles within the presynaptic terminal (Richards, Guatimosin, and Betz, 2000; Wilkinson and Cole, 2001).

Heuser and Reese (1973) proposed, on the basis of experimental evidence, that the membranes of activated synaptic vesicles fuse with the membrane of the presynaptic terminal at the active zone (the region of the presynaptic terminal facing the synaptic cleft) and the vesicles discharge their contents into the synaptic cleft. Membrane is then taken from a region of the presynaptic terminal away from the active zone and used to form new vesicles which are then filled with synaptic transmitter molecules. This is the account that has been more widely accepted and that is presented in the text (pp. 73-74) and in the animation of Study Guide tutorial 3.2.

But in the same number of the same journal in which Heuser and Reese (1973) published their report, another group -- Ceccarelli, Hurlbut and Mauro (1973) -- proposed another mechanism: A small part of the membrane of an active vesicle fuses with and forms a pore through the region of the presynaptic terminal facing the synaptic cleft and the vesicle discharges transmitter molecules (but not its entire contents) into the synaptic cleft. After discharging the transmitter molecules, the intact vesicle then separates from the membrane of the presynaptic bouton and moves to the interior of the bouton to have its store of transmitter molecules replenished. These processes should permit more rapid, sustained synaptic activity than those reported by Heuser and Reese. This more rapid mechanism is now referred to as "kiss and run," a term apparently first proposed in a review by Fesce et al. (1994)

Studying the activity of synaptic vesicles has involved use of electron microscopy, specialized dyes, and related electrophysiology (Betz et al., 2000). Research on this question began with the frog neuromuscular junction and has been extended to other species and synapses. It now appears that there are two pools of vesicles: (1) A readily releasable pool of vesicles located at or close to the active zone of the presynaptic membrane. These are kiss and run vesicles that reform rapidly after electrical stimulation of the neuron. (2) A reserve pool of vesicles located away from the active zone of the presynaptic membrane. These vesicles are reformed relatively slowly from infolding of the cell membrane. During intense electrical stimulation of the neuron, vesicles of the reserve pool are mobilized over 10-15 s and migrate to the active zone. The relative numbers of vesicles in the two pools appears to differ in different parts of the nervous system and to be modulated by extracellular events, so work on these questions is continuing.

References:

Ceccarelli, B., Hurlbut, W.P. and Mauro, A. (1973). Turnover of transmitter and synaptic vesicles at the frog neuromuscular junction. Journal of Cell Biology, 57, 499-524.

Fesce, R., Grohovaz, F., Valtorta, F. and Meldolesi, J. (1994). Neurotransmitter release: fusion or 'kiss-and-run'? Trends in Cell Biology, 4, 1-4.

Heuser, J.E. and Reese, T.S. (1973). Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. Journal of Cell Biology, 57, 315-344.

Richards, D.A., Guatimosin, C. and Betz, W.T. (2000). Two endocytic recycling routes selectively fill two vesicle pools in frog motor nerve terminals. Neuron, 27, 551-559.

Wilkinson, R.S. and Cole, J.C. (2001). Resolving the Heuser-Ceccarelli debate. Trends in Neuroscience, 24, 195-197.