ABSENCE OF SYNAPTOTAGMIN DISRUPTS EXCITATION-SECRETION COUPLING DURING SYNAPTIC TRANSMISSION

Synaptotagmin is an integral synaptic vesicle protein proposed to be i nvolved in Ca2+-dependent exocytosis during synaptic transmission. Nul l mutations in synaptotagmin have been made in Drosophila, and the pro tein's in vivo function has been assayed at the neuromuscular synapse. In the absence of synaptotagmin, synaptic transmission is dramaticall y impaired but is not abolished. In null mutants, evoked vesicle relea se is decreased by a factor of 10. Moreover, the fidelity of excitatio n-secretion coupling is impaired so that a given stimulus generates a more variable amount of secretion. However, this residual evoked relea se shows Ca2+-dependence similar to normal release, suggesting either that synaptotagmin is not the Ca2+ sensor or that a second, independen t Ca2+ sensor exists. While evoked transmission is suppressed, the rat e of spontaneous vesicle fusion is increased by a factor of 5. We conc lude that synaptotagmin is not an absolutely essential component of th e Ca2+ dependent secretion pathway in synaptic transmission but is nec essary for normal levels of transmission. Our data support a model in which synaptotagmin functions as a negative regulator of spontaneous v esicle fusion and acts to increase the efficiency of excitation-secret ion coupling during synaptic transmission.