Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses

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Abstract

Endocytic recycling of synaptic vesicles after exocytosis is critical for nervous system function. At synapses of cultured neurons that lack the two "neuronal" dynamins, dynamin 1 and 3, smaller excitatory postsynaptic currents are observed due to an impairment of the fission reaction of endocytosis that results in an accumulation of arrested clathrin-coated pits and a greatly reduced synaptic vesicle number. Surprisingly, despite a smaller readily releasable vesicle pool and fewer docked vesicles, a strong facilitation, which correlated with lower vesicle release probability, was observed upon action potential stimulation at such synapses. Furthermore, although network activity in mutant cultures was lower, Ca 2+/ calmodulin-dependent protein kinase II (CaMKII) activity was unexpectedly increased, consistent with the previous report of an enhanced state of synapsin 1 phosphorylation at CaMKII-dependent sites in such neurons. These changes were partially reversed by overnight silencing of synaptic activity with tetrodotoxin, a treatment that allows progression of arrested endocytic pits to synaptic vesicles. Facilitation was also counteracted by CaMKII inhibition. These findings reveal a mechanism aimed at preventing synaptic transmission failure dueto vesicle depletionwhen recycling vesicle traffic is backed upby a defect in dynamin-dependent endocytosis and provide new insight into the coupling between endocytosis and exocytosis.

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Lou, X., Fan, F., Messa, M., Raimondi, A., Wu, Y., Looger, L. L., … De Camilli, P. (2012). Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses. Proceedings of the National Academy of Sciences of the United States of America, 109(8). https://doi.org/10.1073/pnas.1121626109

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