Neurons contact each other mostly by synaptic transmission at synapses. The maintenance of synaptic transmission relies on vesicle endocytosis, which recycles fused vesicles for the second round of exocytosis. My goal is to improve our understanding on the cellular and molecular mechanisms underlying synaptic vesicle endocytosis, which are the building block for the maintenance of synaptic transmission and thus the signaling process of the nervous system. Our progress in the last year is described below. 1. Vesicle fusion releases neurotransmitters to mediate synaptic transmission. To sustain synaptic transmission, fused vesicles must be retrieved via endocytosis. Accumulating evidence suggests that calcium influx triggers synaptic vesicle endocytosis. However, how calcium triggers endocytosis is not well understood. Using genetic tools together with capacitance measurements, optical imaging and electron microscopy, we identified two calcium sensors, including protein kinase C and calmodulin, for most commonly observed forms of endocytosis, the slow, rapid and bulk endocytosis. We also found that these two proteins are involved in calcium-dependent vesicle mobilization to the readily releasable pool. These results provide the molecular signaling link among calcium, endocytosis and vesicle mobilization that are essential in sustaining synaptic transmission and neuronal network activity. This work has been submitted for publication. 2. Superresolution microscopy (SM) techniques are among the revolutionary methods for molecular and cellular observations in the 21st century. SM techniques overcome optical limitations, and several new observations using SM lead us to expect these techniques to have a large impact on neuroscience in the near future. Several types of SM have been developed, including structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), and photoactivated localization microscopy (PALM)/stochastic optical reconstruction microscopy (STORM), each with special features. In this Minisymposium, experts in these different types of SM discuss the new structural and functional information about specific important molecules in neuroscience that has been gained with SM. Using these techniques, we have revealed novel mechanisms of endocytosis in nerve growth, fusion pore dynamics, and described quantitative new properties of excitatory and inhibitory synapses. Additional powerful techniques, including single molecule-guided Bayesian localization SM (SIMBA) and expansion microscopy (ExM), alone or combined with super-resolution observation, are also introduced in this session. This work is a collaboration among several labs.

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Shin, Wonchul; Ge, Lihao; Arpino, Gianvito et al. (2018) Visualization of Membrane Pore in Live Cells Reveals a Dynamic-Pore Theory Governing Fusion and Endocytosis. Cell 173:934-945.e12
Wu, Xin-Sheng; Elias, Sharon; Liu, Huisheng et al. (2017) Membrane Tension Inhibits Rapid and Slow Endocytosis in Secretory Cells. Biophys J 113:2406-2414
Wen, Peter J; Grenklo, Staffan; Arpino, Gianvito et al. (2016) Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane. Nat Commun 7:12604
Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong et al. (2016) Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses. Neuron 92:1020-1035
Zhao, Wei-Dong; Hamid, Edaeni; Shin, Wonchul et al. (2016) Hemi-fused structure mediates and controls fusion and fission in live cells. Nature 534:548-52
Baydyuk, Maryna; Xu, Jianhua; Wu, Ling-Gang (2016) The calyx of Held in the auditory system: Structure, function, and development. Hear Res 338:22-31
Xu, Jianhua; Wu, Xin-Sheng; Sheng, Jiansong et al. (2016) ?-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals. J Neurosci 36:4408-14
Park, Soonhong; Ahuja, Malini; Kim, Min Seuk et al. (2016) Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV. EMBO Rep 17:266-78
Baydyuk, Maryna; Wu, Xin-Sheng; He, Liming et al. (2015) Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal. J Neurosci 35:4676-82
Peng, Shiyong; Xu, Jianhua; Pelkey, Kenneth A et al. (2015) Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice. Ann Clin Transl Neurol 2:1085-104

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