Collaborative Research: Biophysical and Molecular Mechanisms of Ultrafast Endocytosis at Neuronal Synapses

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Physical forces determine how the membrane of a living cell changes shape. Endocytosis is a membrane process that is essential for bringing molecules into the cell. Viruses often gain entry into cells by hijacking the endocytic process, and thus it is critical to understand how physical forces contribute to membrane remodeling and, specifically, to endocytosis. One place where endocytosis is important is in the transfer of packets of material from one nerve cell to another at a nerve synapse. How this type of endocytosis occurs remains a mystery. Recent experiments have discovered a novel, ultrafast, endocytic mechanism at synapses that occurs within 50 milliseconds. The mechanisms underlying the ultrafast endocytosis, however, remain poorly understood. The goal of this project is to gain mechanistic insights into this novel endocytic pathway. Since defects in endocytosis at nerve synapses may cause neurodegenerative diseases, the work will lay the foundation to understand synapses in different diseases. To educate citizens and attract young people into science research, the investigators will create opportunities for high-school students to participate in research-based scientific activities, deliver guest lectures about the research at high schools and host high school teachers in the lab.In this research, we will take synergistic experimental and computer modeling approaches to test these models. The Watanabe lab will perform localization and perturbation experiments to reveal the molecular organization and requirements. The Agrawal lab will use the molecular information to build computational modeling to test the passive and active mechanisms and predict the time-scales. The proposed work will be the first unified effort to investigate vesicle dynamics regulated by elastic and dissipative forces. In addition, the proposed research will provide a validated modeling framework for future exploration of membrane-protein dynamics and cellular interface remodeling.