UC San Diego

Synapses are the functional connections between neurons and their targets.Synapse degeneration or dysfunction underlie several neurodevelopmental and neurodegenerative disorders ranging from autism to Alzheimer’s disease, making the study of synapse formation and maintenance highly relevant. Various types of synapses exist within the human nervous system, including en passant synapses, which form along the axon, and terminal synapses, which form at the ends of axons. The nervous system of the nematode C. elegans also forms en passant and terminal synapses, which when coupled with a transparent body, a known connectome and ease of genetic manipulation, makes it an ideal model for the study of synaptogenesis. In the first part of my dissertation, I elucidate the cellular mechanisms that regulate a unique synapse rewiring paradigm in C. elegans motor neurons, where pre-exisiting en passant synapses are completely eliminated and new synapses are formed without any alteration in overall axon morphology. My studies have identified a novel role for dynamic microtubules in facilitating this process, through the modulation of synaptic vesicle transport during remodeling. I also provide in vivo evidence for how molecular motors kinesin and dynein, which move towards opposite ends of the microtubule, engage in a tug-of-war to determine the overall direction of motion of synaptic vesicles. In addition, I uncovered an unexpected role for intermediate filament proteins in regulating microtubule dynamics during synapse formation, and a novel kinase that regulates synapse maintenance after remodeling. Finally, I explore how post-translational modifications of tubulin alter long distance synaptic vesicle transport to terminal synapses, using the mechanosensory neurons in C. elegans as a model. Taken together, my dissertation enhances our current understanding of the different pathways regulating synapse dynamics.