The role of bidirectional transport of lysosome-related organelles in learning and memorystorage

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Project Summary/ Abstract Axonal transport, the movement of cargoes such as organelles between the cell body and the synapse, is key for transporting signals and cargoes that mediate plasticity. Cargoes that undergo bidirectional axonal transport include mitochondrion, which is essential for providing energy to the cell and maintaining neuronal functions, and lysosome-related organelles (LROs), which are necessary for protein degradation and recycling and neuronal health. Yet, the regulation of organelle transport during synaptic plasticity is poorly understood. To fill our gap and understand the role and regulation of axonal transport during learning and memory, I will investigate mitochondrial and LROs axonal transport in Aplysia pre-synaptic sensory neurons and post- synaptic L7 motor neuron during excitatory and inhibitory synaptic plasticity and long-term memory. The central hypothesis underlying this proposal is that excitatory plasticity negatively regulates the flux of LRO transport whereas inhibitory plasticity upregulates it in pre- and post-synaptic neurons. I will test my hypothesis with three aims. My first aim will determine whether long-term synaptic facilitation and depression regulates bidirectional transport of LROs in pre- and postsynaptic neurons and, assess the transport dynamics of LROs using photo-switchable Dronpa-Lysosome-20. My second aim will investigate the role of biogenesis of lysosome-related organelle complex 1 subunit-2 (BLOC1S2) in regulating the flux of LRO transport during long-term synaptic facilitation. The third aim will assess the role of ApBLOC1S2 in sensitization of Aplysia. Scripps Florida and Florida Atlantic University provide the optimal environment and the necessary resources to accomplish the goals of this proposal and fostering my career development. Moreover, my sponsors are eminent neuroscientists, guidance from Dr. Sathya Puthanveettil will support my project progress and career development. Co-sponsor Dr. Ryohei Yasuda’s imaging expertise will me to develop the technical capabilities to utilize photo-switchable Dronpa-Lysosome-20 plasmid and photo-bleaching techniques to study the LROs anterograde and retrograde transport dynamics as described in aim 1. Cosponsor Dr. Ronald Davis is a leader in the field of learning and memory and will help me develop the skills to rigorously assess my data, interpret my findings, and its application, especially when assessing opposing plasticity-types (excitatory and inhibitory long-term plasticity) in my aim 2. Lastly, cosponsor Dr. Robert Hawkins is a leader in behavioral learning in Aplysia, therefore, his guidance and training will be key for my success in assessing the role of ApBLOC1S2 in learning and memory mentioned in aim 3. My findings will be presented at international conferences such as Max Planck Florida Institute’s Bi-Annual Synapse conference, the Society for Neuroscience meeting, Cold Spring Harbor meetings and Gordon Research Conferences. The aims, trainings, and tools proposed in this grant will help contribute to my goal of becoming a Principal Investigator to study long-term memory storage and add to our knowledge of learning, memory, and neurodegenerative diseases.