Long-term memory (LTM) storage requires remodeling of pre-existing synapses and formation of new ones. While the roles of transcription and synaptic protein synthesis in these processes are well described, relatively little is known about how nuclear and synaptic processes are coordinated during LTM storage. We have previously shown that kinesin, the molecular motor that mediates communication between the nucleus and synapses through the microtubule-dependent transport of gene products, has a key role in this process. While these studies established the role of anterograde transport during learning and memory storage, the contribution of retrograde transport during learning is unknown. Understanding retrograde transport will help elucidate the molecular communication from the synapse to the cell body and thus provide a deeper understanding of LTM formation and storage. Based on our genomics, proteomics, gene expression and live cell-imaging experiments described in the preliminary results section, our central hypothesis is that storage of LTM requires regulation of components of the retrograde transport machinery in both pre- and post- synaptic neurons. Here, we focus on the regulation of two protein complexes that are known to mediate retrograde transport: the dynein motor complex, which contains dynein heavy chain (DHC), intermediate chain (DIC), light intermediate chain (DLIC), and light chain (DLC); and the dynactin complex which consists of 23 proteins with dynactin 1 (p150glued) acting as a critical mediator of dynactin function. Exploring the advantages of identified neurons and defined synaptic connections of the sea slug Aplysia californica, we will test our hypothesis by assessing (1) regulation of expression of components of dynein-dynactin machinery by 5HT (serotonin), a modulatory neurotransmitter important for learning in Aplysia; (2) quantitative live cell imaging of cargo and dynein transport machinery; (3) necessity and sufficiency of 5HT regulated components in pre- and post-synaptic neurons of gill withdrawal reflex; (4) role of local translation in modulating retrograde transport and (5) elucidate the molecular nature of cargos transported from the synapses by dynein transport machinery. We anticipate that these studies will be ground breaking because little is known about the role of dynein- dynactin complexes in LTM. Successful completion of these studies is expected to have a major positive impact on mechanisms underlying activity regulated retrograde transport and biology of memory.
Despite the advances in our understanding of the molecular and cellular basis of learning and long-term memory storage, we do not know whether retrograde transport from the synapse mediated by molecular motor dynein is critical for memory storage. Exploring the advantages of identified pre- and post-synaptic neurons of the sea slug Aplysia, we now propose a multidisciplinary approach to unravel the regulation and role of dynein mediated retrograde transport in mediating synapse to nucleus communication during memory storage. Successful completion of these studies will provide novel insights into regulation of memory storage and thus facilitate a better understanding of transport dysfunction in developmental/ neuropsychiatric disorders.
