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, it remains largely unknown how nuclear and synaptic processes are coordinated during LTM storage. We have previously shown that kinesin, the molecular motor that mediates communication between nucleus and synapses through the microtubule-dependent transport of gene products, has a key role in this process. We have discovered that kinesins are necessary and sufficient to induce long-term facilitation (LTF) in marine snail Aplysia and that kinesin transport several protein and mRNA cargos that are relevant for learning. Our guiding hypothesis is that storage of LTM requires regulation of axonal transport of gene products in pre- and post-synaptic neurons of circuits involved in learning. In this proposal, we test our central hypothesis that kinesin mediated transport is differentially regulated in bidirectional plasticity during learning. We will perform our studies using the well-described pre-synaptic sensory and post-synaptic motor neurons of gill withdrawal reflex of Aplysia. The sensory and motor neuron synapses can be re-constituted in vitro and provide experimental flexibility to specifically manipulate these neurons to study regulation of transport in pre- and post-synaptic neurons. Specifically, we aim to understand how the three critical components of anterograde transport: the kinesin motor, cargo and microtubule tracks may be regulated to adjust delivery of cargo to synapses during LTM. An anticipated outcome of this proposed research is that once the molecular regulators of axonal transport are identified, they may be manipulated pharmacologically, producing new and innovative approaches to the treatment of disorders such as tauopathies in which axonal transport is affected.
Presently, there is no cure for dementias such as Alzheimer's disease. Proteins involved in axonal transport are affected in Alzheimer's disease and in number of other neuropsychiatric disorders. This proposal outlines experiments designed to understand how axonal transport is regulated in pre- and post-synaptic neurons involved in learning and memory storage. Once the molecular regulators of axonal transport are identified, they may be manipulated pharmacologically, producing new and innovative approaches to the treatment of these disorders.
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