Kelsey C. Martin

Synaptic plasticity, the modification of connections in the brain by experience, is the best correlate of learning and memory in invertebrate and vertebrate animals. Long-lasting forms of synaptic plasticity have been shown to require gene expression. This means that signals must be transported from the synapse, where they are generated, to the nucleus, where they are converted into changes in gene expression. The products of gene expression must then be transported from the cell soma to the synapse to produce enduring changes in synaptic strength. My lab is interested in both aspects of communication between the synapse and the nucleus during synaptic plasticity in neurons. We study these questions in cultured Aplysia sensory-motor neurons and in cultured rodent hippocampal neurons using cell biological, molecular biological and electrophysiological techniques. Tranport of molecules from the synapse to the nucleus of neurons is particularly challenging because synapses are often very far from the cell body. We are focusing on the role of the active nuclear import pathway in mediating this transport. We find that the importin nuclear transport factors are present in distal synapses, and that distinct stimuli trigger the nuclear translocation of distinct importin alpha isoforms. We are now interested in understanding how synaptic stimulation triggers their nuclear import, in understanding the pathways whereby the importin-cargo complex travels from synapse to nucleus, and in identifying some of the cargoes themselves. Since each neuron has a single nucleus but can form thousands of synaptic connections, the requirement for transcription during synaptic plasticity raises the question of how the products of gene expression can be targeted to alter synaptic strength at select synapses made by a given neuron. We have found that one important mechanism whereby long-lasting, transcription-dependent plasticity can occur in a synapse-specific manner involves the translation of synaptically localized mRNAs. Another mechanism involves local, regulated degradation of proteins via the ubiquitin proteasome pathway. We are using a variety of molecular, cell biological and pharmacological approaches to identify dendritically localized mRNAs, to study the regulated translation of these mRNAs, and to study the role of local protein degradation during synaptic plasticity.