Kelsey Martin, M.D., Ph.D.

Kelsey Martin, Associate Professor in the Department of Psychiatry and Biobehavioral Sciences and the Department of Biological Chemistry, Eleanor Leslie Term Chair in Innovative Brain Research, and Co-Director of the UCLA-Caltech Medical Scientist Training Program (MSTP), is interested in the molecular and cell biology of learning and memory. Her lab studies long-term synaptic plasticity, the process whereby neurons change the strength and number of their synaptic connections with experience. Long-term forms of synaptic plasticity, like long-term memory, require new gene expression. The Martin lab focuses on two questions that emerge from this requirement: 1) how are signals received at distal synapses relayed to the nucleus to turn on transcription? and 2) how can gene expression be spatially restricted within the neuron to allow synapse-specific forms of transcription-dependent plasticity? They study these questions using two model systems of learning-related synaptic plasticity: Aplysia sensory-motor synapses and rodent hippocampal synapses, using a combination of electrophysiology, biochemistry, cell and molecular biology. In 2004, the Martin lab discovered a role for importin-mediated active nuclear transport in carrying signals from the synapse to the nucleus during long-term synaptic plasticity. Current efforts are focused on identifying the synaptically-localized protein cargoes of importins and on understanding the cell biological pathway underlying this long-distance retrograde transport. In 1997, Kelsey Martin discovered that synapse-specific forms of long-term plasticity require translation of localized mRNAs at the synapse. The Martin lab has since identified a large population of mRNAs that are present in neurites of Aplysia sensory neurons and and dendrites of rodent hippocampal neurons. Using a combination of in situ hybridization, live cell imaging of RNA and translational reporters, siRNA-mediated gene silencing and electrophysiological recording, they are investigating the mechanisms underlying mRNA localization and regulated translation in neurons as well as the function of this form of regulated gene expression during synapse formation and synaptic plasticity. The goal of these studies is to understand how the brain forms and stores memories, and to provide insights into the pathophysiology of disorders in which learning and memory are impaired.

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.

Publications: