Synaptic plasticity, changes in the strength of connections between neurons with experience, provides a mechanism for information storage in the brain. Long-lasting forms of plasticity have been shown to require RNA and protein synthesis, indicating that signals can be transported from the synapse, where they are generated, to the nucleus, where they are converted into changes in gene expression. The extreme polarity of neurons and the significant distances that can exist between distal synapses and cell soma present a unique set of challenges to nucleocytoplasmic trafficking.
The aim of this proposal is to delineate the role of the active nuclear import pathway in transporting signals from synapse to nucleus during long-lasting forms of learning-related synaptic plasticity. In this pathway, proteins bearing nuclear localization signals (NLSs) are recognized by a nuclear transport adaptor, called importin alpha, which then binds a nuclear transporter called importin betal. Importin betal docks the heterotrimeric complex at the nuclear pore and mediates its translocation into the nucleus. We plan to study importin-mediated nuclear transport, using both dissociated mouse hippocampal cultures and acute hippocampal slices to study various aspects of synaptic plasticity. In our first aim, we will determine whether importins are localized to the synapse and subsequently translocate following stimuli that lead to transcription-dependent plasticity. In the second aim, we propose to identify synaptically localized proteins that are transported to the nucleus following synaptic stimulation. In the final aim, we will determine how the importin-cargo complex is assembled at the synapse and what cell biological pathways are involved in the translocation of this complex to the nucleus. Relevance to public health: Understanding the mechanisms whereby synaptically generated signals trigger changes in gene expression in the nucleus during memory formation provides a means of identifying therapeutic targets for a variety of disorders including mental retardation, age-related memory loss, Alzheimer's disease, epilepsy, drug addiction as well as many neuropsychiatric diseases.
| Van Driesche, Sarah J; Martin, Kelsey C (2018) New frontiers in RNA transport and local translation in neurons. Dev Neurobiol 78:331-339 |
| Gao, Jie; Marosi, Mate; Choi, Jinkuk et al. (2017) The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. Elife 6: |
| Herbst, Wendy A; Martin, Kelsey C (2017) Regulated transport of signaling proteins from synapse to nucleus. Curr Opin Neurobiol 45:78-84 |
| Ch'ng, Toh Hean; DeSalvo, Martina; Lin, Peter et al. (2015) Cell biological mechanisms of activity-dependent synapse to nucleus translocation of CRTC1 in neurons. Front Mol Neurosci 8:48 |
| Ch'ng, Toh Hean; Uzgil, Besim; Lin, Peter et al. (2012) Activity-dependent transport of the transcriptional coactivator CRTC1 from synapse to nucleus. Cell 150:207-21 |
| Ch'ng, Toh Hean; Martin, Kelsey C (2011) Synapse-to-nucleus signaling. Curr Opin Neurobiol 21:345-52 |
| Ho, Victoria M; Lee, Ji-Ann; Martin, Kelsey C (2011) The cell biology of synaptic plasticity. Science 334:623-8 |
| Martin, Kelsey C (2010) Anchoring local translation in neurons. Cell 141:566-8 |
| Wang, Dan Ohtan; Martin, Kelsey C; Zukin, R Suzanne (2010) Spatially restricting gene expression by local translation at synapses. Trends Neurosci 33:173-82 |
| Dzudzor, Bartholomew; Huynh, Lucia; Thai, Minh et al. (2010) Regulated expression of the Ras effector Rin1 in forebrain neurons. Mol Cell Neurosci 43:108-16 |
Showing the most recent 10 out of 12 publications
