The role of synaptonuclear signaling proteins in long-term hippocampal synaptic plasticity

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Project Abstract: Synaptic plasticity is a fundamental principle of the nervous system and underlies many neurobiological processes including neurodevelopment, sensory processing, and memory storage. New gene transcription is required for long-lasting plasticity, and this requirement for transcription indicates that signals from stimulated synapses must reach the nucleus via synaptonuclear signaling. One such mechanism of synaptonuclear signaling that is essential for long-term plasticity is the physical translocation of signaling proteins from the synapse to the nucleus. While a few dozen proteins are known to undergo activity- dependent synapse-to-nucleus translocation, little work has been done to systematically identify the population of proteins that undergo this translocation. Moreover, little is known about the gene expression programs that these synaptonuclear signaling proteins initiate. This project aims to: 1) Characterize the gene regulatory role of an exemplar synaptonuclear signaling protein, CREB-Regulated Transcriptional Coactivator 1 (CRTC1); and 2) Systematically identify proteins that undergo synapse-to-nucleus translocation during plasticity. For the first aim, electrophysiology will be used to characterize late-phase long-term potentiation (LTP) and long-term depression (LTD) in acute hippocampal slices from CRTC1 conditional knockout mice to study the function of CRTC1 in long-lasting plasticity. These studies will be complemented with RNA sequencing to determine the role of CRTC1 in the transcriptional programs that give rise to long-term plasticity. In the second aim, novel synaptonuclear signaling proteins will be identified using a biochemical screen. In brief, mass spectrometry will be used to identify synaptic proteins that are bound to the importin β1 nuclear transport complex and are therefore likely to be cargo destined for nuclear import. Candidate proteins will be studied in the context of synaptic plasticity. Identifying novel proteins that translocate from synapse to nucleus will provide insight into the types of signals that translocate during plasticity, and the identity and function of these synaptonuclear signaling proteins will provide insights into the regulation of gene expression during plasticity. Synaptic plasticity is widely involved in neurological function and dysfunction, and therefore addressing these fundamental questions about synaptic plasticity will provide insight into the mechanisms underlying many neurological and neuropsychiatric disorders.