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Transcriptional Targets of CREB-Regulated Transcription Coactivator 1 (CRTC1) During Hippocampal Plasticity

  • Author(s): Bonanno, Shivan Luca
  • Advisor(s): Martin, Kelsey C
  • et al.

Synaptic plasticity, the change in number, position, and strength of synapses, requires the synthesis of new cellular components that contribute to changes in synaptic composition, and it has long-been appreciated that there is an important role for de novo transcription in the maintenance of long-term potentiation (LTP). As plasticity-inducing signals are received at synapses that can be hundreds of microns away from the cell’s nucleus, which contains its transcriptional machinery, a signal must be faithfully communicated from synapse to nucleus. CREB-Regulated Transcription Coactivator 1 (CRTC1) acts as a retrograde signaling molecule that travels from stimulated synapses to the nucleus, where it alters gene expression through interactions with bZIP transcription factors such as CREB. CRTC1 has been shown to be necessary for the maintenance of long-term potentiation in the hippocampus, and undergoes dramatic and complex post-translational modifications that correlate with its nuclear transport following synaptic activity. There is little known, however, about the transcriptional targets of CRTC1 after plasticity-induction, and whether it may play a role in modulating specific programs of gene expression during different types of long-term plasticity. To address this question, I first investigated the nuclear translocation of CRTC1 in response to different plasticity-induction protocols. Next, I optimized a Chromatin Immunoprecipitation-sequencing (ChIP-seq) protocol to investigate the genomic targets of CRTC1 following dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in CA1 cells of the hippocampus, and found that CRTC1-containing protein complexes occupy loci including transcriptional start sites, promoters, enhancers, gene bodies, and intergenic regions. The genes associated with these loci include, but are not limited to, immediate-early genes, as well as other important neuronal genes. Finally, I conducted ChIP-seq and RNA-seq on a wider set of stimulations, including an LTP and a different LTD protocol in addition to control and DHPG-LTD samples. Data analysis for this work is ongoing and will allow correlation of transcript level with the genomic targets of CRTC1. Through this work emerges a clearer view of the genomic targets of CRTC1 during the induction of bidirectional synaptic plasticity in the hippocampus, as well as a modified protocol for conducting ChIP-seq from rodent adult brain tissue.

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