Activity-Dependent Transport of the Transcriptional Coactivator CRTC1 from Synapse to Nucleus

• Published in: Cell Vol. 150; no. 1; pp. 207 - 221
• Main Authors: Ch'ng, Toh Hean, Uzgil, Besim, Lin, Peter, Avliyakulov, Nuraly K., O'Dell, Thomas J., Martin, Kelsey C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2012
• Subjects: Animals; calcium; Cell Nucleus - metabolism; Cells, Cultured; cyclic AMP; gene expression regulation; Hippocampus - cytology; Hippocampus - metabolism; memory; Mice; neurons; Neurons - metabolism; nucleus; phosphorylation; Protein Transport; Rats; stimulation; synapse; Synapses - metabolism; transcription (genetics); transcription factors; Transcription Factors - metabolism; translocation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.05.027

Long-lasting changes in synaptic efficacy, such as those underlying long-term memory, require transcription. Activity-dependent transport of synaptically localized transcriptional regulators provides a direct means of coupling synaptic stimulation with changes in transcription. The CREB-regulated transcriptional coactivator (CRTC1), which is required for long-term hippocampal plasticity, binds CREB to potently promote transcription. We show that CRTC1 localizes to synapses in silenced hippocampal neurons but translocates to the nucleus in response to localized synaptic stimulation. Regulated nuclear translocation occurs only in excitatory neurons and requires calcium influx and calcineurin activation. CRTC1 is controlled in a dual fashion with activity regulating CRTC1 nuclear translocation and cAMP modulating its persistence in the nucleus. Neuronal activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of stimuli to specific changes in gene expression. Together, our results indicate that synapse-to-nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity. [Display omitted] ► CRTC1 undergoes calcium-dependent nuclear transport from stimulated synapses ► cAMP increases the persistence of nuclear CRTC1, not its initial translocation ► Neuronal activity induces complex changes in CRTC1 phosphorylation ► CRTC1 is required for stimulus-induced activation of select CREB targets How do calcium and cAMP differentially influence the dynamic gene expression required for neuronal plasticity and long-term memory formation? Local synaptic activity triggers calcium-dependent nuclear transport of CRCT1, whereas cAMP regulates CRCT1's nuclear persistence, suggesting that this transcriptional coactivator integrates both synaptic and neuromodulatory stimuli.