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Memory traces and tags in the brain

開催日 2014/9/11
時間 9:00 - 11:00
会場 Room B(501)
Chairperson(s) 奥野 浩行 / Hiroyuki Okuno (京都大学大学院 医学研究科 メディカルイノベーションセンター / Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan)
尾藤 晴彦 / Haruhiko Bito (東京大学大学院 医学系研究科 神経生化学分野 / Department of Neurochemistry, The University of Tokyo Graduate School of Medicine, Japan)

CRTC1 signaling from synapse to nucleus during long-term neuronal plasticity

  • S1-B-1-5
  • Kelsey Martin:1 Toh Hean Ch'ng:1 Martina DeSalvo:1 Thomas J . O'Dell:2 James Wohlschlegel:1 
  • 1:Biological Chemistry, UCLA School of Medicine / Dept. of Biological Chemistry, University of California, Los Angeles (UCLA), USA 2:Department of Physiology, University of California, Los Angeles, USA 

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. We have shown that the CREB-Regulated Transcriptional Coactivator (CRTC1) localizes to synapses in silenced hippocampal neurons, with synaptic stimulation triggering active transport to the nucleus, where CRTC1 potently activates CREB-dependent transcription. Activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of activity to specific changes in gene expression. We used mass spectrometry to identify 50 phosphorylation sites on CRTC1 that are highly conserved from worm to human. Generation of phosphoincompetent point mutations revealed three residues whose dephosphorylation is required for nuclear import. We find that in neurons, CRTC1 is controlled in a dual fashion with glutamatergic stimulation and calcium influx regulating the amount of CRTC1 translocated to the nucleus and cAMP modulating its persistence. Analysis of the types of stimuli that elevated cAMP to increase the persistence of CRTC1 in the nucleus indicate a central role for noradrenergic inputs. Together, our results indicate that synapse to nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity. They further suggest that the post-transcriptional modification of CRTC1 encodes specific patterns of stimulation to induce specific patterns of transcription, and that neuromodulation enhances long term memory by regulating the persistence and transcriptional activity of CRTC1 in the nucleus.

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