2. Academic Validation
  3. Neuronal activity recruits the CRTC1/CREB axis to drive transcription-dependent autophagy for maintaining late-phase LTD

Neuronal activity recruits the CRTC1/CREB axis to drive transcription-dependent autophagy for maintaining late-phase LTD

  • Cell Rep. 2021 Jul 20;36(3):109398. doi: 10.1016/j.celrep.2021.109398.
Yue Pan 1,  Xingzhi He 1,  Cuicui Li 1,  Yanjun Li 1,  Wenwen Li 1,  Hanbin Zhang 1,  Yang Wang 1,  Guangjun Zhou 1,  Jing Yang 1,  Jiarui Li 1,  Jing Qu 1,  Hao Wang 1,  Zhihua Gao 1,  Ying Shen 1,  Tao Li 1,  Hailan Hu 2,  Huan Ma 3
Affiliations

Affiliations

  • 1 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Affiliated Mental Health Center, Zhejiang University School of Medicine, Hangzhou 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China.
  • 2 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Affiliated Mental Health Center, Zhejiang University School of Medicine, Hangzhou 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; Research Units for Emotion and Emotion Disorders, Chinese Academy of Medical Sciences, Beijing 100730, China.
  • 3 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Affiliated Mental Health Center, Zhejiang University School of Medicine, Hangzhou 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; Research Units for Emotion and Emotion Disorders, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address: mah@zju.edu.cn.
PMID: 34289350 DOI: 10.1016/j.celrep.2021.109398
Abstract

Cellular resources must be reorganized for long-term synaptic plasticity during brain information processing, in which coordinated gene transcription and protein turnover are required. However, the mechanism underlying this process remains elusive. Here, we report that activating N-methyl-d-aspartate receptors (NMDARs) induce transcription-dependent Autophagy for synaptic turnover and late-phase long-term synaptic depression (L-LTD), which invokes cytoplasm-to-nucleus signaling mechanisms known to be required for late-phase long-term synaptic potentiation (L-LTP). Mechanistically, LTD-inducing stimuli specifically dephosphorylate CRTC1 (CREB-regulated transcription coactivator 1) at Ser-151 and are advantaged in recruiting CRTC1 from cytoplasm to the nucleus, where it competes with FXR (fed-state sensing nuclear receptor) for binding to CREB (cAMP response element-binding protein) and drives Autophagy gene expression. Disrupting synergistic actions of CREB and CRTC1 (two essential L-LTP transcription factors) impairs transcription-dependent Autophagy induction and prevents NMDAR-dependent L-LTD, which can be rescued by constitutively inducing mechanistic target of rapamycin (mTOR)-dependent Autophagy. Together, these findings uncover mechanistic commonalities between L-LTP and L-LTD, suggesting that synaptic activity can tune excitation-transcription coupling for distinct long-lasting synaptic remodeling.

Keywords

CREB; CRTC1; L-LTD; L-LTP; LTD; autophagy; excitation-transcription coupling; long-term synaptic plasticity.

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