1. Academic Validation
  2. 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.
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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