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Adaptor protein APPL1 links neuronal activity to chromatin remodeling in cultured hippocampal neurons
Yu Wu1,2 , Xinyou Lv1,2 , Haiting Wang1,2 , Kai Qian1,2 , Jinjun Ding1,2 , Jiejie Wang1,2 , Shushan Hua1,2 , Tiancheng Sun1,2 , Yiting Zhou3,4 , Lina Yu1,2 , Shuang Qiu1,2,5,*
1Department of Neurobiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
2Department of Anesthesiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
3Department of Biochemistry, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
4Department of Orthopaedic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
5NHC 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
*Correspondence to:Shuang Qiu , Email:qiushly@zju.edu.cn
J Mol Cell Biol, Volume 13, Issue 5, May 2021, Pages 335-346  https://doi.org/10.1093/jmcb/mjaa058
Keyword: APPL1, excitation‒transcription coupling, synaptic plasticity, chromatin remodeling, gene transcription

Local signaling events at synapses or axon terminals are communicated to the nucleus to elicit transcriptional responses, and thereby translate information about the external environment into internal neuronal representations. This retrograde signaling is critical to dendritic growth, synapse development, and neuronal plasticity. Here, we demonstrate that neuronal activity induces retrograde translocation and nuclear accumulation of endosomal adaptor APPL1. Disrupting the interaction of APPL1 with Importin α1 abolishes nuclear accumulation of APPL1, which in turn decreases the levels of histone acetylation. We further demonstrate that retrograde translocation of APPL1 is required for the regulation of gene transcription and then maintenance of hippocampal late-phase long-term potentiation. Thus, these results illustrate an APPL1-mediated pathway that contributes to the modulation of synaptic plasticity via coupling neuronal activity with chromatin remodeling.