title: Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation.
abstract: Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.
authors.forename: Xinlu
authors.initials: X
authors.lastname: Ding
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.
authors.forename: Sanxiong
authors.initials: S
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Tian
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: HaiTeng
authors.initials: H
authors.lastname: Deng
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Yichang
authors.initials: Y
authors.lastname: Jia
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.|School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.|Centre for Brain Inspired Computing Research, Tsinghua University, Beijing, China.
authors.forename: Ji-Song
authors.identifier: http://orcid.org/0000-0001-5219-0289
authors.initials: JS
authors.lastname: Guan
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D018920:Coculture Techniques; D003213:Conditioning, Psychological / Q000502:physiology; D044127:Epigenesis, Genetic; D005260:Female; D050980:GATA Transcription Factors; D006624:Hippocampus / Q000502:physiology; D042421:Histone Code / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism / Q000502:physiology*; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D050980:GATA Transcription Factors; C000622115:Gatad2a protein, mouse; D006657:Histones; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D020033:Protein Isoforms; D012097:Repressor Proteins; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2