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PMID: 28346453 Published · ppublish English Journal Article

Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation.

Nature neuroscience ·Vol. 20 ·No. 5 ·2017-05-00 ·Pages 690-699

Ding X, Liu S, Tian M, Zhang W, Zhu T, Li D, Wu J, Deng H, Jia Y, Xie W, Xie H, Guan JS

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.

MeSH Terms
Animals Calcium-Binding Proteins Coculture Techniques Conditioning, Psychological/physiology Epigenesis, Genetic Female GATA Transcription Factors Hippocampus/physiology Histone Code/physiology Histone Deacetylase 2/metabolism Histones/metabolism,physiology Learning/physiology Male Memory/physiology Methyltransferases/metabolism Mice Mice, Knockout Neural Cell Adhesion Molecules/genetics,metabolism,physiology Neurons/metabolism Primary Cell Culture Protein Isoforms/metabolism Repressor Proteins/metabolism
Chemicals
Calcium-Binding Proteins GATA Transcription Factors Gatad2a protein, mouse Histones Neural Cell Adhesion Molecules Nrxn1 protein, mouse Protein Isoforms Repressor Proteins Suv39h1 protein, mouse Methyltransferases Hdac2 protein, mouse Histone Deacetylase 2
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Ding Xinlu
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.
Liu Sanxiong
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.
Tian Miaomiao
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.
Zhang Wenhao
MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Zhu Tao
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.
Li Dongdong
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.
Wu Jiawei
MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Deng HaiTeng
MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Jia Yichang
School of Medicine, Tsinghua University, Beijing, China.
Xie Wei
MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Xie Hong
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.
Guan Ji-Song ORCID
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.
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.4536
Published
2017-05-00
Epub
2017-00-27
Pages
690-699
Language
English
Region
United States
NLM ID
9809671
Subset
IM
External Links
PubMed source DOI: 10.1038/nn.4536 View journal details
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