title: Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice.
abstract: The RNA modification N(6)-methyladenosine (m(6)A) influences mRNA stability and cell-type-specific developmental programming, and is highly abundant in the adult brain. However, it has not been determined whether m(6)A is dynamically regulated by experience. Based on transcriptome-wide profiling of m(6)A, we report that the level of m(6)A increases in the medial prefrontal cortex (mPFC) of mice in response to behavioral experience. The modulation was enriched near the stop codon of mRNAs, including genes related to neuronal plasticity. In primary cortical neurons, in vitro, modulation of m(6)A by the RNA demethylase FTO influenced the degradation profiles of a subset of transcripts with modulated sites. In vivo, the expression of Fto and the m(6)A methyltransferase, Mettl3 correlated with the observed increase in m(6)A levels post-training. Furthermore, targeted knockdown of FTO in the mPFC led to enhanced consolidation of cued fear memory. Thus, together with its role in early development, the dynamic regulation of m(6)A in the adult brain serves as an important epitranscriptomic mechanism associated with behavioral adaptation.
  
  
  
  N(6)-methyladenosine (m(6)A) is the most prevalent internal modification on RNA, however, its cellular dynamics in vivo remains elusive. Here we provide the first demonstration of m(6)A upregulation in the mouse medial prefrontal cortex (mPFC) following behavioral training. Knocking down the m(6)A demethylase FTO in the mPFC, which increases total m(6)A level, results in enhanced consolidation of fear memory. Our findings suggest that m(6)A is regulated in an activity-dependent manner in the adult brain, and may function to fine-tune mRNA turnover during memory-related processes.
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, j.widagdo@uq.edu.au tbredy@uci.edu.
authors.forename: Jocelyn
authors.identifier: 0000-0001-9667-9203
authors.initials: J
authors.lastname: Widagdo
authors.affiliation: Queensland Brain Institute.
authors.forename: Qiong-Yi
authors.identifier: 0000-0002-6341-0416
authors.initials: QY
authors.lastname: Zhao
authors.affiliation: Queensland Brain Institute.
authors.forename: Marie-Jeanne
authors.identifier: 0000-0002-4899-1902
authors.initials: MJ
authors.lastname: Kempen
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute.
authors.forename: Men Chee
authors.identifier: 0000-0002-7304-494X
authors.initials: MC
authors.lastname: Tan
authors.affiliation: Queensland Brain Institute.
authors.forename: Vikram S
authors.initials: VS
authors.lastname: Ratnu
authors.affiliation: Queensland Brain Institute.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Queensland Brain Institute.
authors.forename: Laura
authors.initials: L
authors.lastname: Leighton
authors.affiliation: Queensland Brain Institute.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Spadaro
authors.affiliation: Queensland Brain Institute, Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia, and.
authors.forename: Janette
authors.initials: J
authors.lastname: Edson
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute.
authors.forename: Victor
authors.identifier: 0000-0002-4062-4884
authors.initials: V
authors.lastname: Anggono
authors.affiliation: Queensland Brain Institute, Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, California 92617 j.widagdo@uq.edu.au tbredy@uci.edu.
authors.forename: Timothy W
authors.identifier: 0000-0003-3280-126X
authors.initials: TW
authors.lastname: Bredy
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003214:Conditioning, Classical / Q000502:physiology; D003463:Cues; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D020869:Gene Expression Profiling; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; C010223:N-methyladenosine; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000241:Adenosine
keywords: RNA methylation; epigenetics; mRNA stability; memory; synaptic plasticity; transcription