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Articles, Cellular/Molecular

Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice

Jocelyn Widagdo, Qiong-Yi Zhao, Marie-Jeanne Kempen, Men Chee Tan, Vikram S. Ratnu, Wei Wei, Laura Leighton, Paola A. Spadaro, Janette Edson, Victor Anggono and Timothy W. Bredy
Journal of Neuroscience 22 June 2016, 36 (25) 6771-6777; DOI: https://doi.org/10.1523/JNEUROSCI.4053-15.2016
Jocelyn Widagdo
1Clem Jones Centre for Ageing Dementia Research,
2Queensland Brain Institute,
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Qiong-Yi Zhao
2Queensland Brain Institute,
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Marie-Jeanne Kempen
2Queensland Brain Institute,
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Men Chee Tan
1Clem Jones Centre for Ageing Dementia Research,
2Queensland Brain Institute,
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Vikram S. Ratnu
2Queensland Brain Institute,
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Wei Wei
2Queensland Brain Institute,
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Laura Leighton
2Queensland Brain Institute,
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Paola A. Spadaro
2Queensland Brain Institute,
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Janette Edson
2Queensland Brain Institute,
3Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia, and
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Victor Anggono
1Clem Jones Centre for Ageing Dementia Research,
2Queensland Brain Institute,
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Timothy W. Bredy
2Queensland Brain Institute,
4Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, California 92617
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Abstract

The RNA modification N6-methyladenosine (m6A) influences mRNA stability and cell-type-specific developmental programming, and is highly abundant in the adult brain. However, it has not been determined whether m6A is dynamically regulated by experience. Based on transcriptome-wide profiling of m6A, we report that the level of m6A 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 m6A 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 m6A methyltransferase, Mettl3 correlated with the observed increase in m6A 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 m6A in the adult brain serves as an important epitranscriptomic mechanism associated with behavioral adaptation.

SIGNIFICANCE STATEMENT N6-methyladenosine (m6A) is the most prevalent internal modification on RNA, however, its cellular dynamics in vivo remains elusive. Here we provide the first demonstration of m6A upregulation in the mouse medial prefrontal cortex (mPFC) following behavioral training. Knocking down the m6A demethylase FTO in the mPFC, which increases total m6A level, results in enhanced consolidation of fear memory. Our findings suggest that m6A is regulated in an activity-dependent manner in the adult brain, and may function to fine-tune mRNA turnover during memory-related processes.

  • epigenetics
  • memory
  • mRNA stability
  • RNA methylation
  • synaptic plasticity
  • transcription
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The Journal of Neuroscience: 36 (25)
Journal of Neuroscience
Vol. 36, Issue 25
22 Jun 2016
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Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice
Jocelyn Widagdo, Qiong-Yi Zhao, Marie-Jeanne Kempen, Men Chee Tan, Vikram S. Ratnu, Wei Wei, Laura Leighton, Paola A. Spadaro, Janette Edson, Victor Anggono, Timothy W. Bredy
Journal of Neuroscience 22 June 2016, 36 (25) 6771-6777; DOI: 10.1523/JNEUROSCI.4053-15.2016

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Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice
Jocelyn Widagdo, Qiong-Yi Zhao, Marie-Jeanne Kempen, Men Chee Tan, Vikram S. Ratnu, Wei Wei, Laura Leighton, Paola A. Spadaro, Janette Edson, Victor Anggono, Timothy W. Bredy
Journal of Neuroscience 22 June 2016, 36 (25) 6771-6777; DOI: 10.1523/JNEUROSCI.4053-15.2016
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Keywords

  • epigenetics
  • memory
  • mRNA stability
  • RNA methylation
  • synaptic plasticity
  • transcription

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