Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice

Widagdo, Jocelyn, Zhao, Qiong-Yi, Kempen, Marie-Jeanne, Tan, Men Chee, Ratnu, Vikram S., Wei, Wei, Leighton, Laura, Spadaro, Paola A., Edson, Janette, Anggono, Victor and Bredy, Timothy W. (2016) Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. Journal of Neuroscience, 36 25: 6771-6777. doi:10.1523/JNEUROSCI.4053-15.2016


Author Widagdo, Jocelyn
Zhao, Qiong-Yi
Kempen, Marie-Jeanne
Tan, Men Chee
Ratnu, Vikram S.
Wei, Wei
Leighton, Laura
Spadaro, Paola A.
Edson, Janette
Anggono, Victor
Bredy, Timothy W.
Title Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 1529-2401
0270-6474
Publication date 2016-06-22
Year available 2016
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.4053-15.2016
Open Access Status Not Open Access
Volume 36
Issue 25
Start page 6771
End page 6777
Total pages 7
Place of publication Washington, DC United States
Publisher Society for Neuroscience
Collection year 2017
Language eng
Formatted 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.
Keyword Epigenetics
Memory
MRNA stability
RNA methylation
Synaptic plasticity
Transcription
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
UQ Diamantina Institute Publications
 
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